Index

Pharmacology — MRCOG Part 1 Deep-Dive Study Guide

Last Updated: May 2026 Estimated reading time: ~180 minutes Scope: Pharmacokinetics, pharmacodynamics, drug therapy in pregnancy, lactation, obstetrics, gynaecology, and oncology

---

Table of Contents

1. Fundamentals of Pharmacokinetics
2. Pharmacodynamics & Receptor Theory
3. Pharmacokinetics in Pregnancy
4. Drugs in Lactation
5. Placental Drug Transfer & Fetal Pharmacology
6. Drug Therapy in Obstetric Emergencies
7. Tocolytics
8. Corticosteroids for Fetal Lung Maturity
9. Oxytocics & Uterotonics
10. Antihypertensives in Pregnancy
11. Anticonvulsants in Pregnancy & Eclampsia
12. Antibiotics in Pregnancy
13. Antiemetics in Pregnancy
14. Thyroid Medications in Pregnancy
15. Antidiabetic Drugs in Pregnancy
16. Anticoagulants in Pregnancy
17. Contraceptive Pharmacology
18. Chemotherapy in Gynaecological Cancers
19. Drugs Affecting the Hypothalamic-Pituitary-Ovarian Axis
20. Immunosuppressants & Autoimmune Therapy
21. Anaesthetic Agents in Obstetrics
22. Drug Interactions of Obstetric & Gynaecological Importance
23. Exam-Focused High-Yield Tables & Mnemonics

---

1. Fundamentals of Pharmacokinetics

1.1 ADME — The Four Pillars

Pharmacokinetics describes what the body does to the drug: Absorption, Distribution, Metabolism, Elimination.

(A) Absorption

The movement of a drug from its site of administration into the systemic circulation. Key factors:

Route	Bioavailability	First-pass	Onset	Key Features
Intravenous (IV)	100% (by definition)	None	Immediate	Direct into bloodstream, used in emergencies
Oral (PO)	Variable (5-90%+)	YES — hepatic first-pass	30-90 min	Most common; subject to gut & liver metabolism
Sublingual	High (avoid first-pass)	Minimal	2-5 min	Buccal mucosa drains into SVC directly; e.g. GTN, misoprostol
Rectal	~50% (partial first-pass)	~50% bypasses	15-30 min	Useful for vomiting; e.g. misoprostol, paracetamol
Intramuscular (IM)	~75-100%	None	5-30 min	Depot formulations possible (e.g. DMPA)
Subcutaneous (SC)	~75-100%	None	15-30 min	e.g. heparin, insulin, LMWH
Transdermal	Variable	None	Slow/sustained	Patches; avoids first-pass; e.g. GTN, oestrogen, nicotine
Inhalation	Rapid absorption	None	Seconds	e.g. salbutamol, general anaesthetics
Intrathecal	Direct to CSF	None	Immediate	e.g. spinal anaesthesia, chemotherapy
Vaginal	Moderate-high	Partial	10-30 min	e.g. prostaglandins for induction, pessaries

Oral Bioavailability (F): $$F = \frac{\text{AUC}{oral}}{\text{AUC} \times 100\%$$}

First-pass effect: Drugs absorbed from the GI tract travel via the portal vein to the liver before reaching systemic circulation. Hepatic metabolism can dramatically reduce bioavailability: - High first-pass: lidocaine (~5% oral bioavailability), GTN (<1% oral), morphine (~25%), propranolol (~25%) - Low first-pass: paracetamol (~80%), metformin (~50-60%), phenytoin (~90%)

Strategies to bypass first-pass: Sublingual, buccal, rectal, transdermal, IV, IM, SC, inhalation.

(B) Distribution

The process by which a drug moves from the bloodstream to tissues.

Volume of Distribution (Vd): $$V_d = \frac{\text{Dose}}{\text{[Plasma]}_0}$$

• Low Vd (<10 L): Drug stays primarily in plasma — highly protein-bound or large molecules (e.g. heparin, warfarin)
• Moderate Vd (10-50 L): Distributes throughout ECF (e.g. gentamicin)
• Large Vd (>50 L): Extensive tissue binding, sequestered in fat or cells (e.g. digoxin ~500 L, amiodarone ~5000 L, chloroquine ~13,000 L)

Protein Binding:

Protein	Binds	Clinical Significance
Albumin	Acidic/neutral drugs (warfarin, phenytoin, NSAIDs, valproate)	Decreased in pregnancy, liver disease, nephrotic syndrome → more free drug
α₁-Acid glycoprotein	Basic drugs (lidocaine, propranolol, verapamil, quinidine)	Acute phase reactant — increases in inflammation/stress
Sex hormone-binding globulin (SHBG)	Steroid hormones	Increased in pregnancy, COC use
Transcortin (CBG)	Cortisol, progesterone	Increased in pregnancy

Only unbound (free) drug is pharmacologically active and available for metabolism and elimination. Highly protein-bound drugs (>90% bound) are particularly sensitive to displacement interactions.

Key distribution concepts: - Hydrophilic drugs: Distribute mainly in ECF, low Vd, renally cleared (e.g. aminoglycosides, penicillins, atenolol) - Lipophilic drugs: Cross cell membranes, large Vd, hepatically cleared (e.g. propranolol, fentanyl, amiodarone) - Blood-brain barrier (BBB): Lipid-soluble, non-ionised drugs cross; P-glycoprotein efflux pump limits CNS penetration - Placental barrier: More on this in Section 5

(C) Metabolism (Biotransformation)

Primarily hepatic, but also in gut wall, kidneys, lungs, skin, plasma.

Phase I Reactions — Functionalisation: - Oxidation, reduction, hydrolysis — introduce or expose a polar group - Cytochrome P450 (CYP) family — the dominant enzyme system - Key CYP isoforms in drug metabolism:

Isoform	% of total CYP	Typical Substrates	Inducers	Inhibitors
CYP3A4	~30-40%	Most drugs — nifedipine, simvastatin, amiodarone, carbamazepine, contraceptive steroids, corticosteroids, ciclosporin, tacrolimus, fentanyl, midazolam, sildenafil	Rifampicin, carbamazepine, phenytoin, phenobarbital, St John's Wort, ethanol (chronic), dexamethasone	Ketoconazole, itraconazole, fluconazole, macrolides (erythromycin, clarithromycin), grapefruit juice, HIV protease inhibitors, verapamil, diltiazem, amiodarone
CYP2D6	~2-5%	β-blockers (metoprolol, propranolol), codeine → morphine, tramadol, TCAs, SSRIs, haloperidol, tamoxifen, ondansetron	— (non-inducible)	Paroxetine, fluoxetine, duloxetine, quinidine, amiodarone, cimetidine
CYP2C9	~15-20%	Warfarin, phenytoin, NSAIDs (ibuprofen, diclofenac), glipizide, losartan, S-naproxen	Rifampicin, carbamazepine, phenobarbital	Fluconazole, amiodarone, sulfamethoxazole, metronidazole
CYP2C19	~5-10%	Proton pump inhibitors (omeprazole), voriconazole, diazepam, proguanil, clopidogrel (pro-drug activation), citalopram	Rifampicin, carbamazepine, phenobarbital	Fluconazole, fluoxetine, omeprazole, isoniazid
CYP1A2	~5-15%	Caffeine, theophylline, clozapine, olanzapine, paracetamol (minor), R-warfarin	Smoking (PAHs), chargrilled meat, omeprazole, carbamazepine, phenobarbital	Ciprofloxacin, fluvoxamine, grapefruit juice, oral contraceptives — decreased in pregnancy
CYP2E1	~5-7%	Ethanol, paracetamol (minor pathway → NAPQI, toxic), isoniazid, halothane	Ethanol (chronic), isoniazid	Disulfiram

Genetic Polymorphisms of CYP:

Enzyme	Population	Clinical Consequence
CYP2D6 — 7-10% of Caucasians are poor metabolisers (PM)	PMs: higher levels of metoprolol → bradycardia; codeine ineffective (can't convert to morphine); UMs (ultra-rapid): codeine → morphine toxicity	MRCOG relevance: tamoxifen activation, ondansetron metabolism, codeine in breastfeeding
CYP2C9 — 2-3% are PMs	PMs: warfarin sensitivity → bleeding risk; need lower doses	VKORC1 polymorphism also relevant
CYP2C19 — 3-5% Caucasians, 15-20% Asians are PMs	PMs: omeprazole more effective (higher levels); clopidogrel ineffective (pro-drug activation fails)

Phase II Reactions — Conjugation: - Adds a large water-soluble group to the drug (or Phase I metabolite) - Glucuronidation (UGT1A1, UGT2B7): Morphine, paracetamol, bilirubin, lamotrigine, oestradiol, propofol - Sulphation (SULTs): Paracetamol, oestrogens, steroids, dopamine - Acetylation (NAT2): Isoniazid, hydralazine, dapsone, sulfonamides, procainamide, caffeine - Glutathione conjugation (GSTs): Paracetamol (detoxifies NAPQI), busulfan, ethacrynic acid - Methylation (COMT, TPMT): L-dopa, catecholamines, 6-mercaptopurine (TPMT)

Acetylator Status — NAT2 Polymorphism:

Phenotype	Population	Clinical Relevance
Slow acetylators	~50% Caucasians, ~10-20% Asians	Higher risk of hydralazine-induced SLE, isoniazid peripheral neuropathy, sulfonamide hypersensitivity
Fast acetylators	~50% Caucasians, ~80-90% Asians	May need higher doses; less toxicity

Enterohepatic Circulation: - Drugs conjugated in liver → excreted in bile → gut bacteria deconjugate → reabsorbed → recirculated - Examples: Oestrogens, progesterone, rifampicin, morphine, digitoxin, mycophenolate, NSAIDs - Clinical significance: Prolongs half-life; can be interrupted by antibiotics (kill gut flora → reduced reabsorption → decreased efficacy of COC → contraceptive failure)

(D) Elimination

Renal Excretion:

Three processes: 1. Glomerular Filtration: Free drug only (not protein-bound). Dependent on GFR. - GFR ~120 mL/min (non-pregnant), ~150-180 mL/min (pregnant) 2. Tubular Secretion: Active transport (OAT, OCT, P-glycoprotein) in proximal tubule - Can achieve clearance > GFR - Competition: Probenecid blocks OAT → reduces penicillin secretion → prolongs half-life (used therapeutically) 3. Tubular Reabsorption: Passive diffusion back into blood - pH-dependent: Weak acids (e.g. aspirin, phenobarbital) are reabsorbed more in acidic urine; weak bases (e.g. amphetamine, morphine) in alkaline urine - Ion trapping: Manipulating urine pH can enhance elimination of toxins

Hepatic Elimination:

• Biliary excretion: Drugs >300 Da with polar groups excreted in bile
• High biliary excretion: Rifampicin, erythromycin, ampicillin, oestrogens, pravastatin

Half-Life (t½): $$t_{½} = \frac{0.693 \times V_d}{CL}$$

• Time for plasma concentration to fall by 50%
• After 1 t½: 50% eliminated
• After 2 t½: 75% eliminated
• After 3 t½: 87.5% eliminated
• After 4 t½: 93.75% eliminated
• After 5 t½: 96.875% eliminated (approaches steady state in reverse)
• Clinical steady state (Css) reached in 4-5 half-lives

Clearance (CL): $$CL = \frac{\text{Rate of elimination}}{\text{Plasma concentration}}$$ $$CL_{total} = CL_{renal} + CL_{hepatic} + CL_{other}$$

Steady State Concentration (Css): $$C_{ss} = \frac{\text{Dose rate}}{\text{CL}}$$ - Once steady state is reached, rate of drug administration = rate of elimination - Loading dose: $LD = V_d \times C_{target}$ (used when immediate effect is needed, e.g. digoxin, amiodarone, MgSO₄) - Maintenance dose: $\text{MD} = C_{ss} \times CL$

Therapeutic Index (TI): $$TI = \frac{\text{TD}{50}}{\text{ED}$$ - }Narrow TI (TI <2): Warfarin, digoxin, lithium, theophylline, phenytoin, aminoglycosides, ciclosporin, tacrolimus — require therapeutic drug monitoring (TDM) - Wide TI: Penicillins, cephalosporins, paracetamol (within dose limits)

First-order vs Zero-order Kinetics:

Property	First-order (Most drugs)	Zero-order (Capacity-limited)
Rate of elimination	Proportional to concentration	Constant rate independent of concentration
Half-life	Constant	Changes with dose
Examples	Most drugs at therapeutic doses	Phenytoin, aspirin (high dose), ethanol, theophylline (some), heparin
Clinical risk	Predictable	Dose-dependent accumulation — small dose increase → large concentration rise → toxicity

---

2. Pharmacodynamics & Receptor Theory

2.1 Dose-Response Relationships

• Efficacy (Emax): Maximum effect a drug can produce
• Potency (EC50): Concentration producing 50% of maximal effect
• Graded dose-response: Continuous effect with increasing dose
• Quantal dose-response: All-or-none effect (e.g., anticonvulsant effect, death)

2.2 Receptor Types & Signal Transduction

Receptor Type	Mechanism	Examples	Speed
Type 1 — Ion channels (ionotropic)	Ligand-gated ion flux	Nicotinic AChR, GABA-A, NMDA, 5-HT₃	Milliseconds
Type 2 — G-protein coupled (GPCR)	Second messenger systems (cAMP, IP3/DAG, Ca²⁺)	β-adrenoceptors (Gs), α₂ (Gi), oxytocin receptor (Gq), muscarinic (Gi/Gq)	Seconds
Type 3 — Enzyme-linked	Tyrosine kinase, JAK-STAT, guanylyl cyclase	Insulin receptor, growth factors, ANP receptor, cytokine receptors	Minutes to hours
Type 4 — Nuclear receptors	Transcription regulation	Steroid hormones, thyroid hormone, vitamin D, PPARγ, retinoic acid	Hours to days

2.3 Agonists & Antagonists

Term	Definition	Example
Full agonist	Produces maximal response	Morphine at μ-opioid receptor
Partial agonist	Produces submaximal response even at full occupancy	Buprenorphine, aripiprazole, tamoxifen (mixed)
Competitive antagonist	Binds reversibly to same site; surmountable by increasing agonist	Naloxone (opioid), atropine (mAChR), propranolol (βAR)
Non-competitive antagonist	Binds allosterically or irreversibly; depresses Emax	Ketamine (NMDA), phenoxybenzamine (α, irreversible)
Inverse agonist	Decreases constitutive receptor activity	Some antihistamines, GABA-A negative modulators
Allosteric modulator	Binds different site, alters affinity/efficacy	Benzodiazepines (GABA-A), etomidate

2.4 Drug-Receptor Binding

$$Occupancy = \frac{[D]}{[D] + K_d}$$

• Kd: Dissociation constant — concentration of drug occupying 50% of receptors
• Low Kd = high affinity
• Spare receptors: Maximal response can occur with less than 100% receptor occupancy (e.g., smooth muscle relaxation with β₂ agonists)

2.5 Drug Tolerance & Dependence

Type	Mechanism	Example
Pharmacokinetic tolerance	Increased metabolism (enzyme induction)	Barbiturates, carbamazepine, ethanol
Pharmacodynamic tolerance	Receptor downregulation/desensitisation	β₂-agonists (long-term), opioids, benzodiazepines
Tachyphylaxis	Rapid acute tolerance (desensitisation)	GTN (requires nitrate-free interval), ephedrine
Cross-tolerance	Tolerance to one drug confers tolerance to another	Opioids → other opioids; ethanol → benzodiazepines (GABA)

---

3. Pharmacokinetics in Pregnancy

3.1 The Pregnant Woman as a Unique Pharmacokinetic Compartment

Pregnancy induces profound physiological changes that alter every aspect of ADME. MRCOG commonly tests these alterations.

(A) Absorption

Change	Effect	Clinical Relevance
↓ Gastric emptying (↓ motility)	Delayed and more variable absorption	Oral drugs take longer to reach peak concentration
↑ Gastric pH (less acidic)	Alters ionisation of weak acids/bases	May affect absorption rate
↓ Intestinal peristalsis	↑ Contact time → potentially ↑ absorption	But offset by delayed gastric emptying
↑ Cardiac output (30-50%)	↑ Splanchnic blood flow → ↑ absorption	Faster distribution from gut once absorbed
↓ Gut CYP3A4 activity?	Some evidence of decreased gut wall metabolism	Potentially increased bioavailability for CYP3A4 substrates
↑ Nausea/vomiting (1st trimester)	Decreased compliance, drug loss	May need alternative routes

(B) Distribution

Change	Magnitude	Effect on Drugs
↑ Plasma volume	↑ 40-50% (by 32 weeks)	↑ Vd → ↓ peak concentration; loading doses may need increase
↑ Extracellular fluid	↑ 6-8 L total body water	↑ Vd for hydrophilic drugs
↑ Total body water	↑ 6-8 L	↑ Vd
↑ Body fat	3-4 kg average gain	↑ Vd for lipophilic drugs
↓ Albumin concentration	↓ 10-15 g/L (haemodilution)	↑ Free fraction of acidic drugs (phenytoin, valproate, warfarin, NSAIDs)
↓ α₁-acid glycoprotein	Variable	↑ Free fraction of basic drugs (lidocaine, propranolol)
↑ SHBG, TBG, CBG	↑↑↑	↑ Bound steroid hormones; altered kinetics of steroid drugs
↑ α-fetoprotein	Fetal protein	Minimal effect on binding

Critical Clinical Examples of Changed Free Fractions in Pregnancy:

Drug	Protein	Decreased Binding Effect	Clinical Consequence
Phenytoin	Albumin ↓	↑ Free fraction 2-3×; but total levels fall	TDM of free (unbound) phenytoin levels needed; total levels misleading
Valproate	Albumin ↓	↑ Free fraction	Same issue — monitor free levels if possible
Prednisolone	Transcortin + albumin	Complex — increased free early, then increased clearance	May need dose adjustment in flare-ups
Lidocaine	α₁-acid glycoprotein ↓	↑ Free fraction	Increased toxicity risk
Propofol	Albumin + α₁-AGP	↑ Free fraction	Careful with dosing
Thyroxine	TBG ↑	↑ Total T4; free T4 normal	Don't misinterpret raised total T4 as hyperthyroidism

(C) Metabolism — Altered CYP Activity in Pregnancy

This is highly exam-relevant. Pregnancy does NOT uniformly increase all CYP activity — some go up, some down, some stay the same.

CYP Isoform	Activity in Pregnancy	Clinical Impact
CYP3A4	↑↑ 35-60% (especially 3rd trimester)	↑ clearance of nifedipine, midazolam, fentanyl, methadone, dexamethasone, saquinavir, ciclosporin, tacrolimus — may need higher doses
CYP2D6	↑ 50% (3rd trimester); highly variable by genotype	↑ clearance of metoprolol, fluoxetine, paroxetine, codeine (→morphine increased? caution), tramadol
CYP2C9	↑~20-50%	↑ clearance of phenytoin, glyburide (glibenclamide), losartan, ibuprofen
CYP2C19	↓ 50% (1st and 3rd trimester)	↑ levels of omeprazole, citalopram, proguanil
CYP1A2	↓↓ 65-70% (major decrease — confirmed)	↓ clearance of caffeine, theophylline, clozapine, olanzapine → toxicity risk at non-pregnant doses
CYP2E1	↑~30% (controversial)	May affect paracetamol (minor pathway to NAPQI)
UGT1A1	↑ (controversial — some studies show increase, some no change)	Lamotrigine clearance ↑↑↑ in pregnancy (multiple pathways)
UGT2B7	↑	Morphine, oxazepam, zidovudine clearance increased

Key Clinical Takeaway — Drugs That Need Dose Adjustment in Late Pregnancy:

Drug	Change Needed	Reason
Lamotrigine	↑ dose 2-3×	↑ UGT clearance; pregnancy reduces levels dramatically
Levetiracetam	↑ dose 50-100%	↑ renal clearance + metabolism
Nifedipine	↑ dose (monitor effect)	↑ CYP3A4 clearance
Methadone	↑ dose (watch for withdrawal)	↑ CYP3A4 + UGT clearance
Caffeine	Recommend reduce intake	↓ CYP1A2 → caffeine accumulates → affects sleep
Theophylline	Monitor levels, may need ↓ dose	↓ CYP1A2 → increased levels
Clozapine	Monitor levels, need ↓ dose	↓ CYP1A2 → increased levels
Metoprolol	May need ↑ dose	↑ CYP2D6 clearance
Phenytoin	Monitor free levels	Combination: ↓ albumin → ↑ free fraction, ↑ CYP2C9 clearance → total levels unreliable
Propofol	May need slightly ↑ dose	↑ Vd, ↑ clearance
Rocuronium/suxamethonium	Dose based on TBW, may need ↑	↑ Vd
Thiopental	↓ dose (or use alternative)	↑ Vd but also ↑ protein binding changes → more free fraction available to CNS

(D) Elimination — Renal Changes

Change	Magnitude	Effect
↑ Renal blood flow	↑ 50-80% (by mid-pregnancy)	↑ GFR
↑ Glomerular Filtration Rate	↑ 50% (GFR ~150-180 mL/min)	↑ Clearance of renally excreted drugs
↑ Creatinine clearance	↑ 50%	↓ Serum creatinine (normal ~35-60 μmol/L in pregnancy)
↑ Tubular function	↑ Reabsorption of Na⁺, H₂O; altered secretion	Some drugs may have altered secretion
↑ Proteinuria	Normal up to 300 mg/day	Minimal effect

Drugs with Significantly Increased Renal Clearance in Pregnancy:

Drug	Effect	Action
Gentamicin	CL ↑ 50-80%	Need higher doses, more frequent dosing, TDM
Cefazolin	CL ↑ 30-50%	Higher doses for surgical prophylaxis
Penicillin G	CL ↑ 50%	Higher doses for syphilis (already standard)
Amoxicillin	CL ↑ 30-50%	Ensure adequate dosing
Methotrexate (rarely used)	CL ↑	Toxicity risk if doses not adjusted
Digoxin	CL ↑ 30-50%	May need higher doses (rarely used in pregnancy)
Lithium	CL ↑ 50-100%	Monitor levels closely, doses often need doubling
Levetiracetam	CL ↑ 60-80%	Major dose increase needed
Atenolol	CL ↑	Less accumulation than expected

3.2 Loading Doses & Maintenance Doses in Pregnancy

$$LD = V_d \times C_{target}$$

• ↑ Vd in pregnancy → loading doses may need to increase for drugs where rapid target concentration is critical
• ↑ CL in pregnancy → maintenance doses often need to increase to maintain same Css

Example — MgSO₄ for eclampsia: - Loading dose: 4g IV (same as non-pregnant) — but some argue for higher due to ↑ Vd - Maintenance: 1 g/h (standard) — but clearance is increased, so levels may be lower than expected

---

4. Drugs in Lactation

4.1 Principles of Drug Transfer into Breast Milk

Drug transfer from maternal plasma to breast milk occurs primarily by passive diffusion. Factors that favour transfer:

1. Low molecular weight (<500 Da) — Most drugs are <500 Da → transfer readily
2. Lipid solubility — Lipophilic drugs partition into milk fat globules
3. Non-ionised form — Unionised species diffuse more readily
4. Low protein binding — Only free drug diffuses
5. Weak bases — accumulate in milk (ion trapping — explained below)

4.2 Ion Trapping in Breast Milk

The mechanism: - Breast milk pH is 6.8-7.0 (slightly acidic) - Maternal plasma pH is 7.4 (slightly alkaline) - Weak bases (pKa 7.5-10.5) are more ionised in milk (lower pH) → ionised form cannot diffuse back → trapped → accumulate - Weak acids (pKa 3-6) are more ionised in plasma → less diffusion into milk → lower concentrations

Examples of weak bases that accumulate in milk: - Metoprolol, propranolol, labetalol - Codeine, morphine, tramadol - Amitriptyline, imipramine - Metronidazole - Chloroquine, hydroxychloroquine - Erythromycin - Antihistamines (promethazine, cyclizine)

Milk/Plasma (M/P) Ratio: $$M/P = \frac{\text{Drug concentration in milk}}{\text{Drug concentration in maternal plasma}}$$

• M/P >1 → drug concentrates in milk
• M/P <1 → lower in milk than plasma
• BUT M/P ratio alone is not sufficient — it doesn't account for dose or amount of milk ingested

4.3 Relative Infant Dose (RID)

This is the clinically relevant parameter:

$$RID = \frac{\text{Infant dose via milk}}{\text{Maternal dose}} \times 100\%$$

Alternatively: $$RID = \frac{\text{Concentration in milk} \times \text{Volume of milk ingested}}{\text{Maternal daily dose}} \times 100\%$$

RID Interpretation:

RID	Safety	Action
<10%	Generally considered safe	Compatible with breastfeeding (most drugs)
10-25%	Caution	Monitor infant for side effects; weigh risk-benefit
>25%	Generally avoid breastfeeding	Risk of significant systemic exposure

Examples of RID values:

Drug	RID (%)	Breastfeeding Safety
Paracetamol	1-2	Safe
Ibuprofen	<1	Safe (preferred NSAID in lactation)
Diclofenac	<1	Safe
Amoxicillin	<1	Safe
Cephalexin	<1	Safe
Metronidazole	10-15	M/P ~1; caution; avoid high single doses; 2 g dose → discard milk 12-24h
Prednisolone	5-10 (at low doses)	Safe up to 40 mg/day
Heparin/LMWH	0	Safe (too large to transfer)
Warfarin	<5	Safe (highly protein-bound)
Fluoxetine	10-15	Caution — long half-life, active metabolite
Sertraline	1-3	Preferred SSRI in lactation
Citalopram	5-10	Generally safe
Methotrexate	<1? But active	CONTRAINDICATED — cytotoxic
Codeine	~1-3% but variable	CONTRAINDICATED if mother is CYP2D6 UM → fatal infant opioid toxicity
Carbamazepine	5-10	Compatible (monitor for sedation)
Valproate	1-10	Compatible (low transfer)
Lamotrigine	10-20	Compatible (monitor for rash)
Levothyroxine	Minimal	Safe
Propylthiouracil	<1	Safe
Methimazole	<1	Safe
Omeprazole	<1	Safe
Ranitidine	5	Safe
Sumatriptan	3-15	Safe (low single use)

4.4 Drugs Contraindicated in Breastfeeding

Absolute Contraindications:

Drug	Reason
Cytotoxics (cyclophosphamide, doxorubicin, methotrexate, cisplatin, etc.)	Immunosuppression, neutropenia, potential carcinogenesis in infant
Radiopharmaceuticals	Breastfeeding must be interrupted (variable by isotope half-life)
Lithium	Narrow TI; infant levels can be 30-50% of maternal — toxicity risk
Ergotamine	Vomiting, diarrhoea, convulsions in infant; suppresses prolactin
Amiodarone	High iodine content → infant hypothyroidism; very long half-life (50 days)
Tetracyclines	Dental discolouration, bone growth inhibition (but short courses of doxycycline may be acceptable — low calcium binding)
Street drugs (cocaine, heroin, methamphetamine, cannabis high-dose)	Direct toxicity, withdrawal in infant
Codeine (in CYP2D6 UMs)	Fatal respiratory depression risk; now contraindicated per FDA/MHRA
Aspirin (high dose)	Reye's syndrome risk
Retinoids (isotretinoin, acitretin)	Teratogenic, accumulates in milk

Drugs Requiring Caution or Temporary Interruption:

Drug	Recommendation
Metronidazole (single 2g dose)	Discard milk for 12-24 hours after dose
Radiopharmaceuticals	Interrupt breastfeeding for variable duration
Iodine-131	Cease breastfeeding permanently (concentrates in milk; months to clear)
Phenobarbital, primidone	Sedation in infant — monitor
Benzodiazepines (chronic high dose)	Sedation, accumulation — use low dose, short-acting PRN
Sulfonamides (late preterm/neonate <1 month)	Kernicterus risk (displace bilirubin from albumin)
Nitrofurantoin	Avoid if infant G6PD-deficient; theoretical haemolysis

4.5 Practical Guidance for Breastfeeding Mothers on Medications

1. Choose drugs with low RID (<10%) whenever possible
2. Time feeds relative to dosing:
3. Take medication immediately after breastfeeding (trough in milk)
4. Avoid breastfeeding during peak plasma concentration (1-3 hours post-oral dose)
5. For short half-life drugs, schedule feeds at trough
6. Choose short half-life drugs over long-acting when alternatives exist
7. Monitor the infant for side effects (sedation, diarrhoea, rash, poor feeding, irritability)
8. Use topical/local therapy when possible to minimise systemic exposure
9. Encourage breastfeeding — benefits almost always outweigh minimal risks of most medications

---

5. Placental Drug Transfer & Fetal Pharmacology

5.1 Factors Determining Placental Transfer

Factor	Favours Transfer	Impedes Transfer
Molecular weight	<500 Da (most drugs)	>1000 Da (insulin, heparin, LMWH)
Lipid solubility	Lipophilic (most drugs)	Hydrophilic (aminoglycosides, muscle relaxants)
Ionisation	Non-ionised (unionised)	Ionised (ion trapping)
Protein binding	Low (<90%) — more free drug	High (>95%) — bound drug cannot cross
Placental transporters	Substrate for facilitative transporters	P-glycoprotein efflux back to mother
Placental metabolism	Some drugs metabolised by placenta	Reduced fetal exposure (e.g., corticosteroids by 11β-HSD2)
Gestational age	More transfer at term (thinner trophoblast, increased blood flow)	Less in first trimester

5.2 pKa, Ion Trapping & the Fetus

The fetal pH is ~7.30-7.35 (slightly more acidic than maternal 7.40-7.45). This gradient:

• Weak bases (pKa 7.5-10.5): More ionised in the more acidic fetal compartment → trapped → accumulate in fetus
• Examples: Pethidine, fentanyl, propranolol, metoprolol, lidocaine, bupivacaine
• Clinical relevance: Fetal accumulation of local anaesthetics during epidural; opioids cause neonatal depression
• Weak acids (pKa 3-6): More ionised in maternal plasma → less transfer to fetus
• Examples: Warfarin, aspirin, valproate, phenytoin, NSAIDs

Fetal distress (acidosis) exacerbates ion trapping: - Fetal pH drops → weak bases become even more ionised → even more trapped - Clinical example: Pethidine given in labour — if fetal distress occurs, fetal pethidine accumulation increases → more neonatal respiratory depression

5.3 P-Glycoprotein (P-gp) at the Placenta

• P-gp (MDR1, ABCB1) is an efflux transporter on the maternal-facing brush border of syncytiotrophoblast
• Pumps drug back into maternal circulation → protects fetus
• Substrates: Dexamethasone, tacrolimus, ciclosporin, digoxin, HIV protease inhibitors, ondansetron, loperamide, domperidone (central barrier also)
• P-gp expression varies with gestational age — increases toward term

5.4 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2)

• Placental enzyme that converts active cortisol → inactive cortisone
• Protects fetus from maternal cortisol — "placental barrier" to corticosteroids
• Betamethasone and dexamethasone are poor substrates for 11β-HSD2 → cross placenta freely → reach fetus for lung maturation
• Prednisolone is mostly inactivated → only ~10% reaches fetus
• Hydrocortisone is 80-90% inactivated
• Methylprednisolone — intermediate transfer

5.5 Consequences of Fetal Drug Exposure

Drug Class	Fetal Effect
ACEi/ARBs	Oligohydramnios, renal dysgenesis, skull ossification defects, fetal death (especially 2nd/3rd trimester)
Warfarin	Warfarin embryopathy (nasal hypoplasia, stippled epiphyses) if 1st trimester exposure; fetal haemorrhage
Valproate	Neural tube defects, autism, cognitive impairment, fetal valproate syndrome
Carbamazepine	Neural tube defects (lower risk than valproate); folate antagonism
Phenytoin	Fetal hydantoin syndrome (cleft palate, growth restriction, dysmorphism); folate antagonism
Lithium	Ebstein's anomaly (risk ~0.1-1% — lower than historically thought; still avoid in 1st trimester if possible)
Tetracyclines	Dental discolouration, inhibition of bone growth
Aminoglycosides	Fetal ototoxicity, nephrotoxicity (risk low with short courses)
NSAIDs (3rd trimester)	Premature closure of ductus arteriosus, oligohydramnios, NEC
Misoprostol	Uterine contractions → abortion; Möbius syndrome (if exposure in 1st trimester with failed abortion)
Methotrexate	Methotrexate embryopathy (cranial dysostosis, limb defects); abortifacient
Androgenic steroids	Virilisation of female fetus
DES (diethylstilboestrol)	Vaginal clear-cell adenocarcinoma in daughters (historical)
Retinoids (isotretinoin)	Severe embryopathy (CNS, cardiac, craniofacial)
SSRIs	Persistent pulmonary hypertension (small risk); poor neonatal adaptation syndrome
Benzodiazepines (chronic)	Floppy infant syndrome; withdrawal

---

6. Drug Therapy in Obstetric Emergencies

6.1 Postpartum Haemorrhage (PPH) — WHO 2023 Guidelines

First-line: 1. Oxytocin — 5-10 IU IV slowly (or 10 IU IM) — the cornerstone 2. Tranexamic acid — 1g IV (WOMAN trial — reduces death from bleeding if given within 3 hours) 3. IV fluids, uterine massage, bimanual compression

Second-line (if ongoing bleeding despite oxytocin): 4. Ergometrine — 500 μg IM/IV (contraindicated if hypertension/preeclampsia) 5. Carboprost (PGF2α) — 250 μg IM, repeated q15min up to 8 doses 6. Misoprostol — 800-1000 μg PR/SL/rectal

Third-line: 7. Oxytocin infusion — 40 IU in 500 mL NS at 125 mL/h 8. Surgical interventions — B-lynch, uterine artery ligation, hysterectomy

6.2 Eclampsia — Acute Management

1. MgSO₄ — 4g IV over 5-10 min (loading), then 1g/h IV for 24 hours post-seizure/post-partum
2. Second seizure on MgSO₄: Additional 2g IV bolus
3. If MgSO₄ fails: Diazepam 10 mg IV or lorazepam 4 mg IV
4. Antidote: Calcium gluconate 1g (10 mL of 10%) IV over 10 min
5. Blood pressure control: Labetalol IV or hydralazine IV or nifedipine PO

6.3 Anaphylaxis in Pregnancy

• Adrenaline (epinephrine) 500 μg IM (anterolateral thigh) — first-line
• Airway, breathing, circulation
• Antihistamine (chlorphenamine 10 mg IV)
• Hydrocortisone 200 mg IV

6.4 Amniotic Fluid Embolism (AFE)

• Supportive care
• No specific drug therapy — manage DIC, hypotension, hypoxia
• May need oxytocin for PPH, vasopressors for shock

---

7. Tocolytics

Tocolytics aim to delay delivery by 48 hours to: 1. Allow corticosteroids to maximise fetal lung maturity benefit 2. Allow in-utero transfer to a unit with appropriate neonatal intensive care

Indications: - Preterm labour (24+0 to 33+6 weeks) — short-term tocolysis for steroid benefit - Contraindications: Severe preeclampsia, placental abruption, chorioamnionitis, fetal distress, lethal fetal anomaly, cervical dilation >4-5 cm, PPROM with chorioamnionitis

7.1 Nifedipine — First-Line Tocolysis

Mechanism: L-type calcium channel blocker → inhibits Ca²⁺ influx into myometrial smooth muscle → reduces contractions

Evidence: Most commonly used first-line in UK (APOSTEL trials support safety and efficacy)

Dosing: - Loading: 10-20 mg oral (immediate-release) q30 min for 3-4 doses - Maintenance: 10-20 mg q4-8h for 48 hours - Use immediate-release, not long-acting MR preparations

Side Effects: | Common | Serious | |---|---| | Headache (most common) | Hypotension (monitor BP) | | Flushing, dizziness | Reflex tachycardia | | Palpitations | Pulmonary oedema (rare) | | Nausea | Worsening of preeclampsia (theoretical) |

Contraindications: Hypersensitivity, severe hypotension, aortic stenosis, concurrent IV β-agonist therapy (increased pulmonary oedema risk)

Drug Interactions: - CYP3A4 inhibitors (ketoconazole, erythromycin, grapefruit juice) → ↑ nifedipine levels - CYP3A4 inducers (rifampicin, phenytoin) → ↓ nifedipine levels - MgSO₄ — additive hypotension risk (but combination often used; monitor BP)

7.2 Atosiban — Second-Line Tocolysis

Mechanism: Oxytocin receptor antagonist — competitively blocks oxytocin receptors in myometrium and decidua

Dosing (three-step regimen): 1. Initial bolus: 6.75 mg IV over 1 minute 2. High-dose infusion: 300 μg/min IV for 3 hours 3. Lower-dose infusion: 100 μg/min IV for up to 45 hours

Side Effects: - Nausea/vomiting (most common) - Headache, dizziness - Tachycardia, hypotension - Injection site reactions - Hyperglycaemia

Advantages: - Fewer cardiovascular side effects than β-agonists - No fetal ductal constriction (unlike indomethacin) - No maternal hypotension risk (unlike nifedipine, though less than thought)

Disadvantages: - Expensive (main limiting factor) - Less evidence for efficacy than nifedipine - Need IV access and infusion pump - Not as widely available

Drug Interactions: - Macrolide antibiotics (erythromycin) — may increase atosiban levels (CYP3A4?)

7.3 β₂-Adrenoceptor Agonists (Ritodrine, Salbutamol) — Third-Line

Mechanism: Stimulate β₂-receptors on myometrial smooth muscle → ↑ cAMP → smooth muscle relaxation

Dosing: - Ritodrine: IV infusion starting at 50 μg/min, titrated up to 350 μg/min (not available in all countries) - Salbutamol: IV infusion 10-45 μg/min (off-label use)

Side Effects — SIGNIFICANT: | System | Effect | |---|---| | Cardiovascular | Tachycardia (maternal + fetal), hypotension, palpitations, arrhythmias, myocardial ischaemia, pulmonary oedema (most feared — especially with concurrent steroids, fluids) | | Metabolic | Hyperglycaemia, hyperinsulinaemia, hypokalaemia (shift of K⁺ intracellular), lactic acidosis | | Fetal | Fetal tachycardia, hyperinsulinaemia → neonatal hypoglycaemia after birth | | Other | Nausea, vomiting, tremor, headache, anxiety |

Contraindications: - Cardiac disease (ischaemic heart disease, arrhythmias, valve disease) - Diabetes mellitus (relative — monitor glucose) - Hyperthyroidism - Preeclampsia (increased pulmonary oedema risk) - Tachyarrhythmias - Hypokalaemia

Precautions: - Concurrent K⁺ monitoring — hypokalaemia is common - Fluid restrict (<2 L/day) — to reduce pulmonary oedema risk - Monitor heart rate, blood glucose, chest auscultation - Discontinue if HR >130 bpm, signs of pulmonary oedema, chest pain

Drug Interactions: - Halogenated anaesthetics (increased arrhythmia risk) - Theophylline (additive cardiac effects, hypokalaemia) - Diuretics (worsen hypokalaemia) - Corticosteroids (synergistic hyperglycaemia) - Magnesium sulfate (additive cardiovascular effects)

7.4 Indomethacin — Limited Use (<32 weeks)

Mechanism: Non-selective COX inhibitor → ↓ prostaglandin synthesis (PGs are key to cervical ripening and uterine contractions)

Dosing: - Loading: 50-100 mg PR, then 50 mg PO q6h - Maximum 48 hours total duration - Only used <32 weeks (ductus arteriosus is sensitive to PGs after 32 weeks)

Side Effects — Maternal: - Nausea, vomiting, dyspepsia - GI bleeding (rare with short course) - Headache, dizziness - Renal impairment (reversible)

Fetal/Neonatal Side Effects: | Effect | Mechanism | Clinical Impact | |---|---|---| | Ductus arteriosus constriction | ↓ PGE₂ → ductal closure | In utero — tricuspid regurgitation, hydrops; postnatal — persistent pulmonary hypertension | | Oligohydramnios | ↓ fetal renal PGs → ↓ fetal urine output | Usually reversible on stopping | | NEC risk | Theoretical (PGs protect GI mucosa) | Avoid with concurrent PPROM? | | Intraventricular haemorrhage | Theoretical (COX inhibitors affect platelet function) | Controversial — some studies show no increase |

Contraindications: >32 weeks, oligohydramnios, fetal renal anomaly, duct-dependent congenital heart disease, maternal bleeding disorder, asthma (NSAID-sensitive), peptic ulcer disease

7.5 Glyceryl Trinitrate (GTN) — Fourth-Line

Mechanism: NO donor → ↑ cGMP → smooth muscle relaxation (also used for cervical ripening)

Dosing: - IV infusion starting at 5-20 μg/min, titrated - Transdermal patch (off-label use)

Side Effects: - Hypotension, headache, flushing - Tachycardia (reflex) - Methemoglobinaemia (prolonged high-dose)

Evidence: Limited — not recommended as first-line; used when others contraindicated or fail

7.6 Magnesium Sulfate — Dual Role: Tocolysis & Fetal Neuroprotection

Mechanism: - Competes with Ca²⁺ at voltage-gated channels → reduces intracellular Ca²⁺ → smooth muscle relaxation - Multiple other mechanisms

Neuroprotection: - For women at risk of preterm birth <30 weeks - Loading: 4g IV over 15-30 min, then 1g/h for 12-24 hours or until delivery - Reduces risk of cerebral palsy (number needed to treat: 37) — multiple RCTs (BEAM, ACTOMgSO4, MAGPIE)

Tocolysis: - Some use in PTL, but not primary indication in UK

Side Effects & Monitoring: | Sign | Level (mmol/L) | Action | |---|---|---| | Therapeutic range | 2-4 mmol/L | — | | Loss of patellar reflexes | ~4-5 mmol/L | Reduce infusion; check levels; monitor | | Somnolence, slurred speech | ~5-6 mmol/L | Stop infusion; consider antidote | | Respiratory depression | ~6-7.5 mmol/L | EMERGENCY — stop, give Ca gluconate, support ventilation | | Cardiac arrest | >7.5 mmol/L | Full resuscitation + Ca gluconate |

Antidote: Calcium gluconate 1g (10 mL of 10%) IV over 3-5 minutes

Contraindications: Myasthenia gravis, heart block, renal failure (↑ risk of toxicity — Mg is renally cleared), hypocalcaemia

7.7 Comparison of Tocolytics

Drug	Efficacy Rank	Side Effect Profile	Fetal Safety	Cost	UK Preference
Nifedipine	1st	Moderate (headache, flushing)	Good	Low	First-line
Atosiban	=1st	Mild (nausea)	Excellent	Very high	Second-line (if nifedipine CI)
Ritodrine/Salbutamol	2nd	Poor (pulmonary oedema, tachycardia, metabolic)	Moderate	Low	Third-line/abandoned
Indomethacin	2nd	Mild maternal; fetal ductal	Fetal risk if >32wk	Low	Limited <32wk; short course
GTN	3rd	Moderate (hypotension, headache)	Good	Low	Fourth-line
MgSO₄	3rd	Moderate (monitoring required)	Good (neuroprotection)	Low	Mainly for neuroprotection

---

8. Corticosteroids for Fetal Lung Maturity

8.1 Indications & Evidence

Indications: - All women at risk of preterm delivery between 24+0 and 33+6 weeks (NICE, RCOG, WHO) - Consider up to 36+0 weeks if elective CS before term - Rescue course: If >14 days since initial course and still at risk (RCOG, NICE)

Evidence base (Liggins & Howie 1972 — landmark trial; Cochrane review 2020+):

Antenatal corticosteroids reduce: - RDS: ↓ 34% (RR 0.66) - Neonatal death: ↓ 31% (RR 0.69) - IVH: ↓ 45% (RR 0.55) - NEC: ↓ 28% (RR 0.72) - Need for respiratory support, surfactant - Duration of neonatal intensive care

Number Needed to Treat (NNT): ~11 to prevent one neonatal death

8.2 Betamethasone vs Dexamethasone

Property	Betamethasone	Dexamethasone
Structure	16β-methylpregna-1,4-diene	16α-methylpregna-1,4-diene
Affinity for GR	Higher	Lower
Crosses placenta	Yes (poor substrate for 11β-HSD2)	Yes (poor substrate for 11β-HSD2)
Crosses BBB	Yes	Yes
Relative potency	~1.25× dexamethasone	1.0
Duration of action	Long (26-54 h half-life)	Intermediate (36-54 h half-life)
Mineralocorticoid activity	None	None
Half-life in pregnancy	~6.1h (maternal)	~4.2h (maternal)

Standard Regimens:

Regimen	Drug	Dose	Route	Interval	Total Dose
WHO/NICE/RCOG preferred	Betamethasone	12 mg	IM	2 doses, 24 hours apart	24 mg
Alternative	Dexamethasone	6 mg	IM	4 doses, 12 hours apart	24 mg

Why betamethasone is preferred: 1. Lower incidence of neonatal IVH (meta-analysis: betamethasone > dexamethasone for IVH reduction) 2. Better fetal lung response (more surfactant production, better compliance) 3. Less neonatal side effects (fewer cerebellar haemorrhages, fewer infections?) 4. Fewer doses (2 vs 4) → better compliance, less pain

Timing of maximum benefit: - Onset of effect: ~4-6 hours after first dose - Peak benefit: 24 hours to 7 days after first dose - Benefits persist for at least 7 days - Rescue course (one additional dose) can be given if >14 days since initial course

8.3 Mechanism of Action

Glucocorticoid binds to glucocorticoid receptor (GR) in alveolar type II pneumocytes → nuclear translocation → gene transcription changes:

Gene Target	Effect	Timeframe
Surfactant protein A (SP-A)	↑ production	4-6 hours
Surfactant protein B (SP-B)	↑ production	4-6 hours
Surfactant protein C (SP-C)	↑ production	4-6 hours
Surfactant protein D (SP-D)	↑ production	4-6 hours
Phospholipid synthesis enzymes	↑ surfactant phospholipids	6-24 hours
β-adrenergic receptors in type II cells	↑	Enhanced surfactant secretion
Na⁺ channels (ENaC)	↑	↑ lung fluid clearance at birth
Antioxidant enzymes	↑	Protection against oxidative stress
Collagen/elastin genes	Modulated	Improved lung architecture, compliance
Inflammatory cytokines	↓	Reduced lung inflammation

Summary: Steroids accelerate lung maturity by: 1. ↑ Surfactant production (phospholipids + proteins) → ↓ surface tension 2. ↑ Lung compliance (structural maturation) 3. ↑ Lung fluid clearance (↑ ENaC, Na⁺/K⁺-ATPase) 4. ↓ Capillary permeability → less pulmonary oedema 5. ↑ Antioxidant capacity

8.4 Additional Non-Pulmonary Benefits

Outcome	Relative Risk Reduction	Mechanism
IVH	45%	Stabilises germinal matrix capillaries; reduced BP fluctuations
NEC	28%	Maturation of gut barrier; reduced inflammatory response
Ductus arteriosus closure	Improved	Enhanced ductal response to oxygen
Retinopathy of prematurity	Reduced	↓ VEGF expression?
Neurodevelopmental outcomes	Improved (in some studies)	↑ Myelination, ↓ CP risk

8.5 Contraindications & Cautions

Absolute Contraindications: - Maternal systemic infection (untreated) — relative; treat infection and give steroids if indicated - Active tuberculosis — only if untreated

Cautions: - Diabetes mellitus — monitor glucose; may need sliding scale insulin (hyperglycaemia is ~2× more common) - Preeclampsia — may worsen hypertension/fluid retention - PPROM — steroids still indicated (no increase in infection in meta-analysis) - Maternal sepsis — weigh risks; generally still beneficial for fetus - Chorioamnionitis — steroids still reduce RDS, death (some evidence) - Twin/triplet pregnancies — same regimen, same benefit

8.6 Rescue (Repeat) Courses

RCOG/NICE 2022: - Consider a single rescue course of betamethasone 12 mg IM × 1 dose (or 2 doses 24h apart) - If >14 days since initial course AND still at risk of preterm birth <34 weeks - Not recommended: Routine multiple repeat courses (increased risk of low birthweight, reduced head circumference in some studies) - Maximum: 3 total courses (controversial; most limit to 2 courses)

The MACS Study: Multiple courses → reduced neonatal morbidity BUT reduced birth weight, head circumference → not recommended routinely.

8.7 Steroids for Late Preterm (34-36 weeks)

Indication: Consider for women at risk of delivery at 34+0 to 36+6 weeks if elective CS planned or high risk of delivery (ALPS trial): - Betamethasone 12 mg IM × 2, 24h apart - Reduced neonatal respiratory morbidity (RR 0.80, NNT ~30) - Not yet universal standard — RCOG advises individualised decision

8.8 Steroids for Elective Caesarean Section <39 weeks

• Recommendation: If elective CS planned at 37-38 weeks, consider betamethasone to reduce neonatal respiratory morbidity
• Use same regimen (2 × 12 mg IM, 24h apart)
• Best practice: Delay CS until ≥39 weeks to avoid need

---

9. Oxytocics & Uterotonics

9.1 Oxytocin (Syntocinon)

Structure: Synthetic cyclic nonapeptide — identical to endogenous oxytocin

Mechanism: - Binds to oxytocin receptor (GPCR, Gq/11-coupled) on myometrial cells - Activates phospholipase C → IP3/DAG → ↑ intracellular Ca²⁺ → smooth muscle contraction - Also stimulates decidual PGF₂α production → synergistic effect - Oxytocin receptors ↑↑ in late pregnancy (300× increase at term)

Pharmacokinetics: - IV only for obstetric use (or IM 10 IU for PPH) - IV onset: ~30 seconds; peak effect 2-5 minutes - Half-life: 5-17 minutes (biphasic) - Metabolism: Hepatic and renal (cleared by oxytocinase/vasopressinase — enzyme secreted by placenta) - Oral bioavailability: Low (peptide, gastric degradation)

Clinical Uses:

Indication	Dose	Route	Notes
Induction of labour	1-12 mU/min, titrated	IV infusion	Low-dose regimen (1-4 mU/min increments q30min)
Augmentation of labour	1-12 mU/min, titrated	IV infusion	Same protocol
Active management 3rd stage	5-10 IU	IV/IM	First-line uterotonic
PPH treatment	5 IU slow IV bolus then 40 IU in 500 mL NS at 125 mL/h	IV	Can repeat
Miscarriage/incomplete abortion	10-20 IU in 500 mL NS	IV infusion	Off-licence

Dose-Response Relationship: - Low dose (1-4 mU/min): Rhythmic contractions - Moderate dose (4-8 mU/min): Strong contractions, good for augmentation - High dose (8-12+ mU/min): Risk of hyperstimulation; rarely needed - Maximum recommended: 12-20 mU/min (some protocols up to 36 mU/min)

Side Effects:

Effect	Mechanism	Frequency	Management
Uterine hyperstimulation	Excess uterine activity	1-5%	Reduce/stop infusion; may need tocolytic
Uterine rupture	Especially in scarred uterus	Rare	Emergency CS
Water intoxication	ADH-like activity at high doses (>20 mU/min) — oxytocin is structurally similar to ADH	Rare (but serious)	Fluid restrict; monitor Na⁺; treat hyponatraemia
Hypotension	Vasodilation (especially with rapid IV bolus)	Common with rapid IV	Give slowly over 1-2 minutes
Nausea/vomiting	Direct effect	Common	Antiemetic if needed
Tachycardia	Reflex/vasodilation	Common	Usually self-limiting
Fetal heart rate changes	Related to hyperstimulation	Monitor	Reduce dose/stop
Neonatal jaundice	Osmotic fragility of RBCs?	Controversial association	Phototherapy if needed

Contraindications: - Severe preeclampsia (relative — use judiciously) - Fetal distress where vaginal delivery not appropriate - Placenta praevia (unless in third stage) - Cord presentation - Absolute cephalopelvic disproportion - Active genital herpes (for IOL — vaginal delivery concern) - Hypertonic uterus

Drug Interactions: - Prostaglandins (synergistic → hyperstimulation risk) - Vasopressors (additive pressor effect with some) - Magnesium sulfate (theoretical antagonism? — myometrial relaxation) - Carbamazepine, NSAIDs — no significant interaction

9.2 Ergometrine

Structure: Ergot alkaloid — natural product from Claviceps purpurea

Mechanism: - Partial agonist at α-adrenoceptors (α₁ > α₂) → sustained tonic contraction of myometrium - Also acts at 5-HT₂ receptors and dopamine receptors - Produces powerful, sustained uterine contraction (dose-dependent) - Onset: IM 2-5 min, IV ~1 min - Duration: 2-4 hours (sustained — much longer than oxytocin)

Clinical Use: - Active management of third stage (preferred in many UK protocols? — but oxytocin is more commonly first-line) - PPH treatment (usually 2nd line after oxytocin) - Dose: 500 μg IM (or slow IV if emergency)

Side Effects — SIGNIFICANT:

Effect	Mechanism	Clinical Relevance
Severe hypertension	Vasoconstriction (α₁ agonism)	Can be dangerous — contraindicated if BP >140/90, preeclampsia, eclampsia, hypertension
Nausea/vomiting	Dopamine D₂ stimulation (CTZ)	Very common (20-30%)
Coronary vasospasm	5-HT₂, α₁ on coronary vessels	Myocardial ischaemia, MI (rare but reported)
Headache	Vasoconstriction	Common
Dizziness		Common
Peripheral vasoconstriction	α₁ agonism	Cold extremities, pallor
Uterine tetany	Excessive response	Risk of uterine rupture if undiagnosed obstruction

Contraindications: - Hypertension / preeclampsia / eclampsia (absolute) - Cardiovascular disease (CAD, peripheral vascular, Raynaud's) - Migraine (current hemiplegic or basilar) - Hepatic or renal impairment - Sepsis - Multiple pregnancy (relative — might need cautious use) - NOT used for induction of labour or cervical ripening

Drug Interactions: - Vasopressors (additive hypertension) - β-blockers (unopposed α-vasoconstriction → severe hypertension) - Dopamine agonists (additive) - Macrolides, azole antifungals (CYP3A4 inhibition → ergotism risk) - Triptans (additive vasospasm)

9.3 Carboprost (PGF₂α Analogue — Hemabate)

Mechanism: Prostaglandin F₂α analogue — binds FP receptors on myometrium → ↑ intracellular Ca²⁺ → strong contractions

Clinical Use: - Third-line treatment for severe PPH (when oxytocin + ergometrine fail) - Dose: 250 μg IM (or intramyometrial) - Repeat every 15 minutes, up to 8 doses (max 2 mg) - Onset: 5-10 min IM; peak 15-60 min

Side Effects:

Effect	Frequency	Mechanism
Nausea/vomiting/diarrhoea	>30%	GI smooth muscle contraction (FP receptors)
Bronchospasm	~10-15%	PGF₂α → bronchoconstriction (FP receptors in airways)
Fever/flushing	Common	Prostaglandin-mediated
Hypertension/pulmonary hypertension	Less common	Vascular FP receptors
Injection site pain	Very common	—
Hyperthermia		Resolves with stopping
Hypotension (high dose)	Rare	—

Contraindications: - Asthma (relative — can exacerbate; use cautiously with bronchodilator available) - Pulmonary hypertension - Cardiac disease - Active hepatic/renal disease - Pelvic inflammatory disease (theoretical concern)

Asthma note: PGF₂α is a potent bronchoconstrictor. If patient has asthma, use with extreme caution — have salbutamol nebuliser ready. In severe asthma, avoid or use only as last resort.

9.4 Misoprostol (PGE₁ Analogue)

Mechanism: PGE₁ analogue — binds EP receptors (EP₂/EP₃) → cervical ripening + uterine contractions

Multiple Obstetric Uses:

Indication	Dose	Route	Notes
PPH treatment	600-1000 μg	Sublingual/PR	WHO recommendation
PPH prophylaxis (low-resource)	600 μg	Oral	Inferior to oxytocin
Cervical ripening / IOL	25-50 μg PV q4-6h	Vaginal	Not 200 μg (was used historically — too high)
IOL (oral)	20-50 μg PO q2h	Oral	Titrated
Termination of pregnancy	400-800 μg PV/PO	Vaginal/Oral	Combined with mifepristone
Missed miscarriage	400-800 μg PV	Vaginal	Medical management
Postpartum (3rd stage)	400-600 μg	Oral/PR	Warm climates (storage issues with oxytocin)

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Pyrexia/chills | 10-50% (dose-related) | Common; self-limiting; resolve within 6 hours | | Nausea/vomiting | 20-40% | Dose-related | | Diarrhoea | 10-30% | Prostaglandin effect on GI tract | | Uterine hyperstimulation | 1-5% | Dose-related; higher with >50 μg PV | | Uterine rupture | Rare | Risk in scarred uterus, high doses, grand multiparous | | Shivering | 30-60% | Very common; not dangerous | | Hypotension | Rare | IV not recommended for this reason |

Contraindications: - Previous CS (relative — low-dose regimens may be used with caution; avoid high doses) - Uterine scar (myomectomy) — caution - Asthma? (PGE₁ is a bronchodilator — safe in asthma; contrasts with PGF₂α) - Glaucoma, sickle cell disease (caution)

Drug Interactions: - Oxytocin (synergistic — use with care; avoid simultaneous administration) - MgSO₄ (theoretical antagonism) - Other prostaglandins (additive)

9.5 Comparison of Uterotonics for PPH

Drug	Route	Onset	Duration	Main Limitation	Cost
Oxytocin	IV/IM	IV: 30s	15-30 min	IV access needed; unstable at room temp	Low
Ergometrine	IM/IV	IM: 5 min	2-4 h	Hypertension — avoid if pre-eclampsia	Very low
Carboprost	IM	5-10 min	30-60 min	Bronchospasm — avoid if asthma	High
Misoprostol	PR/SL/PO	5-30 min	1-2 h	Pyrexia, shivering, less effective than oxytocin	Low

---

10. Antihypertensives in Pregnancy

10.1 Principles of Managing Hypertension in Pregnancy

Definitions: - Chronic hypertension: BP ≥140/90 before 20 weeks or pre-existing - Gestational hypertension: New-onset ≥140/90 after 20 weeks, no proteinuria - Preeclampsia: Hypertension + proteinuria (or other end-organ dysfunction) - Severe hypertension: ≥160/110 mmHg (requires urgent treatment)

Treatment targets (NICE 2023): - Aim for BP <140/90 (or <135/85 on treatment) - Avoid iatrogenic hypotension (reduce placental perfusion)

10.2 Labetalol — First-Line

Mechanism: Non-selective β-blocker (β₁, β₂) + α₁-blocker (α₁:β ratio ~1:7 IV, 1:3 oral)

Pharmacokinetics: | Parameter | Value | |---|---| | Bioavailability | ~25% (extensive first-pass) | | Protein binding | ~50% | | Half-life | 6-8 hours (oral); 5-6 hours (IV); ↑ in pregnancy slightly | | Metabolism | Hepatic (glucuronidation — UGT); CYP2C19 minor | | Elimination | Renal (metabolites); parent drug <5% | | Crosses placenta | Yes — M/P ratio ~0.5-1.0 |

Dosing: | Indication | Dose | Route | |---|---|---| | Mild-moderate hypertension (chronic/GH) | 100-200 mg PO bd-tds | Oral | | Severe hypertension (acute) | 50 mg slow IV over 1 min, repeated q10-15min up to 200 mg | IV | | Severe hypertension (alternative) | 200 mg PO every 15-30 min up to 1.2g | Oral | | Maintenance | 200-600 mg PO bd | Oral |

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Fatigue, drowsiness | Very common | Can affect quality of life | | Headache | Common | | | Dizziness (postural) | Common | Advise to get up slowly | | Scalp tingling | Unique to labetalol (~5%) | Benign, self-limiting | | Nausea, epigastric pain | Common | | | Fetal bradycardia | Theoretical (β-blockade) | Usually mild; monitor | | Bronchospasm | Less than non-selective β-blockers (α₁ block offsets some) | Avoid in asthma | | Hepatic injury | Rare (<1%) | Reversible; monitor LFTs | | Positive ANA | ~3-5% | Usually asymptomatic; reversible | | Mask hypoglycaemia | β-blockade blunts tachycardia | Important in diabetic patients | | Plaque psoriasis exacerbation | Rare | |

Contraindications: - Asthma / COPD (β-blockade can trigger bronchospasm) - Bradycardia, heart block - Decompensated heart failure - Raynaud's phenomenon / peripheral vascular disease - Phaeochromocytoma (must use combined α+β block) - Sick sinus syndrome

Advantages: - First-line for all types of hypertension in pregnancy - Both oral and IV formulations - Relatively safe profile across all trimesters - Extensive experience base - Low cost

10.3 Nifedipine (Long-Acting MR) — First-Line Alternative

Mechanism: L-type calcium channel blocker → arteriolar vasodilation → ↓ BP

Nifedipine in hypertension uses the MR (modified release / long-acting) formulation, NOT immediate-release which causes reflex tachycardia.

Dosing: | Indication | Dose | Preparation | |---|---|---| | Mild-moderate hypertension | 20-30 mg PO bd (MR) | Long-acting only | | Severe hypertension | 10 mg PO (immediate-release) q15-30min until controlled | Then switch to MR |

Side Effects: | Effect | Mechanism | Notes | |---|---|---| | Headache | Vasodilation | Very common | | Flushing, dizziness | Vasodilation | Common | | Peripheral oedema (ankle) | Pre-capillary vasodilation | Common; not heart failure | | Reflex tachycardia | Sympathetic response | More with IR; less with MR | | Palpitations | Tachycardia | | | Constipation | Smooth muscle relaxation | Common with Ca channel blockers | | Gingival hyperplasia | Chronic use | <1% | | Hypotension (excessive) | Overdose | Avoid with concurrent MgSO₄ (additive) |

Contraindications: - Severe aortic stenosis - Cardiogenic shock - Concurrent MgSO₄ (additive hypotension risk — but can be used with monitoring) - Unstable angina (reflex tachycardia may worsen) - Kock pouch (short gut — MR preparation may not release properly)

Advantages over labetalol: - Fewer CNS side effects (less fatigue/drowsiness) - No bronchospasm — safe in asthma - No masking of hypoglycaemia - Once useful in women intolerant to labetalol

10.4 Methyldopa — Second-Line

Mechanism: Central α₂-adrenoceptor agonist → ↓ sympathetic outflow → ↓ peripheral vascular resistance

Pharmacokinetics: - Pro-drug — converted to α-methylnoradrenaline - Onset: 4-8 hours (oral) - Half-life: ~8 hours - Metabolism: Hepatic (sulphation) - Excretion: Renal - Crosses placenta: Yes

Dosing: - Starting dose: 250 mg PO bd-tds - Maintenance: 500 mg-1 g PO bd-tds - Maximum: 3 g/day

Side Effects: | Effect | Mechanism | Notes | |---|---|---| | Drowsiness, sedation | Central α₂ effect | Very common; may improve over 2-4 weeks | | Depression | Central noradrenaline depletion | 1-3%; may need to stop | | Dry mouth | Central α₂ effect | Common | | Positive Coombs test (DAT) | Drug-induced autoantibodies | 10-20%; usually no haemolysis; but can complicate cross-matching | | Haemolytic anaemia | Autoimmune (if Coombs + with haemolysis) | Rare (<1%); stop drug | | Dizziness, postural hypotension | Central α₂ | | | Fatigue | Central | Very common | | Parkinsonism | Rare | Central dopamine pathway? | | Extrapyramidal symptoms | Rare | | | Hepatitis | Idiosyncratic | Rare (<1%) |

Advantages: - Longest safety record in pregnancy (decades of use) - No teratogenicity - Low cost - Does not significantly affect uteroplacental blood flow

Disadvantages: - Slow onset (hours) — not for severe acute hypertension - Delayed onset of action limits usefulness for acute management - Sedation, depression — affects quality of life - Positive Coombs test complicates cross-matching - Third-line now in most UK protocols (behind labetalol, nifedipine)

10.5 Hydralazine — Third-Line

Mechanism: Direct vasodilator (arteriolar > venous) → ↓ SVR

Pharmacokinetics: | Parameter | Value | |---|---| | Bioavailability | ~30-50% (slow acetylators have higher levels) | | Half-life | 2-4 hours (short) | | Metabolism | N-acetylation (NAT2) — polymorphic | | Elimination | Renal | | Crosses placenta | Yes |

Clinical Use: - IV for acute severe hypertension (not first-line per NICE — concerns about safety) - Oral for adjunctive therapy - Dose: 5-10 mg slow IV, repeated as needed; then 10-20 mg IV q4-6h

Side Effects — SIGNIFICANT: | Effect | Mechanism | Notes | |---|---|---| | Reflex tachycardia | Vasodilation → sympathetic activation | May need β-blocker co-administration | | Lupus-like syndrome | Drug-induced SLE | 5-10% at doses >200 mg/day (slow acetylators at higher risk) | | Headache | Vasodilation | Common | | Flushing | Vasodilation | Common | | Palpitations | Tachycardia | Common | | Angina exacerbation | Tachycardia + diastolic hypotension | Avoid in CAD | | Fluid retention | Compensatory RAAS activation | May need concurrent diuretic (but avoid in pregnancy) | | Neonatal thrombocytopenia | | Rare; reversible |

Concerns with Hydralazine vs Labetalol for Severe Hypertension: - Meta-analyses show hydralazine is associated with more adverse outcomes than labetalol: - More maternal hypotension - More placental abruption - More caesarean sections - More low Apgar scores - NICE recommends labetalol as first-line IV, not hydralazine - Hydralazine is now third-line after labetalol and/or nifedipine

Contraindications: - Coronary artery disease - Aortic aneurysm - Tachyarrhythmias - Hypersensitivity - SLE (may exacerbate)

10.6 ACE Inhibitors & ARBs — ABSOLUTELY CONTRAINDICATED IN PREGNANCY

Why? — Fetotoxic effects across all trimesters:

Trimester	Effect	Mechanism
1st	Congenital malformations (skull ossification defects, renal anomalies, cardiovascular)	Interference with RAAS in fetal organogenesis
2nd/3rd	Oligohydramnios (most common)	↓ Fetal urine output (↓ GFR via ↓ angiotensin II)
2nd/3rd	Fetal renal dysgenesis (tubular dysplasia)	↓ Renal perfusion
2nd/3rd	Fetal hypotension	↓ Angiotensin II → vasodilation
2nd/3rd	Intrauterine growth restriction	↓ Uteroplacental perfusion
2nd/3rd	Pulmonary hypoplasia	Sequelae of oligohydramnios
2nd/3rd	Limb contractures	Sequelae of oligohydramnios
2nd/3rd	Neonatal anuria / renal failure	↓ Renal perfusion at birth
2nd/3rd	Skull ossification defects	Hypotension → poor ossification
Any	Fetal death

Risk not limited to 2nd/3rd trimester: 1st trimester exposure may still increase risk of cardiac/neural tube defects (some meta-analyses show OR ~1.5-2.0 for major malformations).

Management if exposed: Stop immediately, monitor renal function and amniotic fluid volume, arrange fetal medicine assessment.

10.7 Atenolol — Avoid in Pregnancy

• Associated with IUGR (sympathetic block → ↓ cardiac output → ↓ fetal growth)
• Not recommended in pregnancy (labetalol preferred if β-blocker needed)

10.8 Summary — Antihypertensive Choice in Pregnancy

Drug	Position	Notes
Labetalol	1st line	Oral or IV; safe; avoid in asthma
Nifedipine (MR)	1st line alternative	Safe; avoid IR except for severe acute
Methyldopa	2nd line	Safe but slow onset; use for chronic hypertension
Hydralazine	3rd line (IV only)	For acute severe refractory hypertension
ACEi/ARBs	CONTRAINDICATED	Teratogenic/fetotoxic
Atenolol	Avoid	Associated with IUGR
Verapamil/Diltiazem	Limited data	Use if alternatives unsuitable
Spironolactone	Avoid	Antiandrogenic effects on male fetus?
Diuretics	Avoid (controversial)	Reduced plasma volume may worsen placental perfusion

---

11. Anticonvulsants in Pregnancy & Eclampsia

11.1 Magnesium Sulfate for Eclampsia

Mechanism — Multiple: 1. NMDA receptor antagonist — blocks Ca²⁺ influx through NMDA receptor channels 2. Voltage-gated Ca²⁺ channel blocker — reduces Ca²⁺ entry into neurons 3. Inhibits excitatory neurotransmitter release (glutamate) 4. ↓ Cerebral vasospasm — vasodilation 5. Stabilises neuronal membranes 6. Anti-inflammatory effects — ↓ cytokines, ↓ BBB disruption 7. ↓ Cerebral oedema

MAGPIE Trial (2002): - 10,141 women with preeclampsia; 4g IV load + 1g/h or placebo - Eclampsia: 58% reduction (RR 0.42, NNT = 109 for prophylaxis) - For eclampsia treatment: Stop seizures in 70-80%

Dosing Regimens:

Indication	Loading Dose	Maintenance	Duration
Eclampsia prophylaxis (severe preeclampsia)	4g IV over 5-15 min	1g/h IV	24 hours post-partum or post-seizure
Eclampsia treatment (active seizure)	4g IV over 5-10 min	1g/h IV	24 hours post-last seizure
Recurrent seizure on MgSO₄	2g IV bolus	Continue 1g/h	—
Fetal neuroprotection (<30w PTL)	4g IV over 15-30 min	1g/h for 12-24h or until delivery	—

Monitoring Requirements: | Parameter | Frequency | Significance | |---|---|---| | Respiratory rate | Hourly | Depression at >6 mmol/L | | Patellar reflexes | Hourly | Lost at ~4-5 mmol/L (earliest sign of toxicity) | | Urine output | 4-hourly | >25 mL/h; accumulation if oliguric | | Oxygen saturation | Continuous if severe | Respiratory depression | | Serum Mg²⁺ levels | If high risk / symptoms | Target: 2-4 mmol/L (therapeutic) | | BP, heart rate | Hourly | Underlying preeclampsia | | Fetal heart rate | Continuous | MgSO₄ may reduce variability (benign) |

Signs of Magnesium Toxicity (ascending):

Serum Mg (mmol/L)	Signs	Action
2-3.5	Therapeutic	Continue
3.5-4	Warmth, flushing, nausea, sedation	Monitor more closely
4-5	Loss of patellar reflexes	STOP infusion; check level; monitor
5-6	Somnolence, slurred speech, blurred vision	STOP; give Ca gluconate
6-7.5	Respiratory depression, muscle paralysis	EMERGENCY — ventilate, Ca gluconate
>7.5	Cardiac arrest (widened QRS, bradycardia)	Full resuscitation + Ca gluconate

Antidote — Calcium Gluconate: - 1g (10 mL of 10% calcium gluconate) IV over 3-5 minutes - Rapidly reverses respiratory depression - Does NOT replace Mg²⁺ — chelates free Mg²⁺ temporarily - May need repeat (half-life of Ca is short) - Keep at bedside of any woman on MgSO₄

Contraindications to MgSO₄: - Myasthenia gravis (absolute — can cause severe weakness/paralysis) - Heart block (if symptomatic) - Renal failure (CrCl <30 mL/min) — ↓ excretion → ↑ toxicity risk; reduce dose or avoid - Hypocalcaemia (will worsen) - Hypersensitivity

Drug Interactions: | Drug | Interaction | Mechanism | |---|---|---| | Nifedipine | Additive hypotension | Both vasodilators | | β-blockers | Additive bradycardia | | | CNS depressants (opioids, BZDs) | Increased sedation | Additive CNS depression | | Neuromuscular blockers | Prolonged paralysis | Mg²⁺ potentiates NMBs | | Loop diuretics | May ↑ or ↓ Mg²⁺ levels | Variable | | Aminoglycosides | ↑ Neuromuscular blockade | Additive |

Why MgSO₄ and not other anticonvulsants for eclampsia?

Drug	Evidence for eclampsia	Notes
MgSO₄	Gold standard — Level 1 evidence	Superior to phenytoin, diazepam (magnie trial >magnitude)
Diazepam	Inferior to MgSO₄ (more recurrent seizures, more respiratory depression, more NICU admissions)	Used only if MgSO₄ fails/not available
Phenytoin	Inferior to MgSO₄ from Eclampsia Trial Collaborative Group	No longer recommended
Phenobarbital	Not recommended
Midazolam	No adequate trials

11.2 Antiepileptic Drugs (AEDs) in Epilepsy & Pregnancy

General Principles: - Most women with epilepsy need AEDs during pregnancy — risk of seizures > risk of AED exposure - Pre-conception counselling is essential - Start folic acid 5 mg daily for all women on AEDs (preferably 3 months pre-conception) - Valproate is teratogenic and should be avoided in women of childbearing potential unless no alternative (MHRA/EMA warnings) - Enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital, topiramate, primidone) can reduce efficacy of COC and emergency contraception - Pregnancy-induced changes in clearance require close monitoring and dose adjustment

11.2.1 Valproate — AVOID in Childbearing Potential

Teratogenicity — the highest risk of all AEDs:

Defect	Risk	Background Risk
Major congenital malformations	10-15% (dose-dependent; >800 mg/day worse)	2-3%
Neural tube defects (spina bifida)	1-3% (↑ 10-20×)	0.05-0.1%
Cardiac defects	2-3%	0.5%
Cleft palate	2%	0.2%
Hypospadias	2%	0.3%
Polydactyly, craniosynostosis	Various
Neurodevelopmental effects
↓ IQ (7-10 points lower)	30-40% risk of cognitive impairment	—
Autism spectrum disorder	3-5× increased risk	1%
ADHD	Increased risk
Fetal valproate syndrome	Distinct facies + malformations

Mechanism of teratogenicity: - ↓ Histone deacetylase (HDAC) inhibition → altered gene expression - ↓ Folate antagonism - ↓ Oxidative stress

MHRA Contraindication (2018): - Valproate must NOT be used in women and girls of childbearing potential unless: - No other effective treatment - PREVENT program counselling - Annual review - Pregnancy prevention plan in place

11.2.2 Carbamazepine

Mechanism: Sodium channel blocker → stabilises neuronal membranes

Pregnancy Considerations: | Issue | Detail | |---|---| | Major malformations | 3-5% (NTD ~0.5-1%, cleft palate, cardiac) | | Folate antagonism | Requires 5 mg folic acid | | Dose adjustment | ↓ levels in 3rd trimester? Monitor; may need ↑ dose | | Neonatal | Vitamin K deficiency risk (enzyme induction → ↓ vitamin K) → give mother oral vitamin K 10 mg/day from 36 weeks (NICE); IM vitamin K to neonate | | Enzyme inducer | Induces CYP3A4, CYP2C9, UGTs | | Breastfeeding | Compatible (monitor for sedation) |

Dose: 200-1600 mg/day in divided doses

11.2.3 Phenytoin

Mechanism: Sodium channel blocker

Pregnancy Considerations: | Issue | Detail | |---|---| | Major malformations | 5-10% (fetal hydantoin syndrome: cleft palate, growth restriction, dysmorphism, NTD) | | Folate antagonism | Yes — 5 mg folic acid | | Protein binding | ↓ Albumin → ↑ free fraction in pregnancy; monitor free levels | | Metabolism | ↑ Clearance in pregnancy (CYP2C9, CYP2C19 induced?) | | Dose adjustment | Need monitoring; dose may need ↑ | | Neonatal | Vitamin K deficiency (enzyme inducer) — supplement as per carbamazepine | | Breastfeeding | Compatible |

Note: Phenytoin has zero-order kinetics at therapeutic levels — small dose changes → disproportionate changes in plasma levels. TDM is essential.

11.2.4 Lamotrigine — Preferred in Pregnancy

Mechanism: Na⁺ channel blocker + ↓ glutamate release (presynaptic)

Why preferred in pregnancy: - Low teratogenic risk (~2-3% major malformations — near background) - No NTD risk (good folate safety) - No neurodevelopmental concerns (vs valproate) - No vitamin K interaction

Critical — Pregnancy dramatically increases lamotrigine clearance: - UGT1A4 (glucuronidation) is increased in pregnancy - Clearance ↑ 200-300% by 3rd trimester - Serum levels can drop by 50-70% - Seizure risk increases if dose not adjusted

Dose Management: | Period | Action | |---|---| | Pre-conception | Establish baseline level and effective dose | | 1st trimester | Monitor level monthly | | 2nd trimester | May need 1.5-2× pre-pregnancy dose | | 3rd trimester | May need 2-3× pre-pregnancy dose | | Post-partum (within 1 week) | Rapidly taper back to pre-pregnancy dose (toxic accumulation risk) |

Breastfeeding: - RID ~10-20% — but no known harm - Monitor infant for rash (though rare) - Compatible

11.2.5 Levetiracetam — Preferred Alternative

Mechanism: Binds SV2A → ↓ neurotransmitter release

Pregnancy Considerations: | Issue | Detail | |---|---| | Major malformations | ~2-3% (near background) | | Folate antagonism | No — but give 5 mg folic acid anyway | | Clearance in pregnancy | ↑ 50-100% (↑ renal CL) | | Dose adjustment | Needs increase — may need 1.5-2× by 3rd trimester | | Post-partum | Taper back rapidly | | Breastfeeding | Compatible (RID ~10%) | | Neurodevelopmental | Appears safe |

11.2.6 Topiramate

Issue	Detail
Major malformations	3-5% (cleft lip/palate ↑ 5-10×)
IUGR	↑ Risk
Enzyme inducer	Yes — affects COC efficacy
Cognitive effects	Potential neurodevelopmental delay
Not first-line in pregnancy

11.2.7 Comparison — AEDs in Pregnancy

AED	Malformation Risk	Neuro-developmental Risk	Pregnancy CL Change	Lactation Safety	Enzyme Inducer?
Valproate	10-15% (HIGHEST)	YES (↓IQ, autism)	Varied	Compatible (low transfer)	Yes (complex)
Carbamazepine	3-5% (NTD)	Mixed, less than valproate	↑	Compatible	Yes
Phenytoin	5-10%	Possible	↑ (free fraction)	Compatible	Yes
Lamotrigine	2-3% (low)	No	↑↑↑ 200-300%	Compatible	No
Levetiracetam	2-3% (low)	No	↑ 50-100%	Compatible	No
Topiramate	3-5% (cleft)	Uncertain	↑	Limited data	Yes

11.3 Eclampsia vs Epilepsy — Acute Seizure Management

Aspect	Eclampsia	Epilepsy
First-line	MgSO₄ 4g IV	Benzodiazepine (lorazepam 4mg IV, diazepam 5-10 mg IV)
Second-line	Diazepam/lorazepam if MgSO₄ fails	Phenytoin/fosphenytoin, levetiracetam
Causative treatment	Delivery	None (symptomatic)
Duration of treatment	24 hours	Single seizure; chronic AED
Fetal bradycardia	Common post-seizure (self-limiting)	Also common post-ictal
Risk of recurrence	~10-15% without MgSO₄	Variable

---

12. Antibiotics in Pregnancy

12.1 General Principles

• Most antibiotics cross the placenta (MW <500, lipophilic)
• Choose based on: Safety data, spectrum, pharmacokinetics, trimester
• Avoid in 1st trimester: Controversial; most antibiotics have adequate safety data
• Pregnancy alters pharmacokinetics of many antibiotics (↑ Vd, ↑ clearance → may need higher doses)
• Treat infections aggressively — untreated infection is more harmful than most antibiotics

12.2 Antibiotic Safety Categories

(A) SAFE — Penicillins & Cephalosporins

Penicillins: | Drug | Safety | Notes | |---|---|---| | Penicillin G/V | Safe | Pregnancy category B; decades of experience | | Amoxicillin | Safe | First-line for respiratory/UTI | | Co-amoxiclav | Safe (caution) | Theoretical NEC risk (OR 1.5-2.0 in some studies); but safe in practice | | Flucoxacillin | Safe | For mastitis, skin infections | | Piperacillin-tazobactam | Safe | Limited data but likely safe |

Cephalosporins: | Drug | Safety | Notes | |---|---|---| | Cefalexin | Safe | First-line UTI in pregnancy | | Cefuroxime | Safe | | | Ceftriaxone | Safe | Avoid if neonatal jaundice (biliary sludging) | | Cefotaxime | Safe | | | Ceftazidime | Safe | | | Cefoxitin | Safe | Used at CS prophylaxis | | Cefazolin | Safe | CS prophylaxis |

Penicillins and cephalosporins are the safest antibiotics in pregnancy — use as first-line whenever appropriate.

(B) SAFE — Macrolides

Drug	Safety	Notes
Erythromycin	Safe	Pregnancy category B; drug of choice for chlamydia in pregnancy
Azithromycin	Safe	Short course, well-tolerated; preferred in many guidelines
Clarithromycin	Avoid	Teratogenic in animal studies (cardiac defects); avoid in 1st trimester; some data in humans suggest small ↑ risk — use only if no alternative
Spiramycin	Safe	Used for toxoplasmosis

Caution: Erythromycin estolate is associated with hepatotoxicity in pregnancy — use erythromycin ethylsuccinate or base.

(C) SAFE — Metronidazole

Issue	Detail
Safety	Generally considered safe, but some guidelines advise avoid in 1st trimester (theoretical concern)
Carcinogenicity concerns	Historical concerns from animal studies (high-dose, long-term) — not confirmed in humans
Crosses placenta	Yes
Breastfeeding	Caution with 2g single dose — discard milk 12-24h
Clinical use	BV, trichomonas, anaerobic infections, PID, surgical prophylaxis

Take-home: Metronidazole is safe in pregnancy — treat BV to prevent PTD.

(D) SAFE — Clindamycin

Issue	Detail
Safety	Safe in pregnancy
Crosses placenta	Yes
Use	BV (oral or topical), GBS prophylaxis (penicillin allergy), anaerobic infections, PPROM
Caution	Pseudomembranous colitis (C. difficile)

(E) SAFE — Nitrofurantoin

Issue	Detail
Safety	Safe in 2nd and 3rd trimester
1st trimester	Small risk of malformations (anophthalmia, cleft palate? — some meta-analyses show OR 1.2-1.5); but still used if needed
At term	Avoid near term (>38 weeks) — risk of haemolytic anaemia in G6PD-deficient neonate
Mechanism	Concentrated in urine — UTI only
Use	First-line for asymptomatic bacteriuria and UTI in pregnancy (2nd trimester)

(F) CAUTION — Aminoglycosides

Drug	Risk	Notes
Gentamicin	Fetal ototoxicity (vestibular > cochlear)	Risk with prolonged high-dose courses; short courses (e.g., CS prophylaxis, sepsis) likely safe
Streptomycin	Fetal ototoxicity	Known risk from TB treatment
Neomycin	Low systemic absorption	Safe for topical use
Tobramycin	Similar to gentamicin

Recommendation: Avoid unless no alternative (severe sepsis, TB). Use short courses, monitor levels, check 8th nerve function in neonate if prolonged exposure.

(G) CONTRAINDICATED — Tetracyclines

Drug	Risk	Notes
Tetracycline	Dental discolouration (yellow/brown staining), inhibition of bone growth	Avoid from 2nd trimester onward; 1st trimester risk is lower but still avoid
Doxycycline	Same as tetracycline	Lower calcium binding — some say safer; still avoid in pregnancy
Minocycline	Same	Avoid

Mechanism of toxicity: Tetracyclines chelate calcium and are incorporated into developing teeth and bones → permanent staining, hypoplasia.

Also note: High-dose tetracycline can cause maternal hepatotoxicity (especially IV, in pregnancy).

(H) AVOID — Fluoroquinolones

Drug	Risk	Notes
Ciprofloxacin	Arthropathy in juvenile animals	Human data limited; avoid in pregnancy if alternatives exist
Levofloxacin	Same

Recommendation: Avoid unless no alternative (e.g., multidrug-resistant infection with no other options).

(I) CAUTION — Trimethoprim

Issue	Detail
Mechanism	Folate antagonist (inhibits dihydrofolate reductase)
1st trimester	Avoid — theoretical risk of NTD (folate antagonism)
Folic acid co-administration	If used, give 5 mg folic acid
Sulfamethoxazole component	Co-trimoxazole — sulfonamide risks (kernicterus at term)
Use	Avoid in pregnancy if alternatives exist

12.3 Specific Antibiotic Indications in Pregnancy

Condition	First-Line	Alternative	Notes
Asymptomatic bacteriuria	Nitrofurantoin (2nd tri), amoxicillin, cefalexin	Nitrofurantoin (avoid at term); treat 3-7 days
UTI / Acute cystitis	Nitrofurantoin, amoxicillin, cefalexin	Co-amoxiclav, pivmecillinam
Acute pyelonephritis	IV cefuroxime, ceftriaxone, gentamicin + ampicillin	Oral follow-up 7-14 days
Bacterial vaginosis	Metronidazole (oral 400 mg bd × 5-7 days) or 2% gel	Clindamycin 300 mg bd × 7 days	Treat to reduce PTD risk in high-risk women
Trichomonas	Metronidazole (2g stat or 400 mg bd × 7 days)	—	Treat partner
Candida	Clotrimazole pessary (topical)	Oral fluconazole (single 150 mg) — use only if topical fails (controversial — avoid 1st tri)
GBS prophylaxis (intrapartum)	Benzylpenicillin 3g IV stat, then 1.5g q4h	Cefazolin (if no anaphylaxis), clindamycin (if sensitive), vancomycin (if resistant)
Chlamydia	Azithromycin 1g PO stat OR erythromycin 500 mg qds × 7 days	Amoxicillin 500 mg tds × 7 days (for chlamydia in pregnancy)	Test of cure at 3-4 weeks
Gonorrhoea	Ceftriaxone 1g IM stat	Spectinomycin
Syphilis	Benzathine penicillin 2.4 million units IM weekly × 1-3 doses	Doxycycline (if non-pregnant — avoid in pregnancy); desensitise if penicillin allergy	Only penicillin treats fetal syphilis
PPROM / Preterm	Erythromycin 250 mg qds × 10 days	Co-amoxiclav — avoid (NEC risk?); penicillins	ORACLE trial — erythromycin reduced composite outcome
Endometritis (postpartum)	Gentamicin + clindamycin	Piperacillin-tazobactam
Mastitis	Flucoxacillin 500 mg qds × 7-10 days	Cefalexin, erythromycin, clindamycin
Surgical prophylaxis (CS)	Cefazolin 2g IV once (at cord clamp)	Clindamycin 600 mg + gentamicin 5 mg/kg if penicillin allergy
Toxoplasmosis	Spiramycin (1st tri)	Pyrimethamine + sulfadiazine (after 1st tri)	+ Folinic acid if pyrimethamine used
Malaria prophylaxis	Proguanil + atovaquone (Malarone) OR mefloquine (after 1st tri)	Chloroquine + proguanil (increasingly resistant)
TB treatment	Rifampicin + isoniazid + pyrazinamide + ethambutol (2 months) → rifampicin + isoniazid (4 months)	Moxifloxacin? Avoid	Add pyridoxine (B6) with isoniazid; monitor LFTs
HIV (cART)	Tenofovir disoproxil + emtricitabine + dolutegravir (first-line)	Various	All ARVs cross placenta; consider teratogenicity (dolutegravir — small NTD signal in Botswana, now considered safe)

12.4 Antibiotics & Oral Contraceptive Interaction

• Rifampicin / Rifabutin — CYP3A4 inducer → ↓ COC efficacy → use additional contraception
• Other antibiotics (penicillins, tetracyclines, macrolides) — NO proven interaction with COC despite common myth
• The historical concern about gut flora disruption → ↓ enterohepatic circulation of oestrogens is theoretically possible but not clinically significant for most antibiotics (except rifamycins)
• NICE/FSRH: No need for additional contraception with short courses of non-rifamycin antibiotics

12.5 Penicillin Allergy — Management in Pregnancy

True penicillin allergy (~10% report, but only ~1% have true IgE-mediated allergy)

Alternatives: - Non-severe (non-anaphylactic): Cephalosporins (cross-reaction risk ~1-5%; negligible with modern low-risk assessment) - Severe (anaphylaxis): Avoid cephalosporins → use clindamycin, vancomycin, gentamicin depending on indication - GBS prophylaxis with severe penicillin allergy: Clindamycin (if sensitive on AST) or vancomycin (if resistant)

---

13. Antiemetics in Pregnancy

13.1 Hyperemesis Gravidarum

Definition: Severe vomiting before 20 weeks → >5% weight loss, ketonuria, electrolyte disturbance, need for hospitalisation

Pathophysiology: - ↑ hCG (correlates with severity) - ↑ Oestrogen - Possibly Helicobacter pylori association - Genetic predisposition

13.2 Antiemetic Options

(A) Pyridoxine (Vitamin B6) + Doxylamine

Mechanism: - Pyridoxine (B6): Required for neurotransmitter synthesis; antiemetic effect not fully understood - Doxylamine: First-generation antihistamine (H₁ antagonist) — acts on vomiting centre

Evidence: - Diclectin / Xonvea (B6 10 mg + doxylamine 10 mg): First-line in many countries (Canada, USA, UK NICE 2023 now recommends) - Effective in RCTs — reduces nausea and vomiting - Safe in pregnancy (decades of data) - No teratogenicity

Dosing: 1 tab PO qhs initially, increase to 1 tab am, 1 tab pm if needed (max 4 tabs/day)

Side Effects: Drowsiness (doxylamine) — take at night initially

(B) Cyclizine

Mechanism: H₁ receptor antagonist (piperazine class) — antiemetic via vomiting centre

Evidence: Safe in pregnancy; used for decades

Dosing: 50 mg PO/IV/IM q6-8h PRN

Side Effects: Drowsiness (less than promethazine), dry mouth, blurred vision

Safety: Good data — safe in all trimesters

(C) Promethazine

Mechanism: H₁ antagonist (phenothiazine)

Dosing: 25 mg PO/IV/IM q6-8h

Side Effects: Prominent sedation (more than cyclizine), dry mouth, extrapyramidal reactions (rare)

Safety: Safe in pregnancy

(D) Prochlorperazine

Mechanism: Dopamine D₂ antagonist (phenothiazine) — antiemetic via CTZ

Dosing: 5-10 mg PO/IM q6-8h PRN; buccal 3-6 mg bd

Side Effects: Extrapyramidal (dystonia, akathisia, Parkinsonism) — especially acute dystonia with IV; sedation

Safety: Safe in pregnancy

(E) Metoclopramide

Mechanism: D₂ antagonist + 5-HT₃ antagonist (weak) + 5-HT₄ agonist → ↑ GI motility + antiemetic

Dosing: 10 mg PO/IV/IM q8h PRN (max 30 mg/day)

Evidence: Safe in pregnancy (large Danish cohort — no major teratogenicity)

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Extrapyramidal (acute dystonia) | ~0.2% (more in young women) | Dystonic reactions, oculogyric crisis; give procyclidine/benztropine | | Sedation | Common | | | Diarrhoea | Common (↑ GI motility) | | | Galactorrhoea | D₂ block → ↑ prolactin | With prolonged use | | Tardive dyskinesia | Prolonged use (avoid >12 weeks) | Black box warning — avoid long-term | | Restlessness / akathisia | Less common | |

Recommendation: Avoid high doses and prolonged courses (>5 days) due to EPS risk. Safe for PRN use.

(F) Ondansetron

Mechanism: 5-HT₃ receptor antagonist — blocks serotonin at CTZ and vagus nerve

Dosing: 4-8 mg PO/IV/IM q8h PRN (max 24 mg/day); 8 mg IV for severe cases; oral dissolving tablets available

Evidence: - Effective — strong antiemetic, used as second/third-line in hyperemesis - Safety: The great debate

Safety Concerns:

Issue	Data	Interpretation
Cleft palate	Some meta-analyses show small ↑ risk (OR 1.2-1.5) in 1st trimester	If real, absolute risk increase is <0.1%; still very small
Cardiac defects	Some signal in some studies, not confirmed	Uncertain
QT prolongation	Yes — dose-dependent	Avoid if electrolyte imbalance (K⁺, Mg²⁺) or other QT-prolonging drugs; max single dose 16 mg IV (FDA)
Serotonin syndrome	Rare	With other serotonergic drugs

Current Recommendations: - NICE (2023): Ondansetron is safe to use in pregnancy for hyperemesis - RCOG: Use as second-line after first-line agents (cyclizine, promethazine, metoclopramide) - FDA: Warns of risk of cleft (OR 1.3) — advises prescribing only when other agents have failed - Practical: Use selectively in severe hyperemesis; avoid in 1st trimester if alternatives work; ensure normal electrolytes

(G) Corticosteroids for Severe Hyperemesis

Evidence: Dexamethasone 8-12 mg IV/IM daily or prednisolone 40-60 mg PO daily for refractory cases

Mechanism: Not fully understood; may ↓ hCG-induced vomiting

Caution: - Avoid in 1st trimester if possible (theoretical cleft palate risk) - Usually reserved for severe refractory hyperemesis after 10+ weeks - Use lowest effective dose, shortest duration - Side effects: hyperglycaemia, insomnia, infection risk, osteoporosis risk (prolonged)

13.3 Comparison — Antiemetics for Pregnancy

Drug	Route	Onset	First/Second-Line	Teratogenic	Key Side Effect
Pyridoxine + doxylamine	PO	30-60 min	First-line	No	Drowsiness
Cyclizine	PO/IV/IM	20-60 min	First-line	No	Drowsiness
Promethazine	PO/IV/IM	20-60 min	First-line	No	Marked sedation
Prochlorperazine	PO/IM/buccal	30-60 min	First/second	No	EPS, sedation
Metoclopramide	PO/IV/IM	15-30 min	First/second	No	EPS (avoid long-term)
Ondansetron	PO/IV	15-30 min	Second-line	Minimal risk (cleft)	QT prolongation, constipation
Dexamethasone	IV/IM/PO	Hours	Third-line (refractory)	Small cleft risk (1st tri)	Hyperglycaemia, infection

13.4 Ginger

• Evidence: Some RCTs show benefit comparable to mild antiemetics
• Dose: 250 mg qds (capsules or fresh ginger)
• Safety: Safe in pregnancy
• Limitation: Weak efficacy compared to pharmacological agents

---

14. Thyroid Medications in Pregnancy

14.1 Physiological Changes in Pregnancy

Parameter	Non-Pregnant	Pregnant	Clinical Significance
TBG (thyroid binding globulin)	12-18 mg/L	↑ 2-3× (due to oestrogen)	↑ Total T4 but free T4 unchanged (in euthyroid)
Total T4	64-150 nmol/L	↑ 1.5×	Do not use total T4 to assess thyroid status
Free T4	9-22 pmol/L	Slight ↓ (lower end of normal)	The key test in pregnancy — use trimester-specific ranges
TSH	0.5-4.0 mU/L	↓ (hCG stimulates TSH-R)	Lower in 1st trimester (0.03-2.5 mU/L)
Renal iodide clearance	Normal	↑ 50%	Relative iodine deficiency if intake inadequate

14.2 Hypothyroidism — Levothyroxine

Pharmacokinetics: - L-T4 (synthetic T4) — identical to endogenous - Absorption: 60-80% (oral); variable with food, iron, calcium - Half-life: ~7 days (non-pregnant) — decreases in pregnancy - Crosses placenta: Limited (placental deiodinases inactivate T4 to reverse T3)

Dose Management in Pregnancy: | Period | Action | |---|---| | Pre-conception | Optimise dose to achieve TSH 0.3-2.5 mU/L | | Pregnancy (0-12 weeks) | Increase dose by 30-50% (immediately) — increased TBG, increased degradation, increased Vd | | Titration | Check TSH every 4-6 weeks; adjust L-T4 by 25-50 μg increments | | 2nd trimester | Usually need 40-50% above pre-pregnancy dose | | 3rd trimester | May need 50-60% above pre-pregnancy dose | | Post-partum | Reduce to pre-pregnancy dose (within 4 weeks); monitor TSH at 6 weeks |

Target TSH in Pregnancy: - 1st trimester: 0.3-2.5 mU/L - 2nd trimester: 0.3-3.0 mU/L - 3rd trimester: 0.3-3.5 mU/L

Drug Interactions Affecting L-T4 Absorption: | Drug | Timing | Action | |---|---|---| | Iron supplements | Chelate T4 | Separate by ≥4 hours | | Calcium supplements | Chelate T4 | Separate by ≥4 hours | | Magnesium | Chelate T4 | Separate by ≥4 hours | | PPIs, antacids | ↑ Gastric pH → ↓ T4 absorption | Separate by ≥4 hours | | Sucralfate | Binds T4 | Separate by ≥4 hours | | Soy, fibre | ↓ Absorption | Maintain consistent intake |

14.3 Hyperthyroidism — Antithyroid Drugs

Property	Carbimazole (CBZ)	Propylthiouracil (PTU)
Mechanism	Inhibits thyroid peroxidase	Inhibits TPO + blocks T4→T3 conversion
Crosses placenta	Yes	Yes (but less than CBZ)
Transfer to milk	Low	Low
Half-life	6-8 hours (active metabolite)	1-2 hours (short)
Onset	2-4 weeks	2-4 weeks
Dosing	5-40 mg/day	200-800 mg/day

Teratogenicity:

Drug	Malformation	Risk
Carbimazole	Aplasia cutis congenita (scalp defect) — characteristic	~1%
Carbimazole	Choanal atresia, tracheo-oesophageal fistula, dysmorphic facies (CBZ embryopathy)
PTU	Lower teratogenicity overall	Preferred in 1st trimester
PTU	Hepatotoxicity (rare but severe — may need transplant)	Risk: 1-3/10,000; preferred in 1st tri but switch back

Management Algorithm:

Period	Recommendation	Rationale
Pre-conception	Discuss risks; ideally euthyroid before pregnancy
1st trimester	PTU (preferred) — lower teratogenicity	CBZ → aplasia cutis, choanal atresia
After 1st trimester	Switch to carbimazole (some guidelines); or stay on PTU depending on ADA recommendations	PTU hepatotoxicity risk; both require LFT monitoring
Both drugs	Use lowest dose to maintain free T4 at upper normal limit	Avoid fetal hypothyroidism (goitre, intellectual impairment)
Post-partum	May reduce dose; risk of post-partum thyroiditis

Monitoring: - Free T4 every 2-4 weeks until stable, then q4-6 weeks - Target: Free T4 at or just above upper limit of normal - Do not target TSH (remains suppressed for months in pregnancy) - LFTs on PTU (monitor for hepatotoxicity) - FBC (risk of agranulocytosis — rare <0.5% for both drugs)

Neonatal Effects: - Fetal/neonatal goitre if maternal doses too high - Monitor neonate for transient hyperthyroidism (stimulated by maternal TRAb) or hypothyroidism (drug-induced) - Cord blood TSH at delivery

14.4 Beta-Blockers for Thyroid Storm

• Propranolol — non-selective β-blocker; 40 mg PO q6h
• Controls tachycardia, anxiety, tremor
• Also blocks T4→T3 conversion (high dose)
• Safe for short-term use in pregnancy
• Monitor for fetal bradycardia, IUGR

---

15. Antidiabetic Drugs in Pregnancy

15.1 Insulin

The gold standard for pregestational diabetes and GDM when diet fails:

Insulin Type	Onset	Peak	Duration	Use in Pregnancy
Rapid-acting analogues
Aspart (NovoRapid)	5-15 min	30-90 min	3-5 h	First choice — safe, ↓ hypoglycaemia vs regular insulin
Lispro (Humalog)	5-15 min	30-90 min	3-5 h	First choice — safe, ↓ hypoglycaemia
Glulisine (Apidra)	5-15 min	30-90 min	3-5 h	Limited data
Short-acting
Regular (soluble)	30-60 min	2-3 h	6-8 h	Safe but more hypoglycaemia than analogues
Intermediate-acting
NPH (isophane)	2-4 h	4-8 h	10-18 h	Safe; bedtime dosing covers fasting needs
Long-acting analogues
Detemir (Levemir)	1-2 h	Flat	12-24 h	Safe in pregnancy (RCT data)
Glargine (Lantus)	2-4 h	Flat	20-24 h	Large experience; considered safe (but no RCT in pregnancy)
Degludec (Tresiba)	30-90 min	Flat	>42 h	Limited pregnancy data

Pharmacokinetics in Pregnancy: - ↑ Clearance of exogenous insulin (increased degradation by placental insulinase) - ↑ insulin resistance (human placental lactogen, prolactin, cortisol, oestrogen, progesterone) - Insulin requirements: - 1st trimester — stable or ↓ (morning sickness, ↓ intake) - 2nd trimester — ↑ 50-100% (increasing placental hormones) - 3rd trimester — ↑ 100-200% from pre-pregnancy (peak ~36 weeks) - Post-partum — Immediately ↓ to pre-pregnancy dose (50-80% reduction); monitor for hypoglycaemia

Management Approach: - Bolus-basal regimen: Rapid-acting (meals) + long-acting (basal) - Multiple daily injections or insulin pump (CSII) - Capillary blood glucose targets: - Fasting: 3.5-5.3 mmol/L - 1-hour post-prandial: <7.8 mmol/L - 2-hour post-prandial: <6.4 mmol/L

15.2 Metformin

Mechanism: Insulin sensitiser (AMPK activation) → ↓ hepatic gluconeogenesis, ↑ peripheral glucose uptake

Use in Pregnancy:

Condition	Recommendation	Evidence
GDM	First-line oral agent (NICE, 2023)	Metformin in GDM has good safety data
Type 2 diabetes	Continue metformin (or start if required)	Reduces insulin needs; fewer macrosomia vs insulin?
PCOS	For ovulation induction — stop once pregnant (some continue)	No teratogenicity

Pharmacokinetics: - Crosses placenta (concentrations ~50-100% of maternal) - Half-life: ~6 hours (↑ with renal impairment) - Excretion: Renal (unchanged)

Safety: - No teratogenicity (large cohort studies) - No increase in major malformations - May be associated with ↑ prematurity? (confounded by indication — women on metformin have more comorbidities) - May modestly reduce maternal weight gain, macrosomia, LGA (vs insulin in some studies) - Neonatal: No long-term adverse outcomes at 2-year follow-up (MiG TOFU study)

Side Effects: | Effect | Frequency | Notes | |---|---|---| | GI intolerance (nausea, diarrhoea) | 20-30% | Start low, go slow; use MR formulation | | Lactic acidosis | Rare (<0.01%) | Avoid if renal impairment, sepsis, hypoxia | | B12 deficiency | Chronic use | Monitor B12 on long-term therapy | | Hypoglycaemia | Rare (when used alone) | Not an insulin secretagogue |

Limitations: - ~30-40% of GDM women will need supplemental insulin - Not as effective as insulin for tight glycaemic control in severe hyperglycaemia

15.3 Glibenclamide (Glyburide)

Mechanism: Sulfonylurea — ↑ insulin secretion (K-ATP channel blocker)

Pregnancy Data: - Crosses placenta (significant transfer — contrary to earlier belief) - Avoid in pregnancy (NICE: not recommended) - Higher rates of macrosomia, neonatal hypoglycaemia, neonatal jaundice vs insulin/metformin - Less effective than metformin (and more side effects) - Not recommended in pregnancy

15.4 Other Oral Hypoglycaemics — LIMITED DATA

Drug	Class	Pregnancy Data	Recommendation
Glipizide	Sulfonylurea	Limited	Avoid
Pioglitazone	TZD	Avoid (weight gain, fluid retention — theoretical)	Avoid
Acarbose	α-glucosidase inhibitor	Limited	Avoid
DPP-4 inhibitors (sitagliptin, etc.)		No human data	Avoid
SGLT2 inhibitors (dapagliflozin, empagliflozin)		No human data; animal toxicity (↑ neonatal death)	Contraindicated
GLP-1 agonists (liraglutide, semaglutide)		No human data	Contraindicated (weight loss in pregnancy harmful)

15.5 Corticosteroid-Induced Hyperglycaemia in Pregnancy

• Common in women receiving antenatal corticosteroids for fetal lung maturity
• Betamethasone and dexamethasone → transient hyperglycaemia (24-72 hours)
• Management:
• Monitor blood glucose q2-4h for 24 hours
• If pre-existing diabetes — increase insulin by 30-50% for 48-72 hours
• If GDM — start supplemental insulin if glucose consistently >7.8 mmol/L
• Usually self-limiting (resolves in 48-72h)

---

16. Anticoagulants in Pregnancy

16.1 Physiological Changes in Coagulation

Parameter	Change	Consequence
Procoagulant factors (I, VII, VIII, IX, X, XII, vWF)	↑↑	Hypercoagulable state
Natural anticoagulants (Protein S)	↓ 50%	Decreased anticoagulation
Fibrinolysis	↓ (PAI-1, PAI-2 ↑)	Decreased clot breakdown
Venous stasis	↑ (progesterone, compression)	Increased VTE
Platelet count	Usually stable (↓ in preeclampsia)

16.2 Low Molecular Weight Heparin (LMWH) — Gold Standard

Drug	Dose for Treatment	Dose for Prophylaxis	Half-Life
Enoxaparin	1.5 mg/kg SC od OR 1 mg/kg SC bd	40 mg SC od	4-5 h
Dalteparin	200 IU/kg SC od OR 100 IU/kg SC bd	5000 IU SC od	3-5 h
Tinzaparin	175 IU/kg SC od	3500-4500 IU SC od	4-5 h

Advantages in Pregnancy: - Does not cross placenta (MW >5000 Da) — safe for fetus - No teratogenicity - No fetal haemorrhage risk - No need for monitoring in most cases - Reversible with protamine (80% effective) - Lower risk of HIT than UFH - Lower risk of osteoporosis than UFH (still risk with prolonged use, but less)

Pharmacokinetics in Pregnancy: - ↑ Vd (↑ plasma volume) → may need higher weight-based doses - ↑ Renal clearance (↑ GFR) → may shorten half-life → twice-daily dosing recommended by some experts for VTE treatment in pregnancy - Anti-Xa monitoring: Not routine but consider in extremes of body weight or renal impairment - Target: ~0.5-1.0 IU/mL for treatment (4h post-dose)

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Haemorrhage | 1-2% (treatment dose) | Reversal: protamine (sulfate) 1 mg per 100 IU enoxaparin | | Bruising/hematoma | Very common | Injection site | | Heparin-induced thrombocytopenia (HIT) | <0.1% (LMWH) | More with UFH | | Osteoporosis | ~2-5% (prolonged >6 months) | Less than UFH; use calcium + vitamin D | | Skin reactions | 5-10% | Delayed-type hypersensitivity; may switch to alternative LMWH | | Hepatic transaminitis | ~5% | Reversible |

16.3 Unfractionated Heparin (UFH)

Use in Pregnancy: Limited; still used in: - Renal impairment (CrCl <30) — LMWH accumulates - Near term (some protocols switch at 36-37 weeks) - Women who decline LMWH (twice daily vs once daily for treatment) - HIT (use non-heparin alternatives)

Differences from LMWH: - Crosses placenta: No (also high MW) - Half-life: 1-2 hours (shorter) - Monitoring: aPTT (therapeutic 1.5-2.5× control) — pregnancy alters aPTT - Reversal: Protamine 1 mg per 100 U (full neutralisation) - HIT risk: ~3% (higher than LMWH) - Osteoporosis risk: Higher with prolonged UFH (>2-5% at 6 months)

16.4 Warfarin — AVOID IN PREGNANCY

Mechanism: Vitamin K antagonist → inhibits factors II, VII, IX, X

Hazards: | Trimester | Risk | Details | |---|---|---| | 1st (6-12 weeks) | Warfarin embryopathy | Nasal hypoplasia, stippled epiphyses; 5-30% risk — highest at 6-12 weeks | | 2nd/3rd | Fetal haemorrhage, CNS defects | CNS abnormalities, optic atrophy, microcephaly, intellectual disability | | Any | Fetal loss, IUGR | Increased risk | | Labour | Fetal retroplacental haemorrhage | Avoid vaginal delivery on warfarin — risk of fetal intracranial bleed |

Use in Pregnancy: - Contraindicated in pregnancy except for women with mechanical heart valves (and even then, careful counselling and switch to LMWH in 1st trimester often recommended) - If warfarin cannot be avoided: Switch to LMWH for 1st trimester (6-12 weeks critical), or use warfarin throughout with very careful monitoring (INR 2.0-3.0)

Breastfeeding: Safe — does not transfer into milk (highly protein-bound)

16.5 Direct Oral Anticoagulants (DOACs) — AVOID

Drug	Class	Pregnancy Data
Rivaroxaban	Direct factor Xa inhibitor	Avoid — no human pregnancy data; animal toxicity (fetotoxicity, placental haemorrhage)
Apixaban	Direct factor Xa inhibitor	Avoid — same concerns
Edoxaban	Direct factor Xa inhibitor	Avoid
Dabigatran	Direct thrombin inhibitor	Avoid

Recommendation: DOACs are contraindicated in pregnancy, in women of childbearing potential not using contraception (note uncertainty), and during breastfeeding.

16.6 Fondaparinux

• Synthetic pentasaccharide — indirect factor Xa inhibitor via antithrombin
• Crosses placenta (MW ~1700 Da) — limited human pregnancy data
• Use in pregnancy only if HIT and cannot use danaparoid

16.7 Thrombolysis in Pregnancy

Indications: Massive PE with haemodynamic instability (rare)

Drugs: - Alteplase (tPA): 100 mg IV over 2h - Streptokinase: 1.5 million IU over 60 min

Risks: - Maternal haemorrhage (especially uterine/retroplacental) — 1-5% - Fetal loss, preterm labour, placental abruption - Still used as life-saving therapy (benefit > risk in massive PE)

16.8 Management Specifics

Condition	Anticoagulant	Duration
VTE in pregnancy (proximal DVT/PE)	LMWH (treatment dose)	Min 3 months + until 6 weeks post-partum (minimum total 6 months)
Previous VTE on long-term warfarin	Switch to LMWH (treatment dose)	Throughout pregnancy
Thrombophilia (high-risk) — no VTE	LMWH (prophylactic)	Throughout pregnancy + 6 weeks post-partum
Thrombophilia (low-risk) — no VTE	Surveillance or LMWH	Individualised
Antiphospholipid syndrome (APS)	LMWH (prophylactic/treatment) + aspirin 75 mg	Throughout pregnancy + 6 weeks post-partum
Mechanical heart valve	LMWH (adjusted dose monitoring anti-Xa) OR warfarin (selected cases)	Throughout pregnancy
Recurrent miscarriage + thrombophilia	LMWH (prophylactic) + aspirin	Throughout pregnancy
Caesarean section prophylaxis	LMWH (prophylactic) × 5-7 days	Post-partum
Post-partum VTE prevention (high risk)	LMWH (prophylactic) × 6 weeks	Post-partum

---

17. Contraceptive Pharmacology

17.1 Combined Oral Contraceptive (COC)

Components: Ethinylestradiol (EE) 20-35 μg + progestogen

Mechanism of Action: 1. Ovulation inhibition — oestrogen + progestogen suppress FSH and LH via negative feedback on hypothalamus/pituitary 2. Endometrial atrophy — progestogen-induced thinning (less receptive to implantation) 3. Cervical mucus thickening — progestogen thickens mucus → sperm barrier

Pharmacokinetics of EE: - Absorption: Rapid, complete - First-pass: ~50-60% (gut + liver) - Half-life: ~10-15 hours - Metabolism: CYP3A4 (major) + glucuronidation, sulphation - Enterohepatic circulation: EE undergoes enterohepatic recirculation → contributes to sustained levels

Progestogen Generations:

Generation	Examples	Androgenicity	Metabolic Effects
1st	Norethisterone (norethindrone)	++	↑ LDL, ↓ HDL (worst lipid profile)
2nd	Levonorgestrel	+	Some impact on lipids
3rd	Desogestrel, gestodene, norgestimate	± (low)	Better lipid profile; but ↑ VTE risk vs 2nd gen
4th	Drospirenone	Anti-androgenic	Antimineralocorticoid (K⁺ retention — avoid with K⁺ sparing diuretics, renal disease); no weight gain; slightly ↑ VTE vs 2nd gen
4th	Dienogest	Anti-androgenic	Used for endometriosis
4th	NOMAC (nomegestrol)	Anti-androgenic

VTE Risk:

Status	Risk (per 10,000 woman-years)
Non-user, non-pregnant	~2
Pregnancy / post-partum	~30-60
COC (2nd gen)	~5-7
COC (3rd/4th gen)	~9-12
Obese (BMI >30) + COC	~15-25

Drug Interactions with COC: | Type | Effect | Mechanism | |---|---|---| | Rifampicin, rifabutin | ↓ COC efficacy → breakthrough bleeding, pregnancy | CYP3A4 induction (strong) | | Carbamazepine, phenytoin, phenobarbital, primidone, topiramate, oxcarbazepine | ↓ COC efficacy | CYP3A4/2C9 induction | | St John's Wort | ↓ COC efficacy | CYP3A4 induction | | HIV protease inhibitors | Variable (some ↑, some ↓) | Mixed CYP effects | | Griseofulvin | ↓ COC efficacy | CYP induction | | Lamotrigine | EE ↓ lamotrigine levels by 50% | UGT induction → seizure risk | | Antibiotics (non-rifamycin) | No clinically significant interaction | Myth debunked — no need for additional contraception |

FSRH Guidance on COC + Antibiotic Interaction: - Short courses of non-rifamycin antibiotics: No additional contraception needed - Rifamycin antibiotics (rifampicin, rifabutin): Use additional barrier method AND temporary method (POP/CIC/COC) for duration + 28 days

17.2 Progestogen-Only Pill (POP)

Types:

Type	Progestogen	Dose	Window	Ovulation Inhibition?
Traditional POP	Norethisterone	350 μg	3 hours	No (inconsistent)
	Levonorgestrel	30 μg	3 hours	No
Desogestrel (Cerelle/Cerazette)	Desogestrel	75 μg	12 hours	Yes (in 97% of cycles)

Mechanism: - Cervical mucus thickening (primary — all POPs) - Endometrial atrophy - Ovulation inhibition (desogestrel only — consistent) - Tubal motility alteration

Drug Interactions: Same enzyme inducers as COC — desogestrel POP efficacy reduced; use barrier methods

17.3 Long-Acting Reversible Contraception (LARC)

(A) Etonogestrel Implant (Nexplanon/Implanon)

• Duration: 3 years
• Progestogen: Etonogestrel (active metabolite of desogestrel)
• Mechanism: Ovulation inhibition (99%+), cervical mucus
• Pearl Index: 0.05 (most effective contraceptive method)
• Pharmacokinetics:
• Implant releases ~60-70 μg/day initially, tapering to ~25-30 μg/day at 3 years
• Levels remain above ovulation suppression threshold
• Drug interactions: Enzyme inducers → ↓ levels → may reduce efficacy (consider shortening interval to 2 years)
• Side effects: Irregular bleeding (common), amenorrhoea (~20%), weight gain, breast tenderness, mood changes
• Return to fertility: Immediate on removal

(B) Levonorgestrel IUS (Mirena/Kyleena/Levosert/Jaydess)

IUS	Duration	LNG Content	Release Rate	Indications
Mirena	5 years (some evidence up to 7)	52 mg	20 μg/day	Contraception, menorrhagia, endometrial protection
Levosert	6 years	52 mg	20 μg/day	Contraception
Kyleena	5 years	19.5 mg	17.5 μg/day	Contraception (lower dose)
Jaydess (Skyla)	3 years	13.5 mg	14 μg/day	Contraception (lower dose, smaller)

Mechanism: - Endometrial suppression (primary) — atrophies endometrium - Cervical mucus thickening - Sperm dysfunction in uterine cavity - Ovulation inhibition — NOT consistently (some cycles may be ovulatory with Mirena; less with higher doses) - Non-contraceptive benefits: - ↓ Menstrual blood loss (90% reduction with Mirena) - Treatment of menorrhagia, dysmenorrhoea, endometriosis - Endometrial protection (with oestrogen HRT — Mirena) - Reduction in heavy bleeding with fibroids

Pharmacokinetics: - LNG released directly into uterine cavity → high local effect - Serum levels: ~150-200 pg/mL (Mirena) — much lower than LNG implants/systemic - Systemic effects minimised (but some absorption occurs)

(C) DMPA (Depo-Provera) — Intramuscular

Parameter	Detail
Progestogen	Medroxyprogesterone acetate (MPA) 150 mg
Route	IM (deep gluteal/deltoid)
Frequency	Every 12 weeks (± 2 weeks)
Mechanism	Ovulation inhibition (via gonadotrophin suppression) + cervical mucus
Pearl Index	0.2 (typical use higher — delays)
Onset	Immediate if given within first 5 days of cycle
Return to fertility	Delayed — average 10 months (range up to 18 months)

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Menstrual changes | 100% (irregular → amenorrhoea at 1 year in 50-70%) | Main reason for discontinuation | | Weight gain | 2-3 kg average at 1 year | Concern for adolescents | | Bone mineral density (BMD) loss | ~3-7% over 5 years | Reversible on discontinuation; FDA/EMA: use beyond 2 years only if other methods unsuitable; no increased fracture risk in cohort studies | | Mood changes | Variable | | | Headaches | Common | | | Osteoporosis risk | Theoretical (prolonged hypo-oestrogenic state) | BMD recovers after stopping |

Drug Interactions: Enzyme inducers → theoretical ↓ efficacy (but ovulation suppression robust — no need for adjustment)

17.4 Emergency Contraception

Method	Mechanism	Window	Efficacy	Notes
Ulipristal acetate (UPA) — ellaOne	Progesterone receptor modulator — delays/ inhibits ovulation; may also prevent implantation	Up to 120 hours (5 days)	Most effective oral EC (OR less than LNG) — effective even in ovulatory phase	Requires prescription; do not use with progestogen-containing methods in same cycle
Levonorgestrel (LNG) — Plan B, Levonelle	Delays ovulation (if given before LH surge); ineffective if LH surge has started	Up to 72 hours	Efficacy decreases with time (95% if <24h, 85% if 24-72h)	OTC (pharmacy); less effective than UPA
Cu-IUD (copper intrauterine device)	Toxic to sperm/ovum — copper ions prevent fertilisation and implantation	Up to 5 days (or up to 5 days after ovulation)	>99% effective — best EC method	Also provides ongoing contraception; can be used as LARC

Pharmacokinetics of UPA: - Onset: Rapid absorption; Tmax ~1-2h - Half-life: ~32 hours - Metabolism: CYP3A4 - Drug interaction: CYP3A4 inducers (including enzyme-inducing AEDs) may ↓ UPA efficacy — consider Cu-IUD instead - BMI considerations: - LNG EC: Efficacy ↓ with BMI >26; ineffective if BMI >30 → use Cu-IUD or UPA - UPA EC: Some ↓ in efficacy with BMI >30; still recommended; Cu-IUD preferred if BMI >30 - Cu-IUD EC: No BMI limitation — equally effective at any weight

Comparison of Oral EC Options:

Parameter	LNG (Levonelle)	UPA (ellaOne)
Window	Up to 72h	Up to 120h
Regimen	1.5 mg single dose	30 mg single dose
If already ovulated	Ineffective	Moderate efficacy (can delay ovulation even after LH start)
Bleeding after EC	Next period may come early	Next period may be delayed by ~2-5 days
Repeat use	No safety concern	Not for repeated use (may alter cycle)
Interactions	Induced by enzyme inducers	Induced by enzyme inducers
BMI >26	Less effective	Still effective (some ↓ at BMI >30)
BMI >30	Ineffective	Consider Cu-IUD instead
Prescription	OTC (pharmacy)	Pharmacy/Prescription (UK: OTC since 2022 in some areas)

17.5 Contraception & Enzyme-Inducing AEDs

AED	Enzyme Inducer?	Effect on COC/POP/	Effect on Emergency Contraception
Phenytoin	Yes (strong — CYP3A4, 2C9, 2C19)	↓ Efficacy	Use Cu-IUD (UPA may be less effective — double dose? not studied)
Carbamazepine	Yes (strong)	↓ Efficacy	Same as above
Phenobarbital, primidone	Yes (strong)	↓ Efficacy	Same as above
Topiramate (>200 mg)	Yes (mild-moderate)	↓ Efficacy	Same as above
Oxcarbazepine	Yes (mild-moderate at high doses)	↓ Efficacy	Same as above
Lamotrigine	No (but COC ↓ lamotrigine levels)	↓ Lamotrigine efficacy (seizure risk)↑	Safe
Levetiracetam	No	No interaction	Safe
Valproate	No (inhibitor)	No interaction	Safe
Zonisamide	No	No interaction	Safe
Gabapentin, pregabalin	No	No interaction	Safe

Management: - Women on enzyme-inducing AEDs: Avoid COC/POP (unless using very high dose COC — 50 μg EE — and 3-week cycle) - Preferred methods: Mirena IUS, Cu-IUD, DMPA, implant (some theoretical ↓ efficacy with implant — consider 2-year replacement) - Emergency contraception: Cu-IUD is first choice; UPA may be less effective (double dose? — not recommended currently)

17.6 Contraception & Post-Partum Period

Method	Timing of Initiation	Lactation Safety
Lactational amenorrhoea (LAM)	Immediate if exclusive BF, <6 months, no menses	Safe; 98% effective if all criteria met
POP (desogestrel)	Day 21 post-partum (UK) — immediate if not breastfeeding	Safe (no effect on milk supply)
COC	Day 21 if no VTE risk; not if breastfeeding <6 weeks	↓ Milk supply, ↓ duration of BF — avoid in breastfeeding or delay until 6 weeks
Cu-IUD	Within 48h or after 4 weeks	Safe
LNG-IUS	Within 48h or after 4 weeks	Safe
Implant	Day 21 (or immediately if not BF)	Safe
DMPA	Day 21 (or immediately if not BF)	Safe
Progestogen-only EC	Same cycle	Safe
UPA EC	Same cycle (discard milk 1 week — but unnecessary if single use)	Theoretical concern — discard milk for 1 week; but benefits outweigh minimal risk

---

18. Chemotherapy in Gynaecological Cancers

18.1 General Principles

Important: Pregnancy and chemotherapy is a complex issue — most cytotoxic drugs are teratogenic especially in 1st trimester. Chemotherapy in pregnancy is reserved for life-threatening maternal cancers and given only after 14 weeks if possible.

Key classes used in gynaecological oncology:

18.2 Platinum-Based Agents

(A) Cisplatin

Mechanism: Forms DNA crosslinks (intrastrand > interstrand) → inhibition of DNA replication/transcription → apoptosis

Pharmacokinetics: | Parameter | Value | |---|---| | Route | IV | | Half-life | 20-30 min (initial); 20-30 hours (terminal) | | Elimination | Renal (>90% unchanged) | | Protein binding | >90% (irreversible) | | Vd | ~15 L/m² |

Clinical Use: - Ovarian cancer (primary + recurrent) - Cervical cancer (with radiation — chemoradiation) - Endometrial cancer (some regimens) - Germ cell tumours

Dose: 50-100 mg/m² IV q3-4weeks

Side Effects — SIGNIFICANT:

Toxicity	Frequency	Management
Nephrotoxicity	Dose-limiting — 30-50%	Hydration (mannitol, aggressive IV fluids before/after); ↑↑ Cr, ↓ Mg, ↓ K, ↓ Ca
Peripheral neuropathy	30-70% (dose-dependent)	Dose-limiting; can be irreversible (sensory > motor); can worsen after treatment stops
Ototoxicity	10-30%	High-frequency hearing loss; tinnitus; irreversible
Nausea/vomiting	>90%	Highly emetogenic — give 5-HT₃ antagonist + NK1 antagonist + dexamethasone
Myelosuppression	Moderate	Neutropenia, thrombocytopenia, anaemia
Electrolyte disturbances	Hypomagnesaemia, hypocalcaemia, hypokalaemia	Replace aggressively
Allergic reactions	5-10% (especially after multiple cycles)	Premedicate; may need desensitisation
Gonadal toxicity	Ovarian failure	Consider fertility preservation

Cisplatin vs Carboplatin:

Parameter	Cisplatin	Carboplatin
Mechanism	Same (DNA crosslinking)	Same
Dose-limiting toxicity	Nephrotoxicity, neuropathy, ototoxicity	Myelosuppression (thrombocytopenia)
Emesis	More	Less
Nephrotoxicity	Major	Minimal
Neurotoxicity	Major	Mild
Ototoxicity	Major	Minimal
Route	IV (needs extensive hydration)	IV (shorter infusion, less prehydration)
Dosing	Based on BSA	Based on Calvert formula (target AUC)
Renal impairment	Avoid	Dose reduce (calvert formula accounts for CrCl)
Equivalent AUC	—	AUC 5-7 (ovarian)
Cost	Lower	Higher

Calvert Formula for Carboplatin: $$\text{Dose (mg)} = \text{Target AUC} \times (GFR + 25)$$

Where GFR = creatinine clearance (Cockcroft-Gault or measured), and target AUC = 5-7 for ovarian cancer (5-6 for first-line, 7 for relapsed).

(B) Carboplatin

Mechanism: Same as cisplatin

Clinical Use: - First-line ovarian cancer (with paclitaxel) — often preferred over cisplatin due to better tolerability - Cervical cancer (alternative to cisplatin) - Relapsed ovarian cancer

Dosing: AUC 5-7 IV q3-4weeks

Side Effects: | Toxicity | Notes | |---|---| | Myelosuppression (thrombocytopenia >> neutropenia) | Dose-limiting — monitor FBC closely | | Nausea/vomiting | Moderate emetogenicity (less than cisplatin) | | Nephrotoxicity | Minimal (much less than cisplatin) | | Neuropathy | Mild (much less than cisplatin) | | Ototoxicity | Rare | | Allergic/hypersensitivity | 10-20% after multiple cycles (especially >6 cycles) — premedicate, desensitise |

18.3 Taxanes

(A) Paclitaxel (Taxol)

Mechanism: Microtubule stabiliser — binds β-tubulin → prevents depolymerisation → mitotic arrest → apoptosis

Pharmacokinetics: | Parameter | Value | |---|---| | Route | IV (over 3h or 24h) | | Half-life | 5-50 hours (biphasic) | | Metabolism | CYP3A4 + CYP2C8 → biliary excretion | | Protein binding | 89-98% | | Vd | ~100 L/m² (large — tissue binding) |

Clinical Use: - Ovarian cancer (first-line with carboplatin) - Breast cancer (also for gynae) - Endometrial cancer - Cervical cancer (some regimens)

Dose: 175 mg/m² IV over 3h q3weeks (or weekly dosing 80 mg/m²)

Side Effects:

Toxicity	Frequency	Notes
Peripheral neuropathy	50-70% (sensory)	Dose-limiting — cumulative; may be irreversible
Myelosuppression (neutropenia)	Common	Nadir ~days 8-11; recovers days 15-21
Hypersensitivity reactions	5-10% (without premed)	Premedicate with dexamethasone + antihistamine (H₁/H₂)
Alopecia	>80%	Complete but reversible
Arthralgia/myalgia	30-70%	Days 2-4 after infusion; can be severe
Bradycardia/AV block	<1%	Asymptomatic usually
Nausea/vomiting	Moderate	Premedicate
Extravasation	Irritant (not vesicant)	Flush with NS

Premedication for Paclitaxel: - Dexamethasone 20 mg PO 12 and 6h before (or IV 30min before) - Diphenhydramine 50 mg IV - Ranitidine 50 mg IV (or famotidine) - To prevent hypersensitivity (due to Cremophor EL vehicle)

(B) Docetaxel (Taxotere)

Mechanism: Same as paclitaxel (taxane)

Differences from Paclitaxel: | Parameter | Paclitaxel | Docetaxel | |---|---|---| | Source | Pacific yew (Taxus brevifolia) | European yew (Taxus baccata) — semi-synthetic | | Vehicle | Cremophor EL (causes hypersensitivity) | Polysorbate 80 | | Potency | Reference | 1.5-2× more potent | | Half-life | 5-50 h | 11-18 h | | Metabolism | CYP3A4, CYP2C8 | CYP3A4 | | Neuropathy | +++ | ++ | | Neutropenia | ++ | +++ (more severe) — dose-limited | | Fluid retention | + | +++ (capillary leak) — premedicate with dexamethasone | | Alopecia | +++ | +++ | | Hypersensitivity | ++ | + (less) |

Premedication for Docetaxel: - Dexamethasone 8 mg PO bd × 3-5 days starting 1 day before infusion - To prevent fluid retention + hypersensitivity

18.4 Anthracyclines

Doxorubicin (Adriamycin)

Mechanism: Topoisomerase II inhibitor + DNA intercalation → free radical generation → DNA damage → apoptosis

Clinical Use: - Endometrial cancer (some regimens) - Breast cancer - Ovarian cancer (less common) - Uterine sarcomas

Dose: 50-75 mg/m² IV q3weeks (lifetime max: 450-550 mg/m² due to cardiotoxicity)

Side Effects: | Toxicity | Frequency | Management | |---|---|---| | Cardiotoxicity | Dose-limiting — 5-30% (dose-dependent) | Cardiomyopathy (irreversible); Type I: cumulative dose-related; monitor LVEF; use dexrazoxane for cardio-protection | | Myelosuppression | Common | Neutropenia nadir ~day 10-14 | | Alopecia | >90% | Complete; reversible | | Nausea/vomiting | High | Antiemetics | | Mucositis/stomatitis | 30-50% | Oral care, analgesia | | Red urine | Harmless | Red colour (not haematuria) | | Extravasation | Vesicant — severe tissue necrosis | Treat with DMSO + cold packs; surgical debridement if needed | | Radiation recall | | Recall dermatitis | | Cardiotoxicity types: | | | | Type I (anthracycline) | Cumulative, irreversible | ↓ LVEF, CHF; risk ↑ with cumulative dose, age, prior chest RT, CV risk factors | | Type II (trastuzumab) | Reversible, non-cumulative | ↓ LVEF; reverses on stopping |

Lifetime cumulative dose limits: - Doxorubicin: 450-550 mg/m² (or 400 mg/m² with prior chest RT, age >70, cardiac risk) - Epirubicin: 900-1000 mg/m² - Liposomal doxorubicin: Higher limit (less cardiotoxicity)

18.5 Alkylating Agents

Cyclophosphamide

Mechanism: Alkylates DNA → DNA crosslinks → apoptosis (cell cycle non-specific)

Clinical Use: - Ovarian cancer (older regimens — now mostly replaced by platinum/taxanes) - Breast cancer - Endometrial cancer - Germ cell tumours - Gestational trophoblastic neoplasia (GTN) — single agent for low-risk

Dose: 500-1000 mg/m² IV q3-4weeks

Pharmacokinetics: | Parameter | Value | |---|---| | Pro-drug | Metabolised by CYP2C9, CYP3A4 → active metabolite (phosphoramide mustard + acrolein) | | Acrolein | Causes haemorrhagic cystitis | | Half-life | 4-8 h | | Elimination | Renal (metabolites) |

Side Effects: | Toxicity | Frequency | Management | |---|---|---| | Haemorrhagic cystitis | 5-15% | Mesna (sodium 2-mercaptoethanesulfonate) — binds acrolein in bladder; aggressive hydration | | Myelosuppression | Dose-limiting | Neutropenia, thrombocytopenia | | Nausea/vomiting | Moderate-high | Premedicate | | Alopecia | 50-80% | | | SIADH | Rare | Water retention, hyponatraemia | | Gonadal failure | Common | Ovarian failure (age/dose-dependent); consider fertility preservation | | Secondary malignancies | Long-term | MDS/AML (especially with cumulative high doses) | | Cardiotoxicity | Rare (high dose) | Myocarditis, pericarditis |

Mesna Regimen: - Total mesna dose = 100% of cyclophosphamide dose - Given IV: 20% 15min before CYC, 40% at 4h, 40% at 8h post-CYC - Or oral: 40% × 3 doses (also effective)

18.6 Antimetabolites

(A) 5-Fluorouracil (5-FU)

Mechanism: Thymidylate synthase inhibitor → ↓ dTMP → ↓ DNA synthesis (S-phase specific)

Clinical Use: - Cervical cancer (with radiation as radiosensitiser) - GTN (some regimens) - Breast cancer

Dose: Variable by regimen

(B) Methotrexate

Mechanism: Dihydrofolate reductase (DHFR) inhibitor → ↓ tetrahydrofolate → ↓ purine/pyrimidine synthesis → ↓ DNA/RNA synthesis

Clinical Use: - Low-risk GTN (single agent — highly effective) - Ectopic pregnancy (medical management) - Medical abortion (with misoprostol) - Breast cancer (older regimens) - Rheumatoid arthritis (low dose)

Dosing for GTN: - Intramuscular: 30-50 mg/m² weekly (low risk) - For ectopic: 50 mg/m² IM single dose (day 1), repeat if β-hCG not falling >15% days 4→7

Side Effects: | Toxicity | Notes | |---|---| | Myelosuppression | Dose-limiting | | Mucositis/stomatitis | Common | | Hepatotoxicity | Transaminitis; avoid in liver disease | | Pulmonary toxicity | Pneumonitis, fibrosis (prolonged use) | | Nephrotoxicity | More at high doses (MTX crystalluria) | | Teratogenicity | Highly teratogenic — contraindicated in pregnancy (except for ectopic/GTN) | | Alopecia | Less common than other agents |

Folinic acid (calcium leucovorin) rescue: - "Rescue" from MTX toxicity — provides reduced folate for normal cells (bypasses DHFR block) - Given 24 hours after high-dose MTX - Not needed for low-dose regimens (<100 mg/m²)

(C) Gemcitabine

Mechanism: Nucleoside analogue → inhibits DNA synthesis

Clinical Use: - Ovarian cancer (some regimens — especially platinum-resistant) - Cervical cancer (with radiation) - Breast cancer

Side Effects: Myelosuppression, flu-like syndrome, pneumonitis, oedema

18.7 Targeted Therapies

(A) PARP Inhibitors — for BRCA-Mutated Ovarian Cancer

Mechanism: Inhibit poly (ADP-ribose) polymerase → blocks DNA single-strand break repair → synthetic lethality in cells with defective homologous recombination (e.g., BRCA-mutated)

Drug	Dosing	Key Side Effects
Olaparib (Lynparza)	300 mg PO bd	Nausea, fatigue, anaemia, ↑ risk of MDS/AML
Niraparib (Zejula)	200-300 mg PO od (adjust by weight/platelet)	Thrombocytopenia, hypertension, nausea, fatigue
Rucaparib (Rubraca)	600 mg PO bd	Nausea, transaminitis, fatigue
Talazoparib (Talzenna)	1 mg PO od	Myelosuppression, fatigue, alopecia

Clinical Use: - Maintenance therapy after response to platinum-based chemotherapy for BRCA-mutated or HRD-positive ovarian cancer - First-line maintenance (SOLO-1 trial: olaparib improved PFS by ~36 months in newly diagnosed BRCA-mutated advanced ovarian cancer) - Relapsed ovarian cancer (maintenance after response to platinum)

(B) Anti-Angiogenics — VEGF Inhibitors

Bevacizumab (Avastin): - Mechanism: Monoclonal antibody against VEGF-A → inhibits angiogenesis - Clinical Use: - Ovarian cancer (first-line in combination with carboplatin/paclitaxel, then maintenance) - Cervical cancer (with chemotherapy) - Dose: 15 mg/kg IV q3weeks - Side Effects: | Effect | Frequency | Notes | |---|---|---| | Hypertension | 20-40% | Manage with antihypertensives | | Proteinuria | 10-30% | Monitor urine protein | | Bleeding | 1-5% | Epistaxis, GI bleed; avoid if recent haemoptysis | | GI perforation | 2-5% | Life-threatening — risk ↑ with extensive peritoneal disease, bowel involvement | | Impaired wound healing | | Avoid for 4-6 weeks post-surgery | | Arterial thromboembolism | 2-5% | MI, CVA | | Reversible posterior leukoencephalopathy (RPLS) | Rare | Hypertension + neurological symptoms |

(C) Immune Checkpoint Inhibitors

Pembrolizumab (Keytruda): - Mechanism: Anti-PD-1 monoclonal antibody → blocks PD-1/PD-L1 interaction → activates T-cell immune response against tumour - Clinical Use: - PD-L1 positive advanced cervical cancer (PFS benefit in KEYNOTE-826) - Endometrial cancer (MSI-H/dMMR — high response rates) - Side Effects (immune-related): - Dermatitis, colitis, hepatitis, pneumonitis, thyroiditis, adrenalitis, hypophysitis - Infusion reactions - Most are manageable with corticosteroids + holding therapy

Nivolumab (Opdivo): - Same class; used in cervical, ovarian, endometrial cancers

(D) Anti-HER2 Therapy

Trastuzumab (Herceptin): - Mechanism: Monoclonal antibody against HER2/neu receptor → ↓ proliferation + ADCC - Clinical Use: - Breast cancer (HER2+) - Potential for HER2+ endometrial cancer (rare subtype) - Side Effects: - Cardiotoxicity (Type II) — reversible LVEF decline (not cumulative like anthracyclines) - Monitor LVEF q3months - Not to be used concurrently with anthracyclines (sequential only)

18.8 Hormonal Therapies

(A) Tamoxifen

Mechanism: Selective oestrogen receptor modulator (SERM) — antagonist in breast, agonist in bone/uterus

Clinical Use: - Breast cancer (hormone receptor-positive) — 5-10 years adjuvant therapy - Breast cancer prevention (high-risk women) - Ovulation induction (off-label — for anovulatory infertility)

Pharmacokinetics: | Parameter | Value | |---|---| | Absorption | Well absorbed | | Half-life | 5-7 days (active metabolite: endoxifen, formed by CYP2D6) | | Metabolism | CYP2D6 (to endoxifen — active), CYP3A4 | | Elimination | Faecal (biliary) |

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Hot flushes | 50-80% | Common; bothersome but manageable | | Vaginal discharge | 30-50% | Due to oestrogen agonist effect on vaginal epithelium | | Endometrial cancer | 2-3× relative risk | Oestrogen agonist on uterus → endometrial hyperplasia/cancer; annual surveillance; any bleeding → investigate | | VTE | 1-2% | Increased risk (especially in smokers, obese); avoid with COC | | Cataracts | Increased | | | Hepatosteatosis | 10-20% | NAFLD-like | | Ovarian cysts | In premenopausal | Benign |

CYP2D6 Interaction: - SSRIs (paroxetine, fluoxetine) — strong CYP2D6 inhibitors → ↓ endoxifen → ↓ tamoxifen efficacy - Choose CYP2D6-neutral antidepressants (venlafaxine, citalopram, escitalopram) for tamoxifen users with depression/hot flushes

(B) Aromatase Inhibitors (AIs)

Mechanism: Inhibit aromatase (CYP19A1) → ↓ conversion of androgens to oestrogens → ↓ oestrogen levels

Drug	Generation	Dosing
Letrozole (Femara)	3rd	2.5 mg PO od
Anastrozole (Arimidex)	3rd	1 mg PO od
Exemestane (Aromasin)	3rd (steroidal)	25 mg PO od

Clinical Use: - Breast cancer (postmenopausal women with hormone receptor-positive disease) — adjuvant or advanced - Ovulation induction (letrozole — off-label) — first-line for PCOS (often better than clomiphene; lower multiple pregnancy rate) - Endometriosis (off-label) — ovarian suppression

Side Effects: | Effect | Mechanism | Notes | |---|---|---| | Hot flushes | ↓ Oestrogen | Common | | Arthralgia/myalgia | ↓ Oestrogen | 30-50% — may limit adherence | | Osteoporosis / ↑ fracture risk | ↓ Oestrogen → bone loss | Monitor BMD; give calcium + vitamin D; consider bisphosphonate | | Hypercholesterolaemia | ↑ LDL | Monitor lipids | | Vaginal dryness | ↓ Oestrogen | |

AIs vs Tamoxifen: - In postmenopausal women, AIs are marginally superior to tamoxifen for breast cancer recurrence - AIs have lower VTE/endometrial cancer risk, but higher osteoporosis/arthralgia risk - Sequential therapy (tamoxifen → AI or vice versa) is used

(C) GnRH Agonists

Mechanism: Continuous GnRH receptor stimulation → receptor downregulation → ↓ FSH, ↓ LH → profound hypo-oestrogenism

Drug	Route	Dosing
Leuprolide (Prostap)	IM/SC	3.75 mg monthly or 11.25 mg 3-monthly
Goserelin (Zoladex)	SC implant	3.6 mg monthly or 10.8 mg 3-monthly
Triptorelin	IM	3.75 mg monthly

Clinical Use: - Breast cancer (premenopausal) — ovarian suppression (chemical castration) combined with tamoxifen or AI - Endometriosis — induction of hypo-oestrogenism for 3-6 months - Uterine fibroids — short-term pre-surgical shrinkage (add-back therapy with HRT often used to prevent oestrogen-deficiency symptoms) - Endometrial hyperplasia (some indications) - Precocious puberty - IVF (pituitary downregulation before ovarian stimulation)

Side Effects (oestrogen deficiency): - Hot flushes (90%+) - Vaginal dryness - Mood changes, depression - Insomnia - Bone mineral density loss (significant if >6 months without add-back) - Headache

Add-back therapy: For endometriosis/fibroids: add low-dose HRT (oestrogen + progestogen) or tibolone to maintain bone density and reduce symptoms without reactivating disease.

(D) Progestogens in Gynaecological Oncology

Drug	Use	Mechanism	Dosing
Medroxyprogesterone acetate (MPA)	Endometrial cancer (advanced/recurrent)	↓ Oestrogen receptors + direct anti-proliferative	200-400 mg PO od
Megestrol acetate	Endometrial cancer / breast cancer	Same	80-160 mg PO od
Levonorgestrel IUS (Mirena)	Endometrial hyperplasia (non-atypical) / early endometrial cancer (selected)	Local progestogen → endometrial suppression	IUS release 20 μg/day

---

19. Drugs Affecting the Hypothalamic-Pituitary-Ovarian Axis

19.1 Clomiphene Citrate

Mechanism: SERM (oestrogen antagonist at hypothalamus) → blocks oestrogen negative feedback → ↑ GnRH → ↑ FSH/LH → follicular growth

Clinical Use: - Ovulation induction in anovulatory infertility (PCOS — first-line in some guidelines) - Diagnose: OI for anovulation

Dosing: - Start 50 mg PO od from day 2-6 of cycle (5 days) - If no ovulation: increase by 50 mg each cycle up to 150 mg/day - Record: Ovulation detected (mid-luteal progesterone >30 nmol/L) in ~60-80%

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Hot flushes | 10-20% | Common | | Multiple pregnancy | 5-10% (most twins; 1% triplets) | Main risk — monitor follicular development | | Ovarian hyperstimulation (OHSS) | 1-5% (mild); <1% (severe) | Rare with clomiphene (vs gonadotrophins) | | Mood swings, depression | 5% | | | Visual disturbances | 1-2% (blurring, scotomata) | Stop if occurs — may be serious | | Cervical mucus changes | Anti-oestrogen effect on mucus | Thickened mucus may impair sperm penetration | | Luteal phase defect | | May need progesterone support |

Contraindications: - Ovarian cyst - Liver disease - Unexplained vaginal bleeding - Pregnancy - Visual disturbances

19.2 Letrozole (for Ovulation Induction — Off-Label)

Mechanism: Aromatase inhibitor → ↓ oestrogen → ↑ GnRH → ↑ FSH → follicular growth (same net effect as clomiphene but without anti-oestrogenic side effects on endometrium/cervix)

Evidence in PCOS: - Letrozole is now first-line for PCOS in many guidelines (NICE, 2023) — superior to clomiphene for live birth rate (RR 1.4-1.6 in RCTs) - Lower multiple pregnancy rate than clomiphene - Better endometrial thickness (no anti-oestrogen effect)

Dosing: 2.5-7.5 mg PO od days 3-7 (or 3-7)

19.3 Gonadotrophins (Exogenous FSH/LH)

Drug	Source	FSH Activity	LH Activity
Urinary FSH (Menopur, Menogon)	Postmenopausal urine	FSH + LH	Contains LH
Recombinant FSH (Gonal-F, Puregon, Follitropin)	Recombinant DNA	FSH only	None
Rec. LH (Luveris)	Recombinant	None	LH
hMG (human menopausal gonadotrophin)	Urinary	FSH + LH	Both
hCG (Pregnyl, Ovitrelle)	Urinary/Recombinant	None	LH-like (binds LH receptor)

Use: - Controlled ovarian hyperstimulation (COH) for IVF - Ovulation induction (when clomiphene/letrozole fails) - OI for hypogonadotrophic hypogonadism (need LH + FSH)

Side Effects of Gonadotrophins: | Effect | Notes | |---|---| | OHSS | Major risk — moderate-severe in 3-10% of IVF cycles; consider: | | Mild: Bloating, discomfort, mild ascites | | Moderate: Nausea, distension, moderate ascites | | Severe: Tense ascites, pleural effusion, oliguria, thromboembolism, ARDS | | | Multiple pregnancy | 15-30% | | | Local reactions | Injection site pain | | | Ovarian torsion | Risk with large ovaries | |

OHSS Management: - Prevention: Agonist trigger, low-dose protocols, anti-oestrogen, metformin (PCOS), cabergoline, letrozole - Mild: Observation, hydration - Moderate-Severe: Admission, IV fluids (colloid), Thromboembolism prophylaxis (LMWH), Paracentesis if tense ascites, Monitor urine output, electrolytes, FBC, Consider ICU if severe

19.4 Cabergoline

Mechanism: Dopamine D₂ receptor agonist → ↓ prolactin secretion from pituitary lactotrophs

Clinical Use: - Hyperprolactinaemia (prolactinoma, drug-induced, idiopathic) - OHSS prevention (off-label) — ↓ VEGF-mediated capillary permeability

Dosing: - Hyperprolactinaemia: 0.5-2 mg PO 1-2×/week - OHSS prevention: 0.5 mg PO daily for 8 days starting day of hCG trigger

Side Effects: | Effect | Frequency | Notes | |---|---|---| | Nausea/vomiting | 20-30% | Take with food; start low | | Dizziness, postural hypotension | 10-20% | | | Headache | Common | | | Nasal congestion | Common | | | Fatigue | Common | | | Psychiatric | Rare (mood changes) | | | Cardiac valvulopathy | Rare at low doses (seen with high-dose Parkinson's) | Not a concern at typical doses used |

19.5 Bromocriptine

Mechanism: D₂ receptor agonist (older, less selective than cabergoline)

Clinical Use: - Hyperprolactinaemia (cabergoline is now preferred — better tolerability) - Peripartum cardiomyopathy (some evidence — off-label) - Post-partum lactation suppression (historical)

Dosing: 2.5-7.5 mg PO bd-tds

Side Effects: Nausea, vomiting (more than cabergoline), postural hypotension, mood changes, Raynaud's phenomenon

19.6 GnRH Antagonists

Mechanism: Competitive GnRH receptor blockade → rapid ↓ FSH, ↓ LH (in hours — no flare effect)

Drug	Route	Use
Cetrorelix (Cetrotide)	SC	IVF — prevent premature LH surge
Ganirelix (Orgalutran)	SC	IVF — same
Degarelix (Firmagon)	SC	Prostate cancer (not gynaecological but mention)

Advantages over GnRH agonists in IVF: - No flare effect (agonists cause initial LH surge → risk of premature ovulation) - Shorter treatment duration (can start in mid-follicular phase) - Lower gonadotrophin requirements (some studies) - Lower OHSS risk when used with agonist trigger

19.7 Tamoxifen's Dual Role — Gynae Oncology & Fertility

Tamoxifen has both anti-oestrogenic (breast, hypothalamus) and oestrogenic (bone, endometrium) activities:

• Breast cancer: Anti-oestrogen → blocks ER in breast tissue
• Ovulation induction: Anti-oestrogen at hypothalamus → ↑ GnRH → ↑ FSH
• Endometrial cancer risk: Oestrogen agonist on endometrium → hyperplasia → carcinoma (risk ~2-3×)

---

20. Immunosuppressants & Autoimmune Therapy

20.1 Corticosteroids — Anti-Inflammatory & Immunosuppressive

Mechanism: - Genomic: Bind GR → nuclear translocation → ↑ transcription of anti-inflammatory genes (IL-10, IκBα, lipocortin-1) + ↓ transcription of pro-inflammatory genes (NF-κB, AP-1 → ↓ IL-1, TNFα, IL-6, COX-2) - Non-genomic: Rapid effects (seconds to minutes) — membrane stabilisation, ↓ vasodilation

Relative potencies:

Drug	Anti-inflammatory potency	Na⁺ retention (mineralocorticoid)	Equivalent dose	Half-life
Hydrocortisone	1	+++	20 mg	8-12 h (short)
Prednisolone	4	++	5 mg	12-36 h (intermediate)
Methylprednisolone	5	+	4 mg	12-36 h (intermediate)
Dexamethasone	25-30	0	0.75 mg	36-54 h (long)
Betamethasone	25-30	0	0.6 mg	36-54 h (long)

20.2 Antirheumatic Drugs in Pregnancy

Drug	Safety	Notes
Hydroxychloroquine	Safe — continue in pregnancy	For SLE, rheumatoid arthritis; no teratogenicity; ↓ flare risk
Sulfasalazine	Safe	Give 5 mg folic acid (folate antagonist); safe in all trimesters
Azathioprine	Safe (low-moderate dose <2 mg/kg)	Fetal liver lacks enzyme to convert to active metabolite (6-MP) — partial protection
Ciclosporin	Safe — continue	Monitor levels (↑ Vd, ↑ CL); TDM
Tacrolimus	Safe — continue	Same — TDM; ↑ levels in pregnancy? Variable
Mycophenolate (MMF)	CONTRAINDICATED	Teratogenic (ear, orofacial, limb anomalies); stop 6 weeks before conception
Methotrexate	CONTRAINDICATED	Teratogenic / abortifacient; stop 3 months before conception; folic acid 5 mg
Leflunomide	CONTRAINDICATED	Teratogenic; washout with cholestyramine before pregnancy
Cyclophosphamide	CONTRAINDICATED (except life-threatening)	Teratogenic; gonadal toxicity
Biologics (TNF inhibitors)	Most safe — infliximab, etanercept, adalimumab	Cross placenta in 2nd/3rd trimester; stop at 30 weeks (live vaccines risk in first 6 months neonate)
Rituximab	Limited data	B-cell depletion in neonate; use if necessary
IVIG	Safe	For immune thrombocytopenia, SLE, antiphospholipid

20.3 Drugs for Antiphospholipid Syndrome (APS)

Standard regimen in pregnancy:

• Aspirin 75 mg PO od — antiplatelet (low dose)
• Safe in pregnancy (1st trimester caution — small GI bleed risk)
• Stop at 36-37 weeks for delivery (theoretical bleeding risk)
• LMWH (prophylactic dose) — enoxaparin 40 mg SC od
• For women with previous thrombosis or recurrent pregnancy loss
• Combined — aspirin + LMWH for obstetric APS

Refractory APS: - Consider hydroxychloroquine (immunomodulatory) - Consider prednisolone (low dose) - Consider IVIG - Consider plasma exchange (catastrophic APS)

20.4 Drugs for Immune Thrombocytopenia (ITP) in Pregnancy

Drug	Indication	Notes
Prednisolone	First-line	10-40 mg PO od; aim for safe platelet count >30 × 10⁹/L
IVIG	Second-line / Emergency	1 g/kg IV over 1-2 days; response in 2-3 days
Azathioprine	Steroid-sparing	Safe in pregnancy
Rituximab	Third-line	Limited data but used in severe cases
Thrombopoietin agonists	Avoid — limited data	Romiplostim, eltrombopag — not recommended
Splenectomy	Last resort	Perform in 2nd trimester if needed
Platelet transfusion	Only for emergency/CS

---

21. Anaesthetic Agents in Obstetrics

21.1 Local Anaesthetics

Mechanism: Block voltage-gated Na⁺ channels → prevent nerve impulse conduction

Pharmacokinetics of Local Anaesthetics:

Drug	Potency	Onset	Duration	Protein Binding	pKa	% Ionised at pH 7.4	Max Dose (plain)	Max Dose (with adrenaline)
Lidocaine	Moderate	Fast	1-2 h	65%	7.9	75%	4 mg/kg	7 mg/kg
Bupivacaine	High	Slow	3-6 h	95%	8.1	80%	2 mg/kg	2 mg/kg
Ropivacaine	High	Intermediate	3-6 h	94%	8.1	80%	3 mg/kg	—
Prilocaine	Moderate	Fast	1-2 h	55%	7.9	75%	6 mg/kg	8 mg/kg
Chloroprocaine	Low	Fastest	30-60 min	—	8.7	—	12 mg/kg	—

Key Differences: - Bupivacaine: Most cardiotoxic — cardiovascular collapse at high doses (more than CNS toxicity) - Ropivacaine: S-enantiomer of bupivacaine — less cardiotoxic, less motor block (preferred for labour epidurals) - Lidocaine: Clinically used for local infiltration, IVRA, epidural - Prilocaine: Lower toxicity; methaemoglobinaemia risk (high doses)

Additives: | Additive | Effect | Mechanism | |---|---|---| | Adrenaline (epinephrine) 1:200,000 | ↓ Systemic absorption, ↑ duration | Vasoconstriction | | Bicarbonate | ↑ Onset | ↑ pH → ↑ non-ionised form → faster diffusion | | Dextrose | ↑ Spread (hyperbaric solutions) | For spinal anaesthesia |

Local anaesthetic toxicity (LAST): - Early: Perioral tingling, metallic taste, tinnitus, dizziness, agitation - Late: Seizures, loss of consciousness, cardiotoxicity (QT prolongation, VT, VF, asystole) - Treatment: 1. Stop injection 2. Airway, breathing, circulation 3. Intralipid 20% — 1.5 mL/kg bolus then 0.25 mL/kg/min infusion (lipid sink therapy) 4. Seizure management (benzodiazepines, NOT propofol — can worsen cardiotoxicity) 5. Avoid vasopressin (may worsen hypotension in LAST)

21.2 General Anaesthetics in Obstetrics

Drugs for Caesarean Section — Rapid Sequence Induction (RSI):

Induction Agents: | Drug | Dose | Properties | Notes | |---|---|---|---| | Thiopental | 4-6 mg/kg IV | Barbiturate; rapid onset (30s); ↓ BP; causes fetal sedation | Historical; cross placenta; neonatal respiratory depression | | Propofol | 1.5-2.5 mg/kg IV | Rapid onset (30-45s); ↓ BP; antiemetic | Now first choice for CS GA; crosses placenta; less neonatal depression than thiopental? | | Ketamine | 1-2 mg/kg IV | ↑ BP (sympathomimetic); dissociative; no neonatal depression in low doses | Preferred if haemodynamically unstable (e.g., haemorrhage); hallucination risk |

Neuromuscular Blockers (depolarising): | Drug | Dose | Properties | Notes | |---|---|---|---| | Suxamethonium (succinylcholine) | 1-1.5 mg/kg IV | Onset ~30-45s; duration 5-10 min | Depolarising — risk of hyperkalaemia, MH, malignant hyperthermia; pseudocholinesterase deficiency → prolonged block |

Neuromuscular Blockers (non-depolarising): | Drug | Dose (intubating) | Duration | Notes | |---|---|---|---| | Rocuronium | 0.6-1.2 mg/kg IV | 30-60 min (dose-dependent) | Rapid onset (sugammadex reversal — 2-4 mg/kg); preferred for RSI if suxamethonium contraindicated | | Atracurium | 0.5 mg/kg IV | 20-40 min | Histamine release (↓ BP); Hofmann elimination (independent of renal/hepatic) | | Cisatracurium | 0.15 mg/kg IV | 30-45 min | More stable (no histamine); Hofmann elimination |

Reversal Agents: | Drug | Mechanism | Use | |---|---|---| | Neostigmine (with glycopyrrolate) | Acetylcholinesterase inhibitor | Reverses non-depolarising NMBs | | Sugammadex | Encapsulates rocuronium/vecuronium | Rapid, selective reversal of rocuronium/vecuronium; 2-4 mg/kg for moderate block, 16 mg/kg for immediate reversal |

Volatile Anaesthetics (inhalation agents): | Drug | MAC (%) | Uterine Relaxation | Notes | |---|---|---|---| | Sevoflurane | 2.0 | Moderate | Preferred for volatile induction in obstetrics | | Isoflurane | 1.15 | Moderate | Acceptable; good for maintenance | | Desflurane | 6.0 | Moderate | Rapid onset/offset; pungent — not for inhalation induction | | Halothane | 0.75 | Significant (excessive) | Historical; hepatotoxicity; arrhythmia risk | | Nitrous oxide (N₂O) | 105 | Minimal | Entonox (50% N₂O/50% O₂) for labour analgesia |

Uterine relaxation and volatile agents: - All volatile agents cause dose-dependent uterine relaxation — higher doses → more uterine atony → increased PPH risk - For CS GA: Use <1 MAC volatile agent + ensure adequate oxytocin post-delivery - For external cephalic version (ECV), uterine inversion: Use volatile agents for uterine relaxation

21.3 Opioids in Obstetric Anaesthesia

Drug	Route	Onset	Duration	Crosses Placenta	Neonatal Effects
Morphine	IM/IV/epidural	15-30 min (IM)	2-4 h	Yes	Respiratory depression (peak at 2-4 h neonatal); ↓ variability on CTG
Pethidine (meperidine)	IM/IV	5-15 min	2-4 h	Yes	Active metabolite (norpethidine) — long half-life; neonatal depression; No longer recommended for labour analgesia
Fentanyl	IV/epidural	1-2 min (IV)	30-60 min	Yes	Less neonatal depression than morphine (rapid redistribution); preferred for epidural PCA
Remifentanil	IV (PCA)	1 min	5-10 min (ultra-short)	Yes (but rapidly metabolised)	Minimal neonatal depression (metabolised by plasma esterases — fetus has adequate esterase activity)
Diamorphine (heroin)	IM	5-10 min	2-3 h	Yes	Similar to morphine; used in UK for labour analgesia

Epidural Opioids: - Fentanyl 50-100 μg or diamorphine 2.5-5 mg added to local anaesthetic - Provides synergistic analgesia (allows lower LA concentration → less motor block) - Side effects: Pruritus (60-80%), nausea (20-30%), urinary retention, late respiratory depression (diamorphine — risk at 6-12h)

21.4 Drugs for Labour Analgesia

Method	Drug	Effectiveness	Maternal Satisfaction	Effect on Labour
Entonox (N₂O/O₂)	Nitrous oxide 50%	Moderate (good for early labour)	Moderate	None
Pethidine	Pethidine 50-100 mg IM	Moderate	Low-moderate	May slow labour (↑ interval between contractions); neonatal depression
Diamorphine	Diamorphine 5-10 mg IM	Moderate	Good	Similar to pethidine
Remifentanil PCA	Remifentanil 0.2-0.5 μg/kg IV bolus; 2-min lockout	Good (comparable to epidural in some studies)	High	No known effect on labour; apnoea risk — requires 1:1 midwifery + O₂ saturation monitoring
Epidural	Bupivacaine/ropivacaine + fentanyl 2-10 μg/mL infusion 6-12 mL/h	Excellent	High	Prolonged 2nd stage by ~30 min; ↑ instrumental delivery; no ↑ CS rate (controversial)
Spinal (for CS)	Bupivacaine 0.5% hyperbaric 2-2.5 mL + fentanyl 15-25 μg + morphine 100-200 μg	Excellent	Very high

---

22. Drug Interactions of Obstetric & Gynaecological Importance

22.1 Clinically Significant Interactions

Drug A	Drug B	Interaction	Mechanism	Clinical Consequence
Oxytocin	Prostaglandins	Synergistic uterine stimulation	Both uterotonic → additive	Uterine hyperstimulation, rupture
MgSO₄	Nifedipine	Additive hypotension	Both vasodilators	Significant hypotension; use cautiously
MgSO₄	Aminoglycosides	↑ Neuromuscular blockade	Synergistic at NMJ	Respiratory depression, weakness
COC	Lamotrigine	↓ Lamotrigine by 50%	UGT induction by EE	Seizure risk; need lamotrigine dose adjustment
COC	Enzyme-inducing AEDs	↓ COC efficacy	CYP3A4 induction	Contraceptive failure
COC	Rifampicin	↓ COC efficacy	CYP3A4 induction	Contraceptive failure
Warfarin	Metronidazole	↑ Warfarin effect (↑ INR)	CYP2C9 inhibition	Bleeding risk
Warfarin	Fluconazole	↑ Warfarin effect	CYP2C9 inhibition	Bleeding risk
Labetalol	NSAIDs	↓ Antihypertensive effect	↓ Prostaglandin-mediated vasodilation	Loss of BP control
Methotrexate	NSAIDs	↑ MTX toxicity	↓ Renal clearance of MTX	Severe myelosuppression
Methotrexate	Trimethoprim	↑ MTX toxicity	Synergistic DHFR inhibition	Severe haematological toxicity
Tamoxifen	Paroxetine	↓ Tamoxifen efficacy	CYP2D6 inhibition → ↓ endoxifen	↑ Breast cancer recurrence
Theophylline	Ciprofloxacin	↑ Theophylline toxicity	CYP1A2 inhibition	Seizures, arrhythmias
Lithium	ACEi/ARBs	↑ Lithium toxicity	↓ Renal clearance	Severe neurotoxicity
Lithium	NSAIDs	↑ Lithium toxicity	↓ Renal clearance	Severe neurotoxicity
SSRIs	MAOIs	Serotonin syndrome	Synergistic 5-HT increase	Hyperthermia, rigidity, death
SSRIs	Tramadol	Serotonin syndrome	Additive serotonergic	Agitation, seizures
Heparin	Aspirin	↑ Bleeding risk	Additive anticoagulation	Haemorrhage
DOACs	Strong CYP3A4 inhibitors	↑ DOAC levels	Metabolism inhibition	Bleeding risk
Ciclosporin	Macrolide antibiotics	↑ Ciclosporin toxicity	CYP3A4/P-gp inhibition	Nephrotoxicity
Carbamazepine	COC	↓ COC efficacy	CYP3A4 induction	Contraceptive failure
Phenytoin	Dexamethasone	↓ Dexamethasone effect	CYP3A4 induction	Reduced steroid efficacy
Heparin/LMWH	Uterotonics (high dose)	Additive haemorrhage	Both affect coagulation/haemostasis	PPH bleeding risk

22.2 Grapefruit Juice Interaction

• Affects: Drugs metabolised by CYP3A4 (and P-gp in gut)
• Mechanism: Irreversible inhibition of intestinal CYP3A4 → ↑ oral bioavailability
• Irreversible — one glass inhibits for 24-48h
• Gynaecological drugs affected:
• COC — minimal effect (oral EE levels may ↑ slightly)
• Ciclosporin, tacrolimus — ↑↑ levels (toxicity risk)
• Nifedipine, felodipine (Ca channel blockers) — ↑ levels (hypotension)
• Sildenafil (PDE5 for PAH) — ↑ levels
• Midazolam, other BZDs — ↑ sedation
• Simvastatin, atorvastatin — ↑ myopathy/rhabdomyolysis

22.3 St John's Wort (Hypericum perforatum)

• Herbal antidepressant
• Mechanism: Potent CYP3A4 inducer + P-gp inducer
• Interactions:
• COC → ↓ efficacy → pregnancy (reported cases)
• Ciclosporin, tacrolimus → ↓ levels → transplant rejection
• Warfarin → ↓ INR → thrombosis
• SSRIs → serotonin syndrome (do not combine)
• Digoxin → ↓ levels (P-gp induction)
• Recommendation: Avoid in women on hormonal contraception or immunosuppression

---

23. Exam-Focused High-Yield Tables & Mnemonics

23.1 CYP450 — High-Yield Inducers & Inhibitors

Inducers (RIP CGBS): | Letter | Drug | |---|---| | R | Rifampicin (strong) | | I | Isoniazid (mild) | | P | Phenytoin | | C | Carbamazepine | | G | Griseofulvin? (or just remember) | | B | Barbiturates (phenobarbital) | | S | St John's Wort |

Bonus: Ethanol (chronic), smoking (PAHs for CYP1A2)

Inhibitors (K K K — Ketoconazole, Ketoconazole, Ketoconazole):

Strong Inhibitors	Moderate Inhibitors
Ketoconazole	Fluconazole (CYP2C9, CYP3A4)
Itraconazole	Metronidazole (CYP2C9)
Clarithromycin, erythromycin	Cimetidine
HIV protease inhibitors	Amiodarone
Grapefruit juice (gut only)	Fluoxetine, paroxetine (CYP2D6)
	Verapamil, diltiazem
	Sulfamethoxazole (CYP2C9)

23.2 Teratogenic Drugs — Absolute Avoid in Pregnancy

Acronym	Drug	Effect
A	ACEi/ARBs	Renal dysgenesis, oligohydramnios
V	Valproate	NTD, autism, cognitive impairment
O	Oral retinoids (isotretinoin)	Severe CNS/craniofacial/cardiac defects
I	Irra... (no) — Iodine-131	Fetal thyroid ablation
D	Diethylstilboestrol (DES)	Vaginal adenocarcinoma
A	Androgens	Virilisation of female fetus
T	Tetracyclines	Dental discolouration, bone growth
E	(no) — Ergotamine, ergometrine	Uterine ischaemia, fetal death
M	Methotrexate, mycophenolate, misoprostol	Abortifacient, embryopathy
R	Radioisotopes	Various
S	Street drugs (cocaine, etc.)	Various
W	Warfarin	Embryopathy, CNS defects
A	Antithyroid (CBZ/PTU)	Aplasia cutis, choanal atresia (CBZ)
R	(not) — Retinoids (already)
F	Fluoroquinolones	Arthropathy
S?	Possibly SSRI? (small risk, not absolute)

23.3 Drugs Safe in Breastfeeding — Common Exam Answers

Drug	Safety
Paracetamol	Safe
Ibuprofen	Preferred NSAID in lactation
Heparin/LMWH	Safe (do not reach milk)
Warfarin	Safe (highly protein-bound)
Levothyroxine	Safe
Sertraline	Preferred SSRI in lactation
Carbamazepine	Compatible
Valproate	Compatible (low transfer)
Penicillins, cephalosporins	Safe
Prednisolone (<40 mg/day)	Safe
Insulin	Safe (peptide — destroyed in GI tract)
Metformin	Safe (low RID)

23.4 Tocolysis Mnemonic — "NIFTY AID"

Letter	Drug	Key Fact
N	Nifedipine	First-line — Ca channel blocker; headache main SE
I	Indomethacin	NSAID; <32 weeks only (ductal constriction)
F	Fenoterol (β-mimetic)	Not used much
T	Terbutaline	β-agonist; off-label
Y	—
A	Atosiban	Oxytocin antagonist; expensive but safe
I	(nothing)
D	—

Alternative Mnemonic: Nice Atosiban In Preterm Tocolysis - N = Nifedipine - A = Atosiban - I = Indomethacin - P = (β-agonists — poor choice) - T = (The end)

23.5 Uterotonic Comparison Mnemonic — "COME"

Drug	Key Feature
Carboprost (PGF₂α)	Causes Constriction — bronchospasm, GI effects; 3rd line for PPH
Oxytocin	Old reliable — IV first-line; antidiuretic effect (water intoxication)
Misoprostol (PGE₁)	Multiple uses — IOL, PPH, TOP; cheap; heat-stable; pyrexia/shivering
Ergometrine	Ergot — Elevates BP; contraindicated in hypertension/preeclampsia

23.6 Antihypertensives in Pregnancy — "LAN"

Drug	Position	Key Side Effect
Labetalol	1st line	Scalp tingling, hepatotoxicity, avoid in asthma
Atenolol	Avoid	IUGR
Nifedipine (MR)	1st line	Headache, flushing, oedema
Methyldopa	2nd line	Drowsiness, depression, + Coombs
Hydralazine	3rd line	Tachycardia, lupus-like syndrome
ACEi/ARBs	CONTRAINDICATED	Fetotoxic

23.7 MgSO₄ Toxicity — Ascending Paralysis

Level	Sign	Mnemonic
2-3.5	Therapeutic	T = Therapeutic
~4	Loss of reflexes	R = Reflexes gone
~5	Respiratory depression	R = Respiration
~6	Cardiac arrest	C = Cardiac
Antidote: Calcium gluconate — C = Calcium	→ save the C

Mnemonic for Mg toxicity: "Magnesium makes Mom Miserable: Mumbles, Moribund, Myocardium stops" - Loss of reflexes → Respiratory depression → Resuscitation + Calcium

23.8 Fetal Lung Maturity Steroids

Betamethasone 12 mg IM × 2, 24 hours apart Dexamethasone 6 mg IM × 4, 12 hours apart

Mnemonic: "B-est approach: B-etamethasone is B-est" — Betamethasone is preferred.

Key points: - Better lung response - Best for IVH reduction - Believed to have less neonatal side effects

23.9 Chemotherapy Side Effects Mnemonic

Drug	Mnemonic
Cisplatin	"Cisplatin takes Care of kidneys, Causes Cauda equina? No — Causes nephrotoxicity, neurotoxicity, ototoxicity"
Carboplatin	"Carboplatin = Careful with Blood — myelosuppression (thrombocytopenia)"
Paclitaxel	"Paclitaxel's Painful — Peripheral neuropathy, arthralgia, hypersensitivity"
Doxorubicin	"Dox beats Down the Dox" — Cardiotoxicity (dose-dependent)
Cyclophosphamide	"Cyclo — Cystitis (haemorrhagic) — need Mesna"
Bevacizumab	"Bevacizumab is Bad for Bowel — GI perforation"

23.10 High-Yield Drug Cross-References

Drug	Obstetric Use	Gynaecological Use	Contraceptive Use	Oncological Use
Oxytocin	IOL, augmentation, PPH	—	—	—
Ergometrine	PPH	—	—	—
Misoprostol	IOL, PPH, IOL, termination	Hysteroscopy prep	—	—
Nifedipine	Tocolysis, hypertension	—	—	—
Labetalol	Hypertension	—	—	—
MgSO₄	Eclampsia, neuroprotection, tocolysis	—	—	—
Betamethasone	Fetal lung maturity	—	—	—
Oxytocin antagonists	Tocolysis (atosiban)	—	—	—
Metformin	GDM, T2DM	PCOS (OI)	—	—
Insulin	GDM, T1DM, T2DM	—	—	—
Methotrexate	Ectopic pregnancy	GTN	—	GTN, breast cancer
Tamoxifen	—	Breast cancer, anovulation (OI)	—	Breast cancer
Letrozole	—	PCOS (OI), endometriosis	—	Breast cancer
GnRH agonists	—	Endometriosis, fibroids	—	Breast cancer
Clomiphene	—	Anovulation (OI)	—	—
Carboplatin	—	—	—	Ovarian, cervical, endometrial
Paclitaxel	—	—	—	Ovarian, endometrial
Ulipristal	—	—	EC	Uterine fibroids (former use)
Levonorgestrel	—	—	POP, IUS, EC	Endometrial protection

---

Appendices

Appendix A: Key Equations for MRCOG Part 1

Equation	Formula	Use
Volume of distribution	Vd = Dose / C₀	Calculate loading dose
Half-life	t½ = 0.693 × Vd / CL	Determine dosing interval
Clearance	CL = Rate / Css + loading dose	Maintenance dose calculation
Steady state	Css = Dose rate / CL	After 4-5 half-lives
Loading dose	LD = Vd × Ctarget	Rapid achievement of therapeutic level
Bioavailability	F = AUC_oral / AUC_IV	Compare routes
Creatinine clearance (Cockcroft-Gault)	CrCl = (140 - age) × weight × (0.85 if female) / (72 × SCr)	Carboplatin dosing
Carboplatin dose (Calvert)	Dose (mg) = target AUC × (GFR + 25)	Myelosuppression avoidance
Relative infant dose	RID = Infant dose / Maternal dose × 100%	Breastfeeding safety

Appendix B: Key Clinical Trials in Obstetric Pharmacology

Trial	Drugs	Finding
MAGPIE (2002)	MgSO₄ vs placebo in preeclampsia	58% ↓ in eclampsia (RR 0.42); NNT 109
Collaborative Eclampsia Trial (1995)	MgSO₄ vs diazepam vs phenytoin for eclampsia	MgSO₄ superior to both
WOMAN (2017)	Tranexamic acid vs placebo for PPH	↓ death due to bleeding (RR 0.81) if given <3h
ORACLE (2001)	Erythromycin / co-amoxiclav vs placebo for PPROM	Erythromycin ↓ composite neonatal outcome; co-amoxiclav → NEC
Liggins & Howie (1972)	Betamethasone for preterm labour	↓ RDS, ↓ neonatal death (landmark)
MACS (2007)	Multiple vs single course antenatal steroids	Multiple courses ↓ neonatal morbidity but ↓ birth weight
ALPS (2016)	Betamethasone 34-36w (late preterm)	↓ neonatal respiratory morbidity (NNT 30)
APOSTEL (2009)	Nifedipine vs atosiban for tocolysis	Similar efficacy; nifedipine more side effects
MiG TOFU (2008, 2013)	Metformin vs insulin for GDM	Metformin non-inferior; less weight gain; 2-year outcomes similar
SOLO-1 (2018)	Olaparib maintenance vs placebo (BRCA ovarian)	↑ PFS by ~36 months (landmark PARP inhibitor trial)

Appendix C: Prescribing in Pregnancy — Quick Safety Reference

Category	Examples	Recommendation
Safe throughout	Penicillins, cephalosporins, paracetamol, most antacids, most antihistamines, insulin, LMWH, levothyroxine, prednisolone (low dose), most inhaled medications	Use as indicated
Safe with monitoring	Lamotrigine, levetiracetam, methadone, nifedipine, labetalol, MgSO₄, lithium, carbimazole/PTU, azathioprine, ciclosporin, tacrolimus	TDM or specific monitoring
Caution (risk-benefit)	Ondansetron (cleft? — tiny risk), metronidazole (avoid 1st tri — theoretical), nitrofurantoin (avoid near term — haemolysis), aminoglycosides (short courses OK), SSRIs (PAP, poor adaptation), benzodiazepines, NSAIDs (2nd/3rd tri)	Use only if indicated; weigh risks
AVOID	ACEi/ARBs, AT1 blockers, valproate, tetracyclines, fluoroquinolones, warfarin (except mechanical valves), mycophenolate, methotrexate, cyclophosphamide, isotretinoin, misoprostol (for abortion — and general caution), street drugs, DOACs	Contraindicated
Contraindicated	Danazol, androgens, DES, statins (except pravastatin in some trials — not standard), spironolactone (antiandrogen), eplerenone, finasteride, tamsulosin	Avoid absolutely

---

End of Pharmacology Study Guide for MRCOG Part 1

This comprehensive document covers the full spectrum of pharmacokinetics, pharmacodynamics, and clinical therapeutics in obstetrics and gynaecology. It is designed for deep understanding and exam preparation, with particular emphasis on pregnancy-specific alterations, safety profiles, and high-yield comparisons.

Last updated: May 2026

○ Mark as completed