Key Facts

Prescribing in pregnancy is a common clinical challenge. The key principle is to use the minimum effective dose of the safest available drug, balanced against the risk of untreated disease to both mother and fetus.

Epidemiology

• ~50% of pregnancies are unplanned — teratogen exposure may occur before pregnancy is recognised
• ~90% of pregnant women take at least one medication during pregnancy
• Congenital anomalies: ~2–3% of births; drug-related in ~1–2%

Pharmacokinetic Changes in Pregnancy

• Absorption: delayed gastric emptying, increased gastric pH → altered absorption
• Distribution: increased plasma volume (~50%), increased body fat, reduced albumin → altered Vd and protein binding
• Metabolism: CYP3A4 and CYP2D6 activity increased; CYP1A2 and CYP2C19 decreased
• Excretion: GFR increased by ~50% → increased renal clearance of drugs (lithium, digoxin, lamotrigine)

Pathophysiology of Teratogenesis

• Organogenesis (weeks 3–8): most vulnerable period; structural malformations
• Pre-implantation (weeks 1–2): 'all-or-nothing' — either lethal or no effect
• 2nd/3rd trimester: growth restriction, functional abnormalities (e.g. ACE-i → renal dysgenesis)
• Peripartum: neonatal effects (e.g. SSRI → neonatal adaptation syndrome; opioid → neonatal withdrawal)
• Mechanism: drug crosses placenta → disrupts cell proliferation, migration, differentiation → structural/functional defect

Known Teratogenic Effects

• Valproate: NTDs (spina bifida ~7%), cardiac defects, hypospadias, craniofacial abnormalities, neurodevelopmental delay (~40% risk)
• Warfarin: nasal hypoplasia, stippled epiphyses (chondrodysplasia punctata), CNS abnormalities
• ACE inhibitors/ARBs: renal dysgenesis, oligohydramnios, pulmonary hypoplasia, skull defects
• Retinoids: craniofacial, cardiac, CNS defects — isotretinoin and acitretin
• Methotrexate: NTDs, limb defects, craniofacial abnormalities — potent teratogen
• Lithium: Ebstein's anomaly (tricuspid valve) — risk ~0.1% (lower than previously thought but still increased)
• Carbamazepine: NTDs (~1%), craniofacial defects — less teratogenic than valproate
• Phenytoin: fetal hydantoin syndrome — craniofacial, limb, cardiac defects
• Thalidomide: phocomelia — historical; now used for myeloma with strict pregnancy prevention

Neonatal Effects

• SSRIs (3rd trimester): neonatal adaptation syndrome — jitteriness, irritability, poor feeding, respiratory distress
• Benzodiazepines: floppy infant syndrome, neonatal withdrawal
• Opioids: neonatal abstinence syndrome (NAS) — irritability, poor feeding, seizures
• Beta-blockers: neonatal bradycardia, hypoglycaemia

Red Flags

• Patient on valproate and pregnant or planning pregnancy — URGENT review, MHRA PPP
• Unplanned pregnancy on known teratogen — immediate specialist referral
• Epilepsy in pregnancy — do NOT suddenly stop anticonvulsants (seizure risk to mother and fetus)

Pre-Conception

• Medication review: identify teratogens, switch to safer alternatives
• Folic acid: start 400 mcg OD (or 5 mg if high-risk) pre-conception
• Epilepsy: discuss risks, consider switching from valproate, optimise seizure control

During Pregnancy

• TDM: lamotrigine (levels fall in pregnancy — monthly monitoring, dose increase often needed), lithium (levels fall then rise peripartum), digoxin
• Anomaly scan (18–20 weeks): detailed USS — detects structural anomalies
• Fetal echocardiography: if exposed to lithium, SSRIs, or other cardiac teratogens
• Growth scans: if on drugs affecting fetal growth (beta-blockers, antihypertensives)

Special Tests

• UKTIS consultation: specialist advice on drug safety in pregnancy
• Serum drug levels: as above; frequency depends on drug
• Maternal serology/screening: routine antenatal screening

General Principles

• Avoid drugs in first trimester if possible (organogenesis)
• Use established drugs with known safety profile over newer drugs with less data
• Minimum effective dose: for shortest necessary duration
• Do not stop essential medication without alternative — untreated disease may pose greater risk than drug
• Shared decision-making: discuss risks and benefits with patient

Safe Drug Options in Pregnancy

• Pain: paracetamol (1st choice); avoid NSAIDs (especially 3rd trimester — premature closure of ductus arteriosus)
• Antibiotics: penicillins, cephalosporins, erythromycin (NOT erythromycin estolate) — safe; avoid tetracyclines (tooth/bone staining), quinolones (cartilage), trimethoprim (1st trimester — folate antagonist)
• Antiemetics: cyclizine, prochlorperazine, ondansetron (limited 1st trimester data); doxylamine-pyridoxine (evidence-based for NVP)
• Hypertension: labetalol (1st choice), nifedipine MR, methyldopa; avoid ACE-i/ARBs
• Epilepsy: lamotrigine, levetiracetam — preferred; avoid valproate; monitor levels
• Asthma: inhaled corticosteroids + SABA — continue as normal; poorly controlled asthma is riskier than medication
• Diabetes: insulin (all types); metformin increasingly used (crosses placenta but no major concerns); stop gliclazide
• Anticoagulation: LMWH (e.g. enoxaparin) — does not cross placenta; avoid warfarin (teratogenic)
• Depression: sertraline preferred SSRI; avoid paroxetine (cardiac defects); CBT first-line for mild-moderate
• Thyroid: propylthiouracil (1st trimester) → carbimazole (2nd/3rd); levothyroxine — increase dose by ~25–50%

MHRA Valproate Pregnancy Prevention Programme

• Valproate MUST NOT be prescribed to women of childbearing potential unless on effective contraception AND enrolled in PPP
• Annual specialist review required
• Informed consent and acknowledgement form

Referral Criteria

• Obstetric medicine: complex medication management in pregnancy
• UKTIS: specialist drug safety advice
• Maternal-fetal medicine: high-risk pregnancy, teratogen exposure
• Epilepsy nurse specialist: anticonvulsant management in pregnancy

• Most medications are safe in pregnancy — only a small number are established teratogens
• Untreated maternal disease (epilepsy, hypertension, diabetes, depression) often poses greater risk than medication
• Valproate: up to 40% risk of neurodevelopmental problems — MHRA PPP aims to prevent exposed pregnancies
• Early pre-conception counselling and medication review significantly reduces teratogenic risk
• Folic acid: reduces NTD risk by ~70% when taken pre-conception and in early pregnancy

Key Teratogens Summary

Folic Acid Dosing