Appropriate prescribing in pregnancy and lactation
The default error
- The default error is stopping a needed drug, not starting a harmful one
- Untreated epilepsy, asthma, depression, thyroid disease, SLE, VTE and hypertension harm mother and fetus more than the great majority of the drugs used to treat them
- Every decision is a comparison of two risks, never an absolute judgement
Australian TGA pregnancy categories - and their limits
| Meaning | |
|---|---|
| A | Taken by many pregnant women without an observed increase in malformation |
| B1/B2/B3 | Limited human data; B3 = animal evidence of harm, human significance uncertain |
| C | Pharmacological effects causing harmful reversible effects without malformation |
| D | Increased incidence of malformation or irreversible damage |
| X | High risk of permanent damage - must not be used in pregnancy or where pregnancy is possible |
- *The categories are not a hierarchy of risk - a category B3 drug may be far more dangerous than a category D drug with a well-quantified small risk*
- B reflects lack of data, D reflects the presence of data
- Do not prescribe from the category alone - use a dedicated source (Therapeutic Guidelines, AMH, an obstetric medicine service, or MotherSafe / a state medicines-in-pregnancy service)
Epidemiology
- ~50% of Australian pregnancies are unplanned - the drug decision must be made before conception, at the point of prescribing to any person of childbearing potential
- >80% of pregnant women take at least one medicine; ~50% take a prescription medicine
- Background rate of major congenital malformation is 2-4% - the denominator for every counselling conversation
- Chronic disease in pregnancy is increasing with maternal age
- Almost all trials exclude pregnant women - evidence is observational, registry-based and accumulates slowly
Timing determines the type of harm
| Gestation | Event | Effect of exposure |
|---|---|---|
| 0-2 weeks post-conception | Pre-implantation | "All or nothing" - loss or intact survival |
| 3-8 weeks (organogenesis) | Organ formation | Structural malformation |
| 9 weeks - term | Growth and maturation | Growth restriction, functional and neurodevelopmental effects, fetotoxicity |
| Third trimester / peripartum | Neonatal withdrawal, adaptation syndromes, direct pharmacological effect |
Placental transfer
- Favoured by: low molecular weight (<500 Da), lipid solubility, non-ionised, low protein binding
- Does not cross meaningfully: heparin/LMWH (large, polar), insulin, most monoclonal antibodies in the first trimester
- IgG monoclonals DO cross actively from ~16-22 weeks via FcRn and accumulate in the third trimester -> live vaccine restrictions in the infant
Lactation - principles
Lactation
- Transfer depends on maternal plasma concentration, protein binding, lipid solubility, oral bioavailability in the infant, and infant clearance
- Relative infant dose (RID) <10% is generally regarded as compatible
- Most drugs are compatible with breastfeeding - the more common error is unnecessary cessation of breastfeeding
- Higher risk: premature or unwell neonates, drugs with long half-lives, sedatives, and drugs with narrow therapeutic index
Before prescribing to any person of childbearing potential
"Diagnosis" here = the pre-prescribing assessment.
- Could this person become pregnant? Contraception, plans, fertility
- Is the drug teratogenic, and is there a safer alternative with equal efficacy?
- Is contraception required, and for how long after stopping?
- Folate requirement (see Management)
- Document the discussion
Pre-pregnancy planning - where most of the benefit lies
- Switch to a pregnancy-compatible regimen before conception, allowing time to establish disease control
- Optimise disease activity first - conception during active disease is the greater risk (SLE, IBD, epilepsy)
- High-dose folate 5 mg/day if: previous NTD, diabetes, BMI >=30, antiepileptic drugs, methotrexate exposure, malabsorption, haemoglobinopathy
- Otherwise folic acid 500 micrograms/day from 1 month before conception to 12 weeks
- Iodine 150 micrograms/day; vitamin D if deficient
If exposure has already occurred
- Establish the exact drug, dose and gestational window
- Quantify the absolute risk (background 2-4% + attributable increase)
- Referral to obstetric medicine; consider detailed anomaly ultrasound at 18-20 weeks, fetal echo where indicated
- *Do not advise termination reflexively* - most exposures do not justify it
Drugs to avoid - the absolute list
A. Drugs to avoid - the absolute list
| Drug | Effect |
|---|---|
| Sodium valproate | Major malformation ~10% (NTD, cardiac, facial, limb) AND neurodevelopmental disorder/autism in up to ~30-40%; IQ reduction. Dose-dependent |
| Isotretinoin, acitretin | Retinoid embryopathy - craniofacial, cardiac, CNS. Contraception for 1 month (isotretinoin) and 3 years (acitretin) after |
| ACE inhibitors, ARBs, direct renin inhibitors | Fetal renal failure, oligohydramnios, skull hypoplasia, limb contracture (second/third trimester) |
| Methotrexate | Abortifacient, craniofacial and limb defects. Stop 1-3 months before conception |
| Mycophenolate | Microtia, orofacial clefts, cardiac - pregnancy prevention required; switch to azathioprine |
| Warfarin | Warfarin embryopathy (weeks 6-9), fetal haemorrhage. Exception: some mechanical valves - specialist decision |
| Thalidomide, lenalidomide | Phocomelia |
| Cyclophosphamide | Teratogenic, gonadotoxic |
| Live vaccines | MMR, varicella, yellow fever |
| Tetracyclines (after 18 wks) | Dental staining, bone |
| Fluconazole (high dose), NSAIDs after 20 weeks (ductal constriction, oligohydramnios, renal) | |
| Androgens, oestrogens, finasteride, misoprostol, radioactive iodine |
Valproate specifically
B. Valproate specifically - the highest-stakes prescribing decision in medicine
- Do not prescribe to a person of childbearing potential unless every alternative has failed and effective contraception is in place
- Risk is dose-dependent; neurodevelopmental risk persists at doses that seem modest
- TGA 2025 safety advice extends counselling to male patients - contraception for both partners during treatment and for 3 months after, on signals of paternal-exposure neurodevelopmental risk
- Australia has not mandated the UK's two-specialist requirement, but the counselling, documentation and contraception expectations are the same
- Annual review, written risk acknowledgement, and documented contraception
Common conditions - what to use
C. Common conditions - what to use
| Condition | Preferred in pregnancy |
|---|---|
| Epilepsy | Lamotrigine or levetiracetam (monitor levels - clearance rises markedly). Avoid valproate and topiramate |
| Hypertension | Labetalol, nifedipine, methyldopa. Never ACEi/ARB |
| Asthma | Continue inhaled corticosteroid and salbutamol - uncontrolled asthma is the greater risk |
| Depression/anxiety | Sertraline (also preferred in lactation). Paroxetine - small cardiac signal; counsel on neonatal adaptation syndrome and PPHN |
| Thyroid | Propylthiouracil in the first trimester, switch to carbimazole thereafter (carbimazole embryopathy first trimester; PTU hepatotoxicity later). Levothyroxine dose typically rises ~25-30% |
| VTE / thromboprophylaxis | LMWH - does not cross the placenta; DOACs contraindicated |
| IBD | Azathioprine, mesalazine, anti-TNF (infliximab/adalimumab cross in the third trimester -> delay infant live vaccines). Avoid methotrexate |
| Rheumatic disease | Hydroxychloroquine (continue - reduces flare and congenital heart block), sulfasalazine + folate, azathioprine, low-dose prednisolone |
| Diabetes | Insulin; metformin acceptable. Stop ACEi/ARB and statins |
| Infection | Penicillins, cephalosporins, macrolides generally safe; avoid tetracyclines, high-dose fluconazole, and use trimethoprim with caution in the first trimester (folate antagonist) |
| Nausea/vomiting | Pyridoxine, doxylamine, metoclopramide, ondansetron (small first-trimester cleft signal - weigh against hyperemesis) |
| Analgesia | Paracetamol; avoid NSAIDs after 20 weeks; short-course opioid if needed |
Lactation - practice
D. Lactation
- Most drugs are compatible - assess RID, infant age and health, and timing of feeds relative to dosing
- Preferred: sertraline, paroxetine, labetalol, nifedipine, enalapril/captopril, LMWH, warfarin, insulin, levothyroxine, most antibiotics, ibuprofen, paracetamol
- Avoid or use with caution: codeine (CYP2D6 ultra-rapid metabolisers - infant respiratory depression; avoid), lithium (monitor infant levels), amiodarone, cytotoxics, radioactive iodine, high-dose benzodiazepines, ergotamine
- *Do not stop breastfeeding by default* - check a proper source first
Practical safeguards
E. Practical safeguards
- Advice services: MotherSafe (NSW), the Royal Women's Medicines Information, state obstetric medicine services
- Therapeutic Guidelines and AMH before any decision; never the TGA category alone
- Enrol in pregnancy exposure registries where they exist
- Communicate the plan to the GP, obstetrician, pharmacist and the patient in writing
Associations
- Unplanned pregnancy; contraception failure; adolescent and perimenopausal prescribing
- Epilepsy, bipolar disorder, SLE, IBD, rheumatoid arthritis, transplantation, HIV, chronic hypertension, diabetes
- Polypharmacy and comorbidity in older mothers
- Altered pharmacokinetics of pregnancy - inc Vd, inc GFR, inc hepatic metabolism, dec albumin -> many drugs need dose increases and level monitoring (lamotrigine, levetiracetam, levothyroxine, LMWH, digoxin, lithium)
- Neonatal adaptation syndrome (SSRIs), neonatal abstinence (opioids, benzodiazepines), floppy infant syndrome
- Medico-legal and consent considerations; TGA safety alerts and Blue Card reporting
- Health literacy, interpreter needs, rural access to specialist advice
Background and attributable risk
- Background major malformation risk 2-4% regardless of exposure - always state this first when counselling
- Teratogenic risk is dose- and timing-dependent and usually expressed as an absolute increment on that background
- Long-term outcomes accrue slowly: neurodevelopmental effects of valproate were recognised decades after the structural effects
- Assume the same for newer drugs where data are immature - absence of evidence is not evidence of safety
- Most exposures identified after the fact require reassurance plus targeted ultrasound, not intervention
- Requirements change across pregnancy - antiepileptic and levothyroxine doses usually need to rise, then fall promptly postpartum (lamotrigine toxicity in the first fortnight after delivery is a classic)
- Postpartum: review every drug again for lactation compatibility, and reinstate any teratogenic agent the mother needs only with contraception in place
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