Principles of Prescribing in Pregnancy

Prescribing in pregnancy weighs maternal benefit against embryo and foetal risk while allowing for large physiological changes in drug handling. Untreated maternal disease (epilepsy, asthma, depression, hypertension, diabetes, infection) often harms the foetus more than the medicine that controls it, so stopping effective therapy is rarely the safe default.

Baseline risk. Major congenital malformations occur in about 2 to 4% of births with no exposure. Every exposure discussion states the added risk over this background, never an absolute risk alone.

Timing of exposure. From conception to about day 14 (gestational weeks 2 to 4) effects tend to be all or none. Organogenesis runs from about day 15 to day 60 after conception (gestational weeks 5 to 10) and carries the highest structural risk; after this, risk shifts to growth, organ function, neurodevelopment and neonatal effects.

Placental transfer. Small (under 500 Da), lipid-soluble, unionised and unbound molecules cross freely. Heparin, low molecular weight heparins and insulin (over 1000 Da) cross minimally; IgG monoclonal antibodies are actively transported from the second trimester, peaking in the third.

Pharmacokinetics. Plasma volume rises by 40 to 50% and glomerular filtration by about 50%, so lithium, levetiracetam, aminoglycosides and low molecular weight heparins clear faster. Albumin falls, raising the free fraction of phenytoin and valproate.

Enzyme changes. CYP3A4, CYP2D6, CYP2C9 and UGT1A4 activity rise (lamotrigine clearance can double or more by the third trimester); CYP1A2 and CYP2C19 activity fall (caffeine, theophylline and clozapine levels rise).

Labelling. Current product labels give narrative pregnancy and lactation summaries with data and clinical considerations. Letter categories persist in older references and oversimplify risk.

Selection rules. Choose the medicine with the longest safety record, at the lowest effective dose, for the shortest necessary time. Prefer monotherapy, avoid switching a well-controlled patient to an unfamiliar agent during pregnancy, and make planned changes before conception.

Preconception review. Review every medicine in anyone who could conceive. Switch known teratogens before conception, confirm highly effective contraception while they continue, and test for pregnancy before starting them.

Core supplements.

• Folic acid 400 micrograms orally once daily from at least 1 month before conception until 12 weeks.
• Folic acid 5 mg orally once daily over the same period for higher risk: previous neural tube defect in either parent or a prior pregnancy, antiepileptic therapy, diabetes, BMI 30 kg/m2 or more, sickle cell disease, thalassaemia or malabsorption. In sickle cell disease and haemolytic states 5 mg daily usually continues throughout pregnancy.
• Elemental iron 30 to 60 mg orally once daily for routine supplementation; 100 to 200 mg elemental iron daily for iron deficiency anaemia, moving to intravenous iron (ferric carboxymaltose or iron sucrose) from the second trimester if oral iron fails, is not tolerated or time to birth is short.
• Aspirin 75 to 150 mg orally at night from 12 weeks (ideally before 16 weeks) until 36 weeks for high or moderate risk of pre-eclampsia. 150 mg is usual practice in many regions; 75 mg is used in others.
• Calcium 1.5 to 2 g elemental daily in divided doses from 20 weeks where dietary calcium is low, to reduce pre-eclampsia risk. Separate from iron by at least 2 hours.

Dose drift. Lamotrigine, levetiracetam, lithium and levothyroxine often need dose increases as pregnancy advances and reduction within days to weeks after birth.

Regional points (East Africa). In malaria-endemic areas give sulfadoxine-pyrimethamine 1500 mg/75 mg (3 tablets) orally as a single directly observed dose at each antenatal visit from 13 weeks, at least 1 month apart, aiming for at least 3 doses until birth. Do not give it with co-trimoxazole prophylaxis or in the first trimester.

Folic acid with sulfadoxine-pyrimethamine. Folic acid 5 mg daily or more can reduce its antimalarial effect; use 400 micrograms daily in women receiving it unless a specialist directs otherwise.

Established teratogens. Valproate (malformations in about 10%, neurodevelopmental impairment in up to 30 to 40%), isotretinoin and oral retinoids, mycophenolate, methotrexate, thalidomide, warfarin (embryopathy, highest risk at 6 to 12 weeks), leflunomide, misoprostol, ribavirin, danazol and androgens.

Other first trimester risks. Carbamazepine, phenytoin, phenobarbital and topiramate (orofacial clefts, neural tube and cardiac defects), lithium (cardiac defects, small absolute risk), high-dose fluconazole (150 mg single doses carry little or no added risk).

Later pregnancy risks. ACE inhibitors and angiotensin receptor blockers cause foetal renal failure, oligohydramnios and skull hypoplasia, mainly in the second and third trimesters. NSAIDs after 20 weeks reduce foetal renal output; from 30 weeks they can close the ductus arteriosus.

Near-term risks. Sulphonamides (neonatal jaundice), nitrofurantoin (neonatal haemolysis), benzodiazepines and opioids (sedation, withdrawal), SSRIs (poor neonatal adaptation, small rise in persistent pulmonary hypertension), beta-blockers (neonatal bradycardia and hypoglycaemia), tetracyclines after about 15 weeks (tooth and bone staining).

Interactions. Iron, calcium and antacids reduce absorption of levothyroxine, quinolones and tetracyclines; separate by at least 4 hours. Enzyme-inducing antiepileptics and rifampicin cut hormonal contraceptive efficacy, so preconception contraception must allow for them.

Special groups.

• Adolescents: higher rates of anaemia and pre-eclampsia; check dosing against weight.
• Kidney impairment: serum creatinine normally falls by about a third, so a value in the non-pregnant normal range can reflect real impairment.
• Liver impairment: intrahepatic cholestasis, acute fatty liver and HELLP syndrome alter drug handling and bleeding risk.
• Obesity: weight-based dosing for low molecular weight heparins and some antibiotics.
• Regional: ask specifically about herbal and traditional remedies, several of which are uterotonic or hepatotoxic.

Monitoring. Lithium trough levels 12 hours after the dose every 4 weeks until 36 weeks, then weekly, and within 24 hours of birth. Lamotrigine and levetiracetam levels each trimester against the pre-pregnancy baseline. Phenytoin free levels where available. TSH every 4 to 6 weeks to 20 weeks, then at least once at 26 to 32 weeks.

Foetal surveillance. Offer a detailed anomaly scan at 18 to 22 weeks after any first trimester teratogen exposure, and foetal echocardiography after lithium or when maternal disease raises cardiac risk.

Unplanned exposure. Date the pregnancy by ultrasound, map exposure against embryonic age, record dose and duration, then continue, switch or stop based on the safest effective option. Document counselling; termination is never an automatic response.

Stopping rules. Do not stop antiepileptics, antidepressants, antipsychotics, beta-blockers, long-term corticosteroids or opioid substitution therapy abruptly on discovering pregnancy. Stop ACE inhibitors and angiotensin receptor blockers as soon as pregnancy is confirmed and substitute.

Postpartum adjustment. Return doses raised in pregnancy towards pre-pregnancy levels: lithium on the day of birth, lamotrigine stepwise over about 2 to 3 weeks with level checks.

Referral and escalation. Refer early to obstetric medicine or a joint clinic for valproate, mycophenolate or methotrexate exposure, mechanical heart valves, uncontrolled epilepsy, severe mental illness, organ transplantation, active autoimmune disease or HIV with a detectable viral load.