Drugs in pregnancy
Drugs in pregnancy: teratogens, timing and placental transfer
Teratogens for FCPS Part 1: which drugs cross the placenta, why timing matters, and the defects caused by valproate, warfarin, retinoids and lithium. Also covers safer alternatives, folic acid, valproate toxicity and neonatal effects of late exposure.
What decides placental transfer
- Most drugs cross by simple diffusion, so the rules of membrane crossing apply.
| Favours crossing | Limits crossing |
|---|---|
| Molecular weight under about 500 Da | Over about 1000 Da: heparin, LMWH, insulin |
| High lipid solubility (diazepam, opioids, propofol, warfarin, carbimazole) | Permanent charge: quaternary drugs such as neuromuscular blockers |
| Un-ionised at plasma pH | Highly ionised or polar drugs |
| Low protein binding | High protein binding; efflux pumps (P-glycoprotein) in trophoblast |
- IgG is the exception to the size rule: it is actively carried by neonatal Fc receptors, mainly in the third trimester.
- Ion trapping: weak bases (local anaesthetics, pethidine) ionise in the more acidic fetal blood and accumulate, especially in an acidotic fetus.
- Late exposure lasts longer in the baby because the neonatal liver has little oxidative and glucuronidation capacity and the kidneys are immature. Diazepam and its active metabolite desmethyldiazepam are cleared over days to weeks, so a baby exposed near term is floppy (hypotonia, hypothermia, apnoea, poor feeding); withdrawal (jitteriness, irritability) can follow once sedation wears off. Maternal opioids also give neonatal withdrawal.
Timing decides the type of harm
| Period after conception | Effect of a harmful drug |
|---|---|
| Weeks 0–2 (pre-embryonic) | All or none: loss of the conceptus or complete recovery |
| Weeks 3–8 (embryonic, organogenesis) | Major structural malformations; the most sensitive period |
| Week 9 to term (fetal) | Growth restriction, organ dysfunction, functional and behavioural effects |
- So a teratogenic effect is most likely when the drug is taken during organogenesis, often before the pregnancy is known.
- The neural tube closes by day 28, so folic acid must start before conception: 400 micrograms for all, 5 mg for women on antiepileptics, with diabetes, obesity or a previous neural tube defect.
Antiepileptics
- Folate antagonism links valproate, carbamazepine, phenytoin and phenobarbital to neural tube defects: they lower folate levels or interfere with folate metabolism. Valproate is the classic cause of drug-induced folate deficiency in this setting.
| Drug | Main fetal effect |
|---|---|
| Sodium valproate | Neural tube defects (spina bifida), cleft palate, heart and limb defects (about 10% overall); lower IQ and autism spectrum disorder even with no structural defect |
| Carbamazepine | Spina bifida (about 1%), facial and nail changes |
| Phenytoin | Fetal hydantoin syndrome: hypoplastic nails and distal phalanges, cleft lip, facial dysmorphism; neonatal vitamin K deficiency |
| Lamotrigine, levetiracetam | Lowest risk; preferred in women who could conceive |
- Valproate is avoided in women of childbearing age unless nothing else works, with a pregnancy prevention programme. Before starting it, check liver function (and a pregnancy test).
- Serious adverse effects of valproate: hepatotoxicity (especially young children), pancreatitis, hyperammonaemia with normal liver tests, thrombocytopenia, weight gain, tremor and hair loss, and teratogenicity.
- Valproate is an enzyme inhibitor: it inhibits lamotrigine glucuronidation, so adding valproate doubles lamotrigine levels, causing toxicity and a serious rash (Stevens–Johnson). Carbamazepine and phenytoin are enzyme inducers and reduce contraceptive and warfarin effects.
Classic teratogens
| Drug | Main fetal effect | Mechanism or note |
|---|---|---|
| Warfarin | Weeks 6–12: nasal hypoplasia, stippled epiphyses; later fetal intracranial haemorrhage | Crosses; vitamin K antagonist |
| ACE inhibitors, ARBs | Second and third trimester: fetal renal failure, oligohydramnios, skull hypoplasia, contractures, lung hypoplasia | Fetal GFR depends on angiotensin II |
| Isotretinoin, other retinoids, high-dose vitamin A | Microtia with absent ear canals, small jaw, cleft palate, conotruncal heart defects, hydrocephalus | Disrupts cranial neural crest; prescribed by dermatologists for acne with strict contraception |
| Thalidomide | Phocomelia | Critical window days 20–36 |
| Lithium | Ebstein anomaly (downward displacement of the tricuspid valve) | Fetal echocardiography if used |
| Methotrexate | Skull, facial and limb defects, miscarriage | Folate antagonist |
| Mycophenolate | Microtia, absent ear canals, cleft lip and palate, heart defects | Stop at least 6 weeks before conception and switch to azathioprine; plan this in advance |
| Misoprostol (failed abortion) | Facial and abducent palsy (Möbius), limb defects | Vascular disruption |
| Danazol, androgens | Virilisation of a female fetus | Crosses |
| Diethylstilboestrol | Clear cell adenocarcinoma, T-shaped uterus in daughters | Historical |
| Tetracyclines | Stained teeth, impaired bone growth | Chelate calcium |
| Aminoglycosides | Eighth nerve damage, deafness | Ototoxic |
| Carbimazole (methimazole) | Aplasia cutis, choanal and oesophageal atresia | Crosses; propylthiouracil preferred in the first trimester, then switch back because PTU is hepatotoxic |
| Radioactive iodine | Destruction of the fetal thyroid | Contraindicated |
| Alcohol | Smooth philtrum, thin upper lip, short palpebral fissures, microcephaly, VSD | Commonest preventable cause of intellectual disability |
| Ribavirin | Strongly teratogenic; persists in semen | Contraception for both partners for 6 months |
- Infections act like teratogens too: congenital rubella gives cataract, glaucoma, sensorineural deafness and patent ductus arteriosus or pulmonary stenosis.
- Among antiretrovirals, efavirenz was long avoided in the first trimester because of a possible neural tube defect signal; current guidance is to continue effective treatment and seek specialist advice.
Late pregnancy effects
- NSAIDs after about 30 weeks: premature closure of the ductus arteriosus and reduced fetal urine (oligohydramnios).
- Sulphonamides near term displace bilirubin (kernicterus); chloramphenicol causes grey baby syndrome; nitrofurantoin at term risks neonatal haemolysis.
- Pethidine or morphine near delivery depresses neonatal breathing (naloxone, except in babies of opioid-dependent mothers).
Safer choices
| Problem | Avoid | Use |
|---|---|---|
| DVT in pregnancy | Warfarin | LMWH (does not cross) |
| Hypertension | ACE inhibitors, ARBs | Labetalol, nifedipine, methyldopa |
| Diabetes | Most oral agents except metformin | Insulin (does not cross); metformin acceptable |
| Epilepsy | Valproate | Lamotrigine, levetiracetam |
| Hyperthyroidism, first trimester | Carbimazole, radioiodine | Propylthiouracil |
| Acne | Isotretinoin | Topical agents (not retinoids) |
- A woman with a mechanical heart valve on warfarin planning pregnancy needs specialist pre-pregnancy counselling: options are LMWH (dose adjusted to anti-Xa levels) through weeks 6–12, or continuing low-dose warfarin, balancing embryopathy against valve thrombosis.
- Older risk letters (A, B, C, D, X) are replaced by narrative statements; category X still means risk outweighs benefit (isotretinoin, thalidomide).
Remember Weeks 3–8 make malformations; before that is all or none, after that is growth and function.
Exam trap Heparin and LMWH do not cross the placenta because they are large molecules; warfarin does cross.
Exam trap A normal anomaly scan does not exclude valproate harm: its neurodevelopmental effects appear later.
How FCPS asks about this
- ACE inhibitor in pregnancy causes: fetal renal failure, oligohydramnios and skull hypoplasia.
- Lithium teratogenicity: Ebstein anomaly, downward displacement of the tricuspid valve.
- Microtia, conotruncal heart defect after acne treatment: retinoids (isotretinoin).
- Valproate causes deficiency of: folate; neural tube defects, plus lower IQ and autism.
- DVT in a pregnant woman on warfarin: switch to low-molecular-weight heparin.
- Antithyroid drug that crosses and is teratogenic in early pregnancy: carbimazole; use propylthiouracil in the first trimester.
- Teratogenic effects are greatest in: weeks 3–8 after conception (organogenesis).
Test yourself on this topic
5 of the 23 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A labouring woman with a lidocaine epidural has a fetus whose scalp blood pH is 7.10. After delivery the fetal-to-maternal ratio of lidocaine is higher than in babies born with a normal pH. What explains this?
Answer: Ion trapping in acidotic fetal blood
Lidocaine is a weak base (pKa about 7.9). The un-ionised form crosses the placenta. In acidotic fetal blood more of it becomes ionised, and ionised drug cannot cross back, so it accumulates in the fetus. This ion trapping raises fetal levels of local anaesthetics and opioids when the fetus is acidotic. Fetal protein binding is actually lower than maternal, and there is no active placental transport.
Ion trapping
- Local anaesthetics are weak bases
- Un-ionised form crosses placenta
- In acidic fetal blood it ionises
- Ionised drug is trapped in fetus
Remember Acidotic fetus traps basic drugs.
Exam trap The same mechanism traps weak bases in breast milk, which is slightly more acidic than plasma.
Why the other options are wrong
- Lower fetal hepatic blood flow Hepatic flow does not explain the pH-related difference.
- Higher protein binding in fetal plasma Fetal plasma binds local anaesthetics less than maternal plasma.
- Active transport of lidocaine by placenta Lidocaine crosses by passive diffusion.
- Slower fetal renal excretion Renal excretion is too slow to matter acutely.
A baby is born with an expressionless face, inability to close the eyes or move them outwards, and club feet. At 7 weeks his mother had taken tablets bought from a chemist in a failed attempt to end the pregnancy, and had cramps and bleeding afterwards. Which drug did she most likely take?
Answer: Misoprostol
Moebius sequence is congenital palsy of the facial and abducent nerves, often with limb defects such as club foot. It is linked to failed abortion attempts with misoprostol, a PGE1 analogue that is cheap and widely available. Strong uterine contractions are thought to cause vascular disruption, reducing blood flow to the embryonic brainstem and limbs. Mifepristone alone is not linked to this pattern.
Misoprostol and Moebius
- Failed abortion with misoprostol
- Uterine contractions: vascular disruption
- Facial and abducent nerve palsy
- Limb defects, club foot
Remember Masklike face after failed misoprostol: Moebius.
Exam trap After a failed medical abortion the risk of anomalies must be discussed, as the drug may already have harmed the embryo.
Why the other options are wrong
- Mifepristone Mifepristone is a progesterone receptor antagonist without this association.
- Methotrexate Methotrexate causes skull and limb anomalies, not Moebius sequence.
- Ergometrine Ergometrine is not used for early termination.
- Clomiphene Clomiphene is used before conception, not to end pregnancy.
A woman with hypertension continued enalapril throughout pregnancy. At 30 weeks there is severe oligohydramnios, and the baby is born with renal failure, limb contractures and poorly formed skull bones. What is the mechanism of these fetal effects?
Answer: Fetal renal hypoperfusion, low angiotensin II
The fetal kidney depends on angiotensin II to constrict the efferent arteriole and maintain glomerular filtration. ACE inhibitors cross the placenta, so in the second and third trimesters they cause fetal renal hypoperfusion, renal tubular dysgenesis and anuria. Little fetal urine gives oligohydramnios, which causes lung hypoplasia and limb contractures, while hypoperfusion also impairs skull ossification.
ACE inhibitor fetopathy
- Fetal GFR needs angiotensin II
- ACE inhibitors cause renal hypoperfusion
- Anuria gives oligohydramnios
- Hypocalvaria, contractures, lung hypoplasia
Remember No angiotensin II, no fetal urine.
Exam trap Angiotensin receptor blockers cause the same fetopathy.
Why the other options are wrong
- Direct toxicity of the drug to the nephrons The injury is haemodynamic, not direct toxicity.
- Placental infarction from maternal hypotension Placental infarction does not explain the specific renal pattern.
- Folate antagonism in the first trimester Folate antagonism is the mechanism of methotrexate and trimethoprim.
- Fetal hyperkalaemia damaging the kidneys Hyperkalaemia is not the cause of the renal dysgenesis.
A woman with a mechanical mitral valve stays on warfarin until she labours unexpectedly at 37 weeks; her INR is 2.8. Her baby has an intracranial haemorrhage after a normal vaginal delivery. Why was the fetus so heavily anticoagulated?
Answer: Warfarin crosses, and fetal liver makes few factors
Warfarin is a small, lipid-soluble molecule that crosses the placenta. The fetal liver is immature and already has low levels of vitamin K–dependent factors (II, VII, IX, X), so the fetus becomes more anticoagulated than the mother. The moulding of the head in labour then causes intracranial bleeding. For this reason warfarin is replaced by heparin before planned delivery, which does not cross.
Warfarin at delivery
- Warfarin crosses the placenta
- Fetal liver: low vitamin K–dependent factors
- Fetus more anticoagulated than mother
- Switch to heparin before delivery
Remember Warfarin in labour: the baby bleeds more than the mother.
Exam trap Reversing the mother's INR does not instantly correct the fetus's clotting.
Why the other options are wrong
- Maternal antibodies attack fetal platelets Alloimmune thrombocytopenia is a different condition.
- Heparin bridging crossed the placenta Heparin is too large to cross the placenta.
- Fetal vitamin K stores are higher than maternal Fetal vitamin K stores are low, not high.
- Warfarin is concentrated in amniotic fluid Amniotic fluid concentration is not the mechanism.
A woman was given intramuscular pethidine 100 mg three hours before delivery. Her term baby is pink with a good heart rate but makes only weak, slow breathing efforts after initial resuscitation. Which drug should be given to the baby?
Answer: Naloxone
Pethidine crosses the placenta, and fetal levels peak a few hours after a maternal dose. The newborn eliminates pethidine and its metabolite norpethidine slowly, so respiratory depression can occur. Naloxone, a competitive mu-receptor antagonist, reverses opioid depression after ventilation has been established. Its action may be shorter than pethidine's, so the baby must be observed for recurrence.
Neonatal opioid depression
- Pethidine crosses the placenta
- Neonate clears it slowly
- Weak breathing after good heart rate
- Naloxone once ventilation is established
Remember Ventilate first, then naloxone if opioid-depressed.
Exam trap Naloxone is avoided in babies of opioid-dependent mothers because it can precipitate withdrawal seizures.
Why the other options are wrong
- Flumazenil Flumazenil reverses benzodiazepines.
- Doxapram Doxapram is a non-specific respiratory stimulant, not an opioid antagonist.
- Neostigmine Neostigmine reverses non-depolarising relaxants.
- Atropine Atropine treats bradycardia, which this baby does not have.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Drugs in obstetrics and gynaecology, Drugs in pregnancy: teratogens and placental transfer
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