Obstetrics and Gynaecology chapters
Teratogens and drugs in pregnancy
How drugs reach the fetus, why the timing of exposure decides the damage, which drugs are known teratogens, and what to prescribe instead in a pregnant woman.
- A teratogen damages the embryo in a dose-dependent way, causes a recognisable pattern of defects, and acts during a critical period of organ formation.
- Weeks 3-8 (organogenesis) is the time of major structural defects; later exposure mainly harms growth and function.
- Learn the pairs: warfarin with nasal hypoplasia, valproate with neural tube defects, ACE inhibitors with fetal kidney damage, retinoids with multiple malformations, tetracyclines with stained teeth.
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Overview
A teratogen is an agent that disturbs the growth or structure of the embryo or fetus. Most malformations are not caused by drugs: even with no known exposure, roughly 3% of babies have an abnormality, and only a small number of drugs are proven human teratogens. The exam, however, tests the classic drug-defect pairs, the timing of damage, and the safer substitute for each hazardous drug.
To call a drug a teratogen, three things should hold: a characteristic pattern of malformations, action at a particular stage of development, and a dose-dependent rise in incidence.
How drugs reach the fetus
Most drugs taken by a pregnant woman cross the placenta. Transfer depends on:
| Property | Effect on transfer |
|---|---|
| Lipid solubility | Lipophilic drugs diffuse across easily (thiopental reaches the baby almost at once) |
| Ionisation | Highly ionised drugs such as suxamethonium cross slowly and reach low fetal levels |
| Molecular size | Below about 500 daltons crosses easily; above about 1,000 crosses very poorly, which is why heparin does not reach the fetus |
| Protein binding | Heavily bound drugs transfer more slowly, since only unbound drug diffuses |
| pH difference | Fetal blood is slightly more acidic than maternal blood, so weak bases become trapped on the fetal side |
Two mechanisms protect the fetus: the placenta metabolises some drugs (it converts prednisolone to inactive prednisone, so prednisolone is usable in pregnancy), and placental transporters such as P-glycoprotein pump some drugs back into the maternal circulation. From the second trimester the placenta also carries immunoglobulins across, which matters for biological drugs and for rhesus disease.
"Does not cross the placenta" is a property of large, polar molecules. Heparin and low molecular weight heparin do not cross; warfarin does.
Timing: critical periods
| Stage | Weeks after fertilisation | Effect of a harmful exposure |
|---|---|---|
| Pre-embryonic | 1-2 | All-or-none: either the conceptus dies or it recovers fully; malformation is unusual |
| Embryonic (organogenesis) | 3-8 | Major structural malformations; each organ has its own short window |
| Fetal | 9 weeks to term | Growth restriction, functional and minor structural damage, and effects on brain development |
"Three to eight, shapes your fate." Weeks 3-8 decide structure; after that, drugs mainly affect growth and function.
Limb malformation from thalidomide happens only with exposure in roughly the fourth to seventh week, when the limbs are forming. The same drug later in pregnancy would not cause phocomelia.
Drugs with known harmful fetal effects
| Drug | Main fetal effect |
|---|---|
| Thalidomide | Phocomelia (shortened or absent long bones) and internal malformations |
| Isotretinoin, etretinate (retinoids) | Very high risk of brain, face and ear malformations |
| Warfarin | First trimester: nasal hypoplasia, chondrodysplasia punctata; later: brain malformation and fetal intracranial bleeding |
| Sodium valproate | Neural tube defects, cardiac and limb defects, developmental delay; risk rises with dose |
| Carbamazepine, phenytoin, phenobarbitone | Neural tube defects, facial clefts, cardiac defects; phenytoin gives the fetal hydantoin pattern |
| Topiramate | Oral cleft |
| ACE inhibitors and angiotensin receptor blockers | Fetal and neonatal kidney damage, poor skull ossification (hypocalvaria); worst in the second and third trimesters |
| Lithium | Ebstein anomaly; neonatal toxicity after late exposure |
| Methotrexate, cyclophosphamide, aminopterin, mycophenolate | Multiple malformations |
| Tetracyclines | Discoloured teeth and altered bone growth |
| Aminoglycosides (streptomycin) | Deafness in the newborn |
| Carbimazole, propylthiouracil, iodide | Fetal goitre and hypothyroidism if the dose is high |
| Diethylstilboestrol | Vaginal adenosis and clear cell adenocarcinoma of the vagina in the exposed daughter |
| Misoprostol | Möbius sequence after failed first-trimester use |
| Androgens | Virilisation of a female fetus |
| Alcohol | Fetal alcohol spectrum disorder: growth failure, facial changes, brain damage |
| Smoking | Growth restriction, preterm birth, sudden infant death |
| Sulfonamides near term | Displace bilirubin and raise the risk of kernicterus |
| NSAIDs in late pregnancy | Early closure of the ductus arteriosus, reduced fetal urine output |
| Opioids used long term | Neonatal withdrawal after birth |
Prostaglandin inhibitors close the duct; prostaglandin E keeps it open. Indometacin given as a tocolytic can shut the fetal duct, most of all after 32 weeks.
Teratogenic effects are not only structural. Growth restriction, miscarriage, stillbirth and later cognitive problems count as well.
Safer alternatives: the substitution table
| Condition | Avoid | Prefer in pregnancy |
|---|---|---|
| Hypertension | ACE inhibitors, sartans, atenolol | Labetalol, nifedipine, methyldopa |
| Anticoagulation | Warfarin | Low molecular weight heparin |
| Epilepsy | Valproate (and polytherapy) | Lamotrigine or levetiracetam; single drug at the lowest effective dose |
| Thyrotoxicosis | Radioactive iodine (absolutely) | Propylthiouracil or carbimazole at the lowest acceptable dose |
| Diabetes | Most other oral agents | Insulin, with metformin where appropriate |
| Infection | Tetracyclines, aminoglycosides, quinolones | Penicillins, cephalosporins, erythromycin or azithromycin |
| Pain | NSAIDs, especially late | Paracetamol |
| Severe acne | Retinoids | Topical treatment; delay systemic treatment |
| Nausea and vomiting | - | Antihistamine antiemetics are long established |
Radioactive iodine is absolutely contraindicated in pregnancy because it destroys the fetal thyroid gland. Live vaccines such as rubella are also avoided; a woman vaccinated after delivery should use contraception for a month.
Prevention and counselling
- Preconception review of every long-term drug: stop, swap or reduce before conception, not after the pregnancy test.
- Folic acid 400 micrograms daily before conception and through the first trimester lowers the risk of neural tube defects. A 5 mg daily dose is advised where risk is higher: previous affected baby, diabetes, epilepsy or antiepileptic drugs, obesity.
- Weigh the harm of the untreated disease: uncontrolled fits, thyrotoxicosis, asthma or depression hurt mother and baby. Stopping treatment is not automatically the safe choice.
- Offer a detailed anomaly scan after a first-trimester exposure.
- Any drug grading system (such as the old lettered categories) is a rough guide only; use the current national guideline, which can change.
"Fix the drugs before the bump." Most teratogenic damage is done before the first antenatal visit.
Expect: the definition of a teratogen and the three criteria; the all-or-none period and weeks 3-8 as the time of major malformation; which drug causes which named defect (warfarin with nasal hypoplasia, valproate with neural tube defects, lithium with Ebstein anomaly, thalidomide with phocomelia, diethylstilboestrol with vaginal clear cell cancer, tetracycline with stained teeth, ACE inhibitors with fetal kidney damage); the properties that allow placental transfer and why heparin does not cross while warfarin does; the correct substitute drug for hypertension, anticoagulation, epilepsy, thyrotoxicosis and infection; folic acid dose and which women need 5 mg; radioactive iodine and live vaccines as absolute contraindications; the baseline 3% malformation rate used in counselling.
Quick revision
- Background malformation risk is about 3%; proven drug teratogens are few.
- Teratogen criteria: typical pattern, critical stage, dose dependence.
- Weeks 1-2 all-or-none; weeks 3-8 structural defects; after that growth and function.
- Lipophilic, small, unionised, poorly bound drugs cross the placenta best.
- Heparin and low molecular weight heparin do not cross; warfarin does.
- Valproate is the worst antiepileptic; lamotrigine and levetiracetam are preferred.
- Stop ACE inhibitors, sartans and atenolol; use labetalol, nifedipine or methyldopa.
- Radioactive iodine and live vaccines are contraindicated in pregnancy.
- Folic acid 400 micrograms for all, 5 mg where risk is raised.
- Untreated maternal disease is itself a risk; substitute rather than simply stop.
Written by The House Job from standard references (Obstetrics by Ten Teachers; Gynaecology by Ten Teachers; Basic and Clinical Pharmacology by Katzung).
FAQ
Why is exposure in the first two weeks after conception unlikely to cause a malformation?
The cells are still unspecialised, so damage either kills the conceptus or is repaired completely; organ formation has not yet begun.
Which anticoagulant is used in pregnancy and why?
Low molecular weight heparin, because it is a large polar molecule that cannot cross the placenta, unlike warfarin.
Is it safer to stop an antiepileptic drug once pregnancy is confirmed?
No. Sudden withdrawal risks fits that harm mother and fetus; the aim is a single safer drug at the lowest effective dose, settled before conception.
Which women need the higher dose of folic acid?
Those with a previous baby with a neural tube defect, diabetes, epilepsy or antiepileptic treatment, and obese women.