Drugs in Pregnancy and Lactation

Max Brinsmead MB BS PhDFebruary 2015

Thalidomide – a lesson in medicine

Thalidomide

• Developed in Germany in 1954• Promoted as a tranquiliser and anti emetic• Taken by thousands of pregnant women• Resulted in >10,000 children with birth deformities• McBride in Australia and Lenz in Germany raised the

alarm• Withdrawn in 1961• Has found new uses as an immune modulator & for

multiple myeloma

Teratogenic action of Thalidomide

• Inserts itself into DNA of embryonic promotor zones for ears, limbs and eyes

• 15+ possible mechanisms of action• Inhibits the angiogenic network• Will have different teratogenic effects

when taken at different stages of pregnancy

Lessons from Thalidomide

• The placental barrier is not effective against most orally administered drugs

• Animal teratogenic testing can be misleading• Drug companies have a powerful commercial

agenda• But are not the sole culprits in a tragedy such

as this

When considering drugs in pregnancy there are 4 different scenarios

• A pregnant woman who has ingested a drug and is seeking information about its possible consequences

• A pregnant woman with a medical condition for which a drug is usually prescribed - what is the safest and most effective drug to use?

• A woman planning pregnancy who requires long term medication seeks your advice about the teratogenicity of that medication

• Safe drugs to use in a woman of childbearing age

We need to remember that:

• We are in the post-thalidomide era• Drug metabolism is altered by pregnancy• Most drugs cross the placenta freelyBut• Only a handful have been shown to be

teratogenicAnd• Some of the defects are relatively minor

Effects on the fetus:

• Can be irreversible teratogenesis e.g. Thalidomide

• Can be reversible side effects of the drugs e.g. anti depressant medication

Principles of safe prescribing:

• Is there a non pharmacological alternative?• Do the benefits outweigh the risks?• Extra caution in the first trimester• Use drugs tested by TIME in WOMEN• Choose the least harmful drug for the

minimum time possible

Drug categorisation for Pregnancy

• Different in different countries• Australian Drugs in Pregnancy – see website– A Okay to use• B1 – no known effects in women or animals but more data

required• B2 – no known effects in women or animals but more testing

required• B3 – no known effects in women but teratogenic in some

animals– C Harmful effects - not teratogenic– D Suspected of causing irreversibe damage– X High risk of permanent damage.

Known Teratogenic Drugs

• Systemic retinoids e.g Isotretinoin. Category X Drug– CNS abnormalities– Congenital heart defects– Facial dysmorphism– Risk approx. 40%

• Stilboestrol – Vaginal adenocarcinoma– Male & female genital tract abnormalities– Risk varies 22 – 58%

• Folic acid antagonists e.g. Methotrexate– Neural tube defects– Craniofacial abnormalities & Limb defects– Risk approx. 30%

Why is a drug not always teratogenic?

Known Teratogenic Drugs (2)

• Thalidomide– Phocomelia– Congenital heart defects, GIT & renal malformations– Risk approx. 20%

• Cytotoxic drugs e.g. Cyclophosamide– Various effects including fetal death & IUGR– Risk approx. 20%

• Anticonvulsants e.g. Phenytoin, Valproic acid, Carbamazepine– Risk 3 – 9%

• Warfarin– Dysmorphic face, congenital heart disease, genital defects, Brain

effects– Risk 4 – 8%

Known Teratogenic Drugs (3)

• Tetracyclines e.g. Doxycycline– Dental staining– Non dysforming skeletal effects– Risk rate unknown

• Misoprostol– Moebius sequence i.e. Paralysis 6th & 7th cranial nerves– Risk may be as high as 50%

• Paroxetine– Congenital heart defects– Risk rate unknown

Known Teratogenic Drugs (4)

• Alcohol (Ethanol)– Fetal alcohol syndrome – characteristic face– Mental retardation, neurobehavioural abnormalities– Risk is dose dependent (no safe level?)

• Cocaine– Renal tract malformations– Risk rate unknown

• Heroin, Marijuana and Amphetamines– Are not teratogenic

Antibiotics in Pregnancy

• Penicillins• Erythromycin• Cephalosporins• Nitrofurantoin• Metronidazole• Trimethoprim• Sulpha drugs• Chloramphenicol• Tetracycline• Gentamicin

• A• A• A• A• B2• B3• C• A• D• D

Anti-malarial drugs for Pregnancy

• Chloroquine• Quinine• Paludrine (Proguanil)• Maloprim, Daroprim• Larium• Fansidar• Doxycycline

• A• D• B2• B3• B3• D• D

HAART drugs for Pregnancy

• AZT• Lamivudine• Nevirapine• 3TC• Abacavir

• B3• B3• B3• B3• B3

Anti-emetics for Pregnancy

• Pyridoxine• Diphenhydramine• Metoclopromide• Hyoscine• Ondansetron• Promethazine• Prochlorperazine

• A• A• A• B2• B1• C• C

Antihypertensive drugs in Pregnancy

• Aldomet• Hydralazine• Beta blockers• Ca channel blockers• Thiazides• ACE Inhibitors

• A• C• C• C• C• D• ↑risk of CNS & CHD defects 3-

fold in 1st trimester, ?cause fetal death in 3rd trimester

Analgesic Drugs for Pregnancy

• Paracetamol• Codeine• Aspirin• Narcotics• NSAIDs

• A• A• C• C• C• Have the potential to cause

in utero closure of the ductus arteriosus >34w

Anticonvulsant Drugs for Pregnancy• All anticonvulsants are teratogenic

• But there is a genetic component because epileptics on no drugs have ↑rate defects

• Offspring of epileptic men have ↑rate defects

• Maternal and fetal risk of fits is greater than the teratogenic risk

• Some defects can be detected by prenatal testing• Spina bifida with sodium valproate

• Others are deemed acceptable risks• 1% risk of isolated oral clefts with Lamatrogine

• Dilantin is best avoided• Carbamazepine & Na valproate reasonable alternatives

Psychiatric Drugs for Pregnancy

• Most anti-depressants are Category C• Except for Moclobemide & MAO Inhibitors (B3)• Tricyclics slightly safer than SSRI’s• Fluoexetine is the SSRI with the lowest known risk• Paroxetine is teratogenic (D)

• Benzodiazepines and Barbiturates are (C)• Benzo’s particularly bad because they accumulate

in the fetus• And the neonate metabolises them slowly• But barbiturates actually hasten the resolution of

neonatal jaundice

Drugs and Lactation:

• Most drugs which circulate in the blood will appear in breast milk

But• The dose which reaches the infant is smallAnd• In general it is inappropriate to deny the

BABY and the MOTHER the benefits of breastfeeding

X Rays and Pregnancy:

• The first 4 weeks of amenorrhoea is not a critical period of radiosensitivity in humans

• Risk of microcephaly is linear from 8 - 15wAnd ? no threshold• Thereafter threshold is 50-150 rads– Chest Xray is <1 rad– IVP is about 15 rads– CT may involve 15 rads

If a pregnant woman is exposed to radiation:

• Carefully calculate the dose involved

• Consult the best available authority

• Counsel along the same lines as for a woman inadvertently exposed to a drug

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