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Drugs in Pregnancy and Lactation

Drugs in Pregnancy and Lactation. Max Brinsmead MB BS PhD February 2014. 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

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Drugs in Pregnancy and Lactation

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  1. Drugs in Pregnancy and Lactation Max Brinsmead MB BS PhD February 2014

  2. Thalidomide – a lesson in medicine

  3. 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10,000 children with birth deformities • McBride in Australia and Lenz in Germany raised the alarm • Withdrawn in 1961 • Has found new uses as an immune modulator & for multiple myeloma

  4. 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

  5. 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

  6. 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

  7. We need to remember that: • We are in the post-thalidomide era • Drug metabolism is altered by pregnancy • Most drugs cross the placenta freely But • Only a handful have been shown to be teratogenic And • Some of the defects are relatively minor

  8. Effects on the fetus: • Can be irreversible teratogenesis e.g. Thalidomide • Can be reversible side effects of the drugs e.g. anti depressant medication

  9. 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

  10. Drug categorisation for Pregnancy • Different in different countries • Australian Drugs in Pregnancy – see MIMS • 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.

  11. 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%

  12. Why is a drug not always teratogenic?

  13. 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%

  14. 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

  15. 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

  16. Antibiotics in Pregnancy • Penicillins • Erythromycin • Cephalosporins • Nitrofurantoin • Metronidazole • Trimethoprim • Sulpha drugs • Chloramphenicol • Tetracycline • Gentamicin • A • A • A • A • B2 • B3 • C • A • D • D

  17. Anti-malarial drugs for Pregnancy • Chloroquine • Quinine • Paludrine • Maloprim, Daroprim • Larium • Fansidar • Doxycycline • A • D • B2 • B3 • B3 • D • D

  18. HAART drugs for Pregnancy • AZT • Lamivudine • Nevirapine • 3TC • Abacavir • B3 • B3 • B3 • B3 • B3

  19. Anti-emetics for Pregnancy • Pyridoxine • Diphenhydramine • Metoclopromide • Hyoscine • Ondansetron • Promethazine • Prochlorperazine • A • A • A • B2 • B1 • C • C

  20. 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

  21. 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

  22. 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

  23. 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

  24. Drugs and Lactation: • Most drugs which circulate in the blood will appear in breast milk But • The dose which reaches the infant is small And • In general it is inappropriate to deny the BABY and the MOTHER the benefits of breastfeeding

  25. 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 - 15w And ? no threshold • Thereafter threshold is 50-150 rads • Chest Xray is <1 rad • IVP is about 15 rads • CT may involve 15 rads

  26. 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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