Drugs in pregnancy and lactation
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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

Drugs in Pregnancy and Lactation

Max Brinsmead MB BS PhD

February 2014


Thalidomide a lesson in medicine

Thalidomide – a lesson in medicine


Thalidomide

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  • Withdrawn in 1961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

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

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

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 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


Effects on the fetus

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

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

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.


Known teratogenic drugs

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

Why is a drug not always teratogenic?


Known teratogenic drugs 2

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

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

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

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

Anti-malarial drugs for Pregnancy

  • Chloroquine

  • Quinine

  • Paludrine

  • Maloprim, Daroprim

  • Larium

  • Fansidar

  • Doxycycline

  • A

  • D

  • B2

  • B3

  • B3

  • D

  • D


Haart drugs for pregnancy

HAART drugs for Pregnancy

  • AZT

  • Lamivudine

  • Nevirapine

  • 3TC

  • Abacavir

  • B3

  • B3

  • B3

  • B3

  • B3


Anti emetics for pregnancy

Anti-emetics for Pregnancy

  • Pyridoxine

  • Diphenhydramine

  • Metoclopromide

  • Hyoscine

  • Ondansetron

  • Promethazine

  • Prochlorperazine

  • A

  • A

  • A

  • B2

  • B1

  • C

  • C


Antihypertensive drugs in pregnancy

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

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

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

    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

    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


    X rays and pregnancy

    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


    If a pregnant woman is exposed to radiation

    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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