Endocrine (anki)

• Medicines account for less than 1% of birth defects
• Teratogen


  Any agent that causes a congenital abnormality following foetal exposure during pregnancy. The overall effect depends on dosage and time of exposure
• It is equally important to consider the potential harmful implications of the maternal condition not being treated
• Risk vs Benefit

  The safe use of medicines in pregnancy requires a comprehensive understanding of risk vs benefit profiles for individual treatments. Dose and critical periods of development/timing of exposure must be considered when assessing risk
• Critical periods of human development

  • Last Menstrual period
  • Week 1
  • Week 2
  • Week 3
  • Week 4
  • Week 5
  • Week 6
  • Week 7
  • Week 8
  • Week 9
  • Week 10
  • Week 11
  • Week 18
  • Week 34
  • Week 40
• Pharmacokinetics of drugs in pregnancy

  Physiologic changes that occur during pregnancy (such as slower gastric emptying, increased plasma volume, altered sex steroid levels, changed enzyme activity etc) can potentially lead to changes in absorption, distribution, metabolism and elimination of medicines
• Different advice from various references for aciclovir

  • TGA: Category B3
  • MIMS: Should not be used during pregnancy unless the benefits to the patient clearly outweigh the potential risks to the foetus
  • AMH: First trimester exposure to Aciclovir has not been associated with an increased risk of congenital malformations. Adverse effects in the newborn have not been reported following in utero exposure to Aciclovir. Aciclovir is considered safe to use for all stages of pregnancy
  • RWH Pregnancy and Breastfeeding Medicine Guide: Safe to use (extensive clinical experience)

  
• Product information (PI) and Consumer Medicines Information (CMI) leaflets are medico-legal documents, have conservative/defensive wording, almost universally do not recommend use in pregnancy (and breastfeeding), and are rarely updated in line with new pregnancy/breastfeeding safety data/information. They are not reliable sources for assessing safety of medicine use in pregnancy

  
• TGA Australian Categorisation System for registered medicines in pregnancy

  Category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the human foetus having been observed
• Aciclovir is considered safe to use for all stages of pregnancy
• Product information (PI) and Consumer Medicines Information (CMI) leaflets

  • Medico-legal documents
  • Conservative/defensive wording (produced by drug company and their lawyers)
  • Almost universally do not recommend use in pregnancy (and breastfeeding)
  • Rarely are updated in line with new pregnancy/breastfeeding safety data/information
  • Not reliable sources for assessing safety of medicine use in pregnancy

  
• TGA Australian Categorisation System for registered medicines in pregnancy

  • Category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed
  • Category B (1-3): Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed
  • Category B1: Studies in animals have not shown evidence of an increased occurrence of fetal damage
  • Category B2: Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage
  • Category B3: Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans
  • Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible
  • Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects
  • Category X: Drugs which have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy
• The Australian pregnancy category system is overly simplistic which can (and often does) lead to false assumptions about medications based on their category alone
• The alphabetical letter code is not a simple graduated ranking of risk
• Category B drugs are not generally safer choices than category C drugs because the defining quality of the B grading is the lack of human pregnancy safety data associated with these drugs
• Pregnancy categories often do not change despite the availability of new (often reassuring) information
• Once a category has been assigned to a drug, there is no defined timeframe when it must be reviewed by the TGA – instead, the manufacturer is responsible for initiating a review
• Sponsors (aka manufacturers) are allowed to legally apply "a more restrictive category than can be justified on the basis of the available data"
• The assigned category of risk for a drug may not be relevant for all stages of pregnancy
• Pregnancy categories do not differentiate between use of a medicine for a more or less significant condition
• The Australian pregnancy category system has significant limitations
• Inadvertent exposures during pregnancy to drugs with teratogenic potential should be referred to MotherSafe/similar specialist service for tailored risk analysis/advice

  
• Females of child-bearing potential must be provided with

  • Comprehensive information on pregnancy prevention
  • Advised to use adequate/effective contraception during treatment (and sometimes for a period afterwards too)
• Approach to contraception counselling

  Should be appropriate for level of teratogenic risk
• If unsure about the teratogenic potential of a medication, consult MotherSafe for a risk assessment

  
• It is important that ALL patients are warned of the potential teratogenic risks associated with the medication use
• Advice should include

  • Appropriate handling and disposal of medication
  • Instruction not to share their medication with other people
• For contra-indicated drugs (e.g. Category X medications), advice should be

  Directive, e.g. "It is important to NOT fall pregnant on this medication"
• For contra-indicated drugs (e.g. Category X medications), at a minimum requirement

  At least one effective method of contraception should be used
• Roaccutane (oral isotretinoin)


  • Known human teratogen where fetal exposure is associated with a significant risk of congenital abnormalities, spontaneous abortion, perinatal mortality and premature birth
• For other drugs of known/suspected risk (e.g. Category D), advice needs to be

  Nuanced/tailored, e.g. "This medication is associated with an increased risk of (a) birth defect(s) (which may be small or large depending on the drug/dose/timing) when used during pregnancy so it is important to use contraception while taking the medication and for you to seek advice about whether it would be appropriate for you to continue the medication if/when you should want to become pregnant"
• Valproate

  • May require different advice depending on the indication (harm vs benefit assessment)
• Methotrexate (Category D)

  • Generally contra-indicated in pregnancy due to its folic acid antagonism and potential to interfere with DNA synthesis which could result in congenital malformations and/or fetal death
  • Can be prescribed to women of child-bearing age so effective contraception is important
  • Advice regarding minimum safe interval between ceasing methotrexate and conception varies greatly between references
• Spironolactone (Category B)

  • May sometimes be prescribed to women of child-bearing age for acne and/or PCOS etc
  • There is a theoretical risk that spironolactone might affect genital development of a male fetus due to its anti-androgen potential BUT this has not been demonstrated in human case reports

  
• Paternal medicine exposures during pregnancy are generally not associated with increased risks of birth defects as there is no blood connection between a man and the developing baby
• Paternal radiotherapy, chemotherapy and a small number of medicines (like anabolic steroids and sulfasalazine) may affect male fertility
• Principles for prescribing in pregnancy

  • Topical preparations should be considered before oral treatments (if efficacious) because less systemic absorption means less (if any) exposure to foetus
  • Always consider dose and period of gestation when making risk assessments, as well as consequences of maternal condition not being treated
  • The TGA pregnancy category system has a number of limitations and should NOT be used as a sole guide for assessing safety of medicines in pregnancy
  • Drugs that have been widely used for many years are preferable to newer alternatives as they generally have more human pregnancy data BUT the drug must be effective otherwise there is no point in taking it
  • Use the lowest effective dose for the shortest duration of time
  • Individualised approach to harm vs benefit assessment
  • Ensure discussion and education that allows the parents to give informed consent about medication choices

  
• When to refer to MotherSafe

  • If there is no pregnancy data or where the information available is unclear/conflicting
  • When an exposure has already occurred, and the medical information suggests some risk
  • Complicated cases
  • Patient/physician anxiety
  • Whenever you do not feel confident
• If in doubt about the safety of a drug in pregnancy/breastfeeding, always check first BEFORE advising the patient about risk

  
• Diabetes screening and monitoring