In 1963, the Australian Drug Evaluation Committee (ADEC) was established to provide guidance on the use of medications during pregnancy. A system was then developed to categorise the risk posed by individual drugs which was published in the first ‘Medicines in Pregnancy’ booklet in 1989.

The ADEC categorisation system applies an alphabetical designation to medications according to their known and potential risks. An explanation of the categories can be seen in Table 1. Due to its simplicity and inclusion in prescribing guides, this system is widely used to assess the safety of medication use during pregnancy.

Table 1. ADEC risk categorisation for medication use in pregnancy Adapted from information provided by the Therapeutic Goods Administration.

Category Definition
A Drugs that have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the incidence of direct or indirect harmful effects on the foetus.
B1 Drugs that have been taken by only a limited number of pregnant women and women of childbearing age without an increase in the frequency of direct or indirect harmful effects on the foetus.

Animal studies have not shown any evidence of increased risk.

B2 Drugs that have been taken by only a limited number of pregnant women and women of childbearing age without an increase in the frequency of direct or indirect harmful effects on the foetus.

Animal studies are inadequate or may be lacking. However, available data has not shown any evidence of increased risk.

B3 Drugs that have been taken by only a limited number of pregnant women and women of childbearing age without an increase in the frequency of direct or indirect harmful effects on the foetus.

Animal studies show an increased risk of foetal damage, the significance of which is uncertain in humans.

C Medications which, due to their pharmacological effects, have caused or are suspected of causing harmful effects. These effects may be reversible. Further information should be sought.
D Drugs that have caused, are suspected to have caused, or are expected to cause an increased incidence of foetal malformations or irreversible damage. Further information should be sought.
X Drugs with a high risk of causing permanent damage to the foetus. Should not be used during pregnancy or when pregnancy is a possibility.

 

The obvious problem with this risk categorisation tool is the implication that there is a hierarchy of risk. For example, one may assume that a category C medication has a higher risk of foetal harm than a category B medication. This would be an incorrect assumption as medications in category B do not have adequate human data to compare with the known risks associated with medications in category C.

There are some other limitations to this system. It may be reasonable to assume that drugs within the same category denote a similar risk. However, this would also be an incorrect assumption. For example, valproate and paroxetine are both assigned to category D. Valproate is associated with a significantly higher risk of birth defects and neurodevelopmental complications. In comparison, paroxetine is associated with a slightly increased risk of foetal heart defects in some studies, although other studies suggest no increased risk.

The ADEC categories assign one categorisation per medication without taking the stage of pregnancy into account. Many medications known to cause adverse foetal effects do so at very specific stages of development. For example, doxycycline is designated a category D medication due to its ability to cause enamel hypoplasia and permanent discolouration of the teeth. However, this is only relevant during the period of tooth mineralisation. During the first 18 weeks of pregnancy, doxycycline is considered safe to use.

It is also important to consider the clinical context of any therapy. For example, many anticonvulsant medications are used off-label to treat a variety of conditions including neuropathic pain, restless leg syndrome, and migraine prevention. However, the simple categorisation system does not differentiate between the use of medications for conditions that may be considered more or less serious.

This system also does not usually consider the dose or route of administration. An interesting example of the importance of dose is vitamin A. Vitamin A is frequently found in prenatal vitamin supplements, despite its category D listing. This agent is innocuous when given at doses of less than 5,000 IU per day. However, doses more than 10,000 IU per day taken during early pregnancy may increase the risk of adverse foetal events. It is equally important to consider the route of administration. Many medications are poorly absorbed after inhalation or application to the skin. Systemic exposure is therefore considerably less than what occurs after oral or intravenous administration.

Another limitation of the system is that categories are often based on old data. When new medications are marketed, they tend to receive an overly cautious categorisation. Due to ethical constraints, premarketing data is only obtained from animal reproductive studies. It is often only in the postmarketing surveillance stage that human reproductive data is obtained. However, the initial category often remains unchanged even in the face of new data suggesting no adverse effects on the foetus.

This categorisation system also fails to capture a significant proportion of therapies used by women of childbearing age. Complementary and alternative medicines, used by over 40% of the Australian population, are not subject to the same classification system. Although herbal preparations are exempt from pregnancy classification, they are not inherently safe to use. Some pregnant women may self-medicate with these products due to the perception that they are natural and, therefore, safer. However, these products usually have very limited safety and efficacy data for their use during pregnancy.

When discussing the potential risks of medication during pregnancy, it is important to balance these risks with the benefits. Although many anti-epileptic medications are associated with malformations, poorly controlled epilepsy is also associated with adverse clinical outcomes for the mother and child. It is also important to be aware of the background risk of malformations with any pregnancy. It is estimated that between 2% and 3% of all pregnancies will result in a congenital abnormality. It is important to keep this in mind when discussing the risks with patients. For example, valproate is associated with a two to three-fold increase in the rate of congenital abnormalities. This translates to a 6% to 9% risk of having a child with a malformation following valproate therapy. This significant risk needs to be weighed against the considerable risks of uncontrolled epilepsy. Prolonged convulsive seizures can result in sustained foetal hypoxia, and abdominal trauma could lead to miscarriage.

In general, advice given to women about medications in pregnancy is cautious and not always evidence-based. Misleading advice and confusion regarding the ADEC categorisation system can have serious consequences for both mother and baby. Ceasing medication may place the mother, and potentially also their baby, at risk due to exacerbation of the underlying illness. An improved understanding of the classification system may allow healthcare professionals to address safety concerns with their patients better and put the risks into perspective.

In light of the limitations posed by pregnancy classification systems, the way in which they are used is changing. The US Food and Drug Administration (FDA) is phasing out the use of pregnancy classifications in the product information. Instead, more useful information will be provided to help guide clinical decision-making processes. In January 2016, the Australian Medicines Handbook stopped including the ADEC category in their printed and electronic publications, favouring a more detailed explanation of potential risks. It is acknowledged that many women will require medication during their pregnancy, and access to useful, up-to-date information is imperative for making informed decisions.

References:

  1. Genetic and Rare Diseases Information Center. Fetal valproate syndrome. Tuscon: National Center for Advancing Translational Sciences, 2010.
  2. Gunatilake R, Patil AS. Drugs in pregnancy. Kenilworth: Merck Manual – Professionals Edition; 2016.
  3. Kennedy D. Classifying drugs in pregnancy. Aust Prescr. 2014; 37: 112-4.
  4. Therapeutic Goods Administration. Australian categorisation system for prescribing medicines in pregnancy. Canberra: Therapeutic Goods Administration; 2011.

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