Letters to the Editor

(Aust Prescr 2006;29:3-5)

Letters, which may not necessarily be published in full, should be restricted to not more than 250 words. When relevant, comment on the letter is sought from the author. Due to production schedules, it is normally not possible to publish letters received in response to material appearing in a particular issue earlier than the second or third subsequent issue.

Assessment of thyroid function in pregnancy

Editor, - Some further points on testing thyroid function need to be added to the useful information in Associate Professor Tran's review, 'Biochemical tests in pregnancy' (Aust Prescr 2005;28:98-101). First, a small but significant decrease in the concentration of serum free T4, most marked in the third trimester, has been clearly documented.1,2 In addition, albumin-dependent methods of free T4 estimation show marked negative bias, relative to the non-pregnant reference interval; in the late third trimester, such methods may give subnormal free T4 estimates in up to 50% of samples.3

These methods are unsuitable for assessing thyroid status during pregnancy4, unless results are evaluated in relation to reference intervals that reflect method-specific bias at various stages of pregnancy. Clinical chemists need to be aware of this issue when choosing an appropriate free T4 method for obstetric practice and by indicating appropriate reference intervals.

Professor Tran's counsel that 'Graves' disease needs to be rigorously controlled' in pregnancy goes beyond interpretation of test results. This advice must be tempered by the fact that any degree of maternal hypothyroidism in the first trimester can have an adverse effect on fetal brain development5,6, and that overtreatment in the third trimester can be associated with fetal goitre.6 As thyrotoxicosis of immune origin often becomes less severe during pregnancy, it is often advisable to decrease the dose of antithyroid drug to minimise the chance of these adverse effects.6 As pointed out by Professor Tran, the exact cause of newly-diagnosed thyrotoxicosis can be difficult to establish in early pregnancy. When the disorder is mild, as judged by clinical rather than laboratory criteria, it may be best followed without treatment for several months until there is a clear indication for active treatment.6

Jim R. Stockigt
Epworth and Alfred Hospitals
Professor of Medicine, Monash University
Melbourne

References

1. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-33.

2. McElduff A. Measurement of free thyroxine (T4) levels in pregnancy. Aust N Z J Obstet Gynaecol 1999;39:158-61.

3. Roti E, Gardini E, Minelli R, Bianconi L, Flisi M. Thyroid function evaluation by different commercially available free thyroid hormone measurement kits in term pregnant women and their newborns. J Endocrinol Invest 1991;14:1-9.

4. National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Free thyroxine (FT4) and free triiodothyronine (FT3) estimate tests, in pregnancy. Section 3B 3c(i). http://www.nacb.org/lmpg/thyroid_LMPG_Word.stm [cited 2006 Jan 13]

5. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-55.

6. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354-9.

Associate Professor H.A. Tran, author of the article, comments:

Professor Stockigt's comments are appreciated. As usual, they are incisive and informative. The small but significant decrease in serum free tetra-iodothyronine (fT4) can, in part, be explained by the peak of thyroid binding globulin concentrations in the third trimester, although these remain within the reference range in most cases.1

Selecting a special method for the obstetric population serviced by the relevant laboratory would always be a challenging task given the large scope of services imposed upon large laboratories by the current practice of pathology. The nuances of such a task are probably best reserved within the realm of clinical biochemists' practice.

As emphasised, the management of thyrotoxicosis in pregnancy is not a simple task. It should not be simply a matter of medication adjustment according to biochemical results, which are never error proof. The literature is littered with, sometimes fatal, adverse reactions2 where laboratory results as given, are acted upon, when instead a considered and competent clinical assessment is warranted. As inferred by Professor Stockigt, it is best to first do no harm; a caveat that is not applicable to pregnancy alone.

References

1. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-33.

2. Gutierrez-Macias A, Lizzaralde-Palacios E, Martinez-Odriozola P, Miguel-De la Villa F. Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia. Br Med J 2005;331:623-4.

Antibiotics for unapproved indications

Editor, - I would like to revisit the use of various antibiotics for 'orphan' indications. One example is rifampicin for deep infections due to methicillin-resistant Staphylococcus aureus (MRSA). There are few oral antibiotics available for the treatment of MRSA infections, but the combination of rifampicin and fusidic acid is commonly used and is recommended in Therapeutic Guidelines: Antibiotics.

In 1994, Australian Prescriber published a response to a query (Aust Prescr 1994;17:95) asking why rifampicin was not subsidised for osteomyelitis. The response said that no application had been submitted for the use of rifampicin for this indication.

Would it be possible for the Therapeutic Goods Administration to approve an 'orphan' indication for well-known drugs where they are recommended by recognised guidelines? Perhaps for such indications, a simplified application to the Australian Drug Evaluation Committee could be made by clinicians or their representative bodies.

Allen Cheng
Infectious diseases physician
Geelong Hospital
Menzies School of Health Research
Geelong, Vic.

Dr Leonie Hunt, Director, Drug Safety & Evaluation Branch, Therapeutic Goods Administration, comments:

The Therapeutic Goods Administration (TGA) is able to approve indications for extensions of use of medicines, including antibiotics, after it has received an application from a sponsoring company, supported by data to establish quality, safety and efficacy for the intended use.

For an extension of indication, quality will usually have been established and the focus is on safety and efficacy. In order to facilitate the lodgement of applications for the treatment of rare conditions, which may otherwise not be cost-effective, the TGA has introduced an Orphan Drug Scheme, whereby all evaluation fees are waived provided the sponsor obtains designation for the product for the indication. The usual criteria for determining a disease is rare are the orphan criteria that it is not likely to affect more than 2000 people.

The TGA has also adopted a number of modifications to data packages to facilitate applications for older, off-patent or orphan products. These include literature based submissions, whereby companies can submit published papers as the basis for an approval of a product or an extension of use of a product. Unfortunately, the TGA has no power to approve products for new indications in the absence of an application, but it is always happy to discuss with sponsors the modified data requirements for products where there is a demonstrated clinical need.