The Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. When letters are published, they are usually accompanied in the same issue by their responses or comments. The Committee screens out discourteous, inaccurate or libellous statements. The letters are sub-edited before publication. Authors are required to declare any conflicts of interest. The Committee's decision on publication is final.

Letter to the Editor

Editor, – The article by Peter Donovan advises that ACE inhibitors and angiotensin receptor blockers are teratogenic in the first trimester of pregnancy (Aust Prescr 2012;35:47-50). These are commonly used antihypertensives which have specific benefits for individuals with chronic proteinuric renal disease and diabetes. Almost half of women aged 16–45 years attending a hypertension clinic in the UK were taking them.1 The first ACE inhibitor, captopril, became available over 30 years ago.

Adverse fetal outcomes with ACE inhibitors in the first trimester had not been reported until a study in 2006 which described an increased risk of major cardiovascular and central nervous system congenital malformations.2 This study however was widely criticised for unrealised confounding bias.3 In particular, women with diet-controlled or undiagnosed diabetes were not excluded, and no adjustment was made for pre-pregnancy body mass. These are known risk factors for fetal malformations.

A subsequent study reported that ACE inhibitors in early pregnancy were associated with an increased risk of major congenital malformations, but this risk was attributable to maternal diabetes and not the drug.4 Three more studies did not find an increased risk of major malformations with ACE inhibitors or angiotensin receptor blockers.5-7

The weight of evidence strongly suggests that ACE inhibitors and angiotensin receptor blockers are not teratogenic in early pregnancy, and that women of child-bearing age who may specifically benefit from their use may continue to do so while waiting to conceive.

Adam Morton
Obstetric physician
Mater Hospital
Brisbane

Author's comments

Peter Donovan, author of the article, comments:

I agree with Dr Morton that there is increasing evidence for the safety of ACE inhibitors and angiotensin receptor blockers in the first trimester of pregnancy. The retrospective cohort study8 provides the strongest evidence of safety thus far. Although it appears that the teratogenic effects of ACE inhibitors or angiotensin receptor blockers are unlikely to be as strong as originally suggested,9 and may be no worse than some other drugs,8,10 I would advocate a cautious approach.

There are alternatives for treating chronic hypertension, including nifedipine and methyldopa. There is much stronger evidence for their safety, hence they should remain first line. For women with chronic proteinuric renal disease, the harm:benefit ratio may favour the use of ongoing ACE inhibitors or angiotensin receptor blockers based on the current safety data. However, there are no data suggesting that ceasing ACE inhibitors or angiotensin receptor blockers in women trying to conceive has detrimental effects on clinical endpoints, such as the need for renal replacement therapy, adverse pregnancy events or mortality.

As always, doctors should discuss all the relevant risks and benefits with the patient so she is able to make an informed decision about what is best for her and her future child. Pre-pregnancy counselling with a specialist such as an obstetric physician or obstetrician would be appropriate in these cases.

References

  1. Martin U, Foreman MA, Travis JC, Casson D, Coleman JJ. Use of ACE inhibitors and ARBs in hypertensive women of childbearing age. J Clin Pharm Ther 2008;33:507-11.
  2. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51.
  3. Ray JG, Vermeulen MJ, Koren G. Taking ACE inhibitors during early pregnancy: is it safe? Can Fam Physician 2007;53:1439-40.
  4. Malm H, Artama M, Gissler M, Klaukka T, Merilainen J, Nylander O, et al. First trimester use of ACE-inhibitors and risk of major malformations. Reprod Toxicol 2008;26:67
  5. Walfisch A, Al-maawali A, Moretti ME, Nickel C, Koren G. Teratogenicity of angiotensin converting enzyme inhibitors or receptor blockers. J Obstet Gynaecol 2011;31:465-72.
  6. Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 2011;343:d5931.
  7. Karthikeyan VJ, Ferner RE, Baghdadi S, Lane DA, Lip GY, Beevers DG. Are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers safe in pregnancy: a report of ninety-one pregnancies. J Hypertens 2011;29:396-9.
  8. Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ 2011;343:d5931.
  9. Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51.
  10. Mitchell AA. Fetal risk from ACE inhibitors in the first trimester [editorial]. BMJ 2011;343:d6667.