Published: July 2000


Letter to New Zealand doctors, midwives and pharmacists about third generation oral contraceptive pills - June 2000

Information on this subject has been updated. Read the most recent information.

Medsafe Editorial Team

June 2000

Dear Doctor/Midwife/Pharmacist

The purpose of this letter is to:

  • reiterate the Ministry of Health’s (Medsafe’s) advice on the prescribing of combined oral contraceptives;
  • inform you of the results of the study by Professor Skegg and colleagues on fatal pulmonary embolism in NZ women;
  • discuss the inaccuracies published in 2 recent NZ articles on oral contraceptives and the risk of thrombosis;
  • provide consumer information leaflets on this issue.

Prescribing combined oral contraceptives

The Ministry of Health’s position on this issue is based on advice from the Medicines Adverse Reaction Committee (MARC). The MARC continues to review new evidence about third generation oral contraceptives (OCs) and is of the opinion that there is approximately double the risk of venous thromboembolism (VTE) with the use of third generation OCs, containing desogestrel or gestodene, compared with the use of low dose second generation OCs, containing levonorgestrel or norethisterone.

The Ministry wishes to reiterate its advice of the last 4 years that when initiating therapy the practitioner should consider prescribing a low dose second generation OC, where the woman has no contraindications and has indicated that she wishes to take a combined OC. Full prescribing advice is enclosed (see below).

It is important that practitioners remain vigilant about the risk of VTE with combined OCs and the higher risk of VTE with the third generation pills. Women should be fully advised of the risks of VTE and be assessed for their personal risk factors. The prescribing of OCs should then be based on clinical judgement and the woman’s informed personal choice.

Women need to be informed at the time of prescribing about the symptoms of VTE, and situations of increased risk. Medical practitioners also need to have a high index of suspicion for the diagnosis of VTE, especially pulmonary embolism (PE), in women taking combined OCs.

NZ study of deaths from pulmonary embolism in women of child-bearing age

A research team from Otago University led by Professor David Skegg has published a study in The Lancet on deaths from PE in New Zealand women of child-bearing age.1

This case-control study covered the period from January 1990 to August 1998 and included as cases women identified from NZHIS mortality statistics who were aged 15-49 years and who died of confirmed PE. There were 26 cases eligible for analysis. Women with a past history of VTE were excluded. Two of the cases had other potential causes of VTE but neither was using an OC.

Table: Results of New Zealand study of deaths from pulmonary embolism in women aged 15-49 years.

Type of OC Cases Controls Adjusted odds ratio (95% CI)
Non-user 9 86 1.0
Second generation 3 8 5.1 (1.2-21.4)
Third generation 12 15 14.9 (3.5-64.3)
Diane-35 2 1 17.6 (2.7-113)
All types 17 25* 9.6 (3.1-29.1)

* one control using a combined OC containing norethisterone, not included with second generation OC users

Odds ratios calculated in the study found third generation pills to be associated with a 3-times higher risk of death from PE than second generation pills. However, because of the small case numbers the confidence intervals were wide and the difference in risk not statistically significant. The odds ratio for Diane-35 (containing cyproterone) was similar to that for the third generation pills, but the same limitations apply to this estimate. The median age of the women who died taking OCs was 29 years.

During the 10-year period 1990-1999, 3 additional necropsy-confirmed cases of death from PE in users of third generation pills were submitted to the Centre for Adverse Reactions Monitoring (CARM). Including the study data, the total number of cases of fatal PE in NZ women taking OCs during this period becomes at least 20, or 2 women per year.

The study authors used national distribution data to estimate the absolute risk of death from PE in users of OCs to be 10.5 per million woman-years. This result is similar to a British study which found a risk of death of 14 per million.2 Using an estimated case-fatality rate of 3%, there would be expected to be about 70 cases of VTE in women taking OCs in New Zealand each year (given that there are approximately 200,000 on combined OCs).

Recent articles in New Ethicals Journal and NZMJ

An article by Egermayer and Roke in New Ethicals Journal3 and a letter by the New Zealand Committee of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) in the New Zealand Medical Journal4 expressed the view that there is no difference in risk between second and third generation OCs. The New Ethicals Journal article has been widely distributed as a reprint to general practitioners by Pharmaco (NZ) Ltd. The MARC and the Ministry have reviewed these articles and consider them to be misleading and inaccurate.

The Ministry wishes to correct a number of points made in the article and letter:

  • In the opinion of the MARC none of the cited potential biases (eg. prescription bias) either singly or in combination are of sufficient magnitude to account for the difference in risk for VTE between the second and third generation OCs. For further comment on this issue refer to a recent article by Farley et al.5
  • The UK Department of Health (and Medicines Commission)6, and the American College of Obstetricians and Gynaecologists7 hold that there is a difference in risk of VTE between second and third generation OCs and recommend taking this into consideration when prescribing.
  • A recent well-conducted study has found a higher resistance to the anticoagulant action of activated protein C in women taking an OC containing desogestrel compared with those taking one containing levonorgestrel.8 Taken in conjunction with other evidence, this difference may prove to be a biological basis for the difference in risk of VTE.
  • The Egermayer and Roke article questioned the validity of diagnosis in 7 of the 9 reports of death from PE in women using third generation OCs received by CARM. The authors claimed that post-mortem reports had not been received for these cases, but in fact at the time of finalisation of the article post-mortem reports confirming the diagnosis were available for all of the 9 cases.
  • Also, in regard to the CARM reports of death, the RANZCOG letter comments about incompleteness of data, reporting rates increasing following adverse publicity and causality not being confirmed by the presence of reports. All of these arguments have been addressed by the Otago study, which covered the entire New Zealand population, and found a clear association between the use of combined OCs and death.

Consumer Information Leaflet

Enclosed is an updated copy of the consumer leaflet Oral Contraceptives and Blood Clots, prepared by Medsafe. Bulk copies have been sent to general practitioners, pharmacies, hospitals, family planning centres, O&G specialists etc. Please make them available to women.

Additional copies of the leaftet are available - phone 04 496 2277, fax 03 479 0979, e-mail or post an order to the Ministry of Health c/- Wickliffe Ltd, PO Box 932, Dunedin. The leaflet and all articles published by Medsafe on combined OCs and VTE are available on Medsafe's web site

A toll-free telephone line (0800 930 039) has been set up to provide women with up-to-date information on OCs and blood clots.

Yours sincerely,
Stewart S Jessamine
Senior Medical Advisor

  1. Parkin L, Skegg DCG, Wilson M, Herbison GP, Paul C.  Oral contraceptives and fatal pulmonary embolism.  Lancet 355:2133-4; 17 June 2000.
  2. Jick H, Jick SS, Gurewich, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestogen components. Lancet 346:1589-93, 16 December 1995.
  3. Egermayer P, Roke C. OCs and the risk of thrombosis. A New Zealand update. New Ethicals Journal 3(1):49-55, January 2000.
  4. NZ Committee, RANZCOG. Oral contraceptives and venous thromboembolism.   NZMJ 113:196; 26 May 2000.
  5. Farley TMM, Meirik O, Collins J. Cardiovascular disease and combined oral contraceptives: reviewing the evidence and balancing the risks.  Human Reproduction Update 5(6):721-35, Nov/Dec 1999.
  6. Oral contraceptives - clearer information for women and health professionals.  Media release, Department of Health, United Kingdom, 7 April 1999.
  7. ACOG Committee revises recommendations on OCs with third-generation progestins.  ACOG Today 42(6):5, July 1998, and confirmed by personal communication through the ACOG email January 2000.
  8. Rosing J, Middeldorp S, Cuvers J, et al.  Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study.  Lancet 354:2036-40; 11 Dec 1999.


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