EXECUTIVE SUMMARY
Results from two United Kingdom population-based, case-control nested studies using two large primary care databases indicate risks of venous thromboembolism associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for second generation drugs.
- Data from the study indicate a higher risk of thrombosis for some newer type of oral contraceptive pills; however, the risk is lower than the risk of thrombosis that naturally occurs during pregnancy, researchers note.
- There is no suggestion that women should stop or change their current pill prescriptions without medical advice, the researchers note.
Results from two United Kingdom population-based, case-control nested studies using two large primary care databases indicate risks of venous thromboembolism (VTE) associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for second generation drugs.1
To examine the association between use of combined oral contraceptives and VTE risk, researchers from the University of Nottingham in England used prescription data from the Clinical Practice Research Datalink and QResearch primary care database to measure the associations between use of combined oral contraceptives and risk of VTE in women ages 15-49, adjusting for other known risk factors. Women ages 15-49 with a first diagnosis of VTE in 2001-2013 were each matched with up to five controls by age, practice, and calendar year.
PILL WARNING SIGNS FOR WOMEN: ACHES
Abdominal pain
- Blood clot in pelvis or liver
- Benign liver tumor or gallbladder disease
- Pregnancy in your tubes
Chest pain
- Blood clot in the lungs
- Heart attack
- Angina (heart pain)
- Breast lump
Headaches
- Stroke
- Migraine headache, blurred vision, spots, zigzag lines, weakness, difficulty speaking
- High blood pressure
Eye problems
- Stroke
- Blurred vision, double vision, or loss of vision
- Migraine headache, blurred vision, spots, zigzag lines
- Blood clots in the eyes
- Change in shape of cornea (contacts don't fit)
Severe leg pain
Inflammation and blood clots of a vein in in the leg
Source: Nelson AL, Cwiak C. Combined oral contraceptives. In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology: 20th revised edition. New York: Ardent Media; 2011.
The main outcome measures were odds ratios for incident VTE and use of combined oral contraceptives in the previous year, adjusted for smoking status, alcohol consumption, ethnic group, body mass index, comorbidities, and other contraceptive drugs. Results were combined across the two datasets.
In all, 5,062 cases of VTE from the Datalink and 5,500 from the QResearch database were analyzed. Current exposure to any combined oral contraceptive was associated with an increased risk of VTE (adjusted odds ratio 2.97, 95% confidence interval 2.78 to 3.17) compared with no exposure in the previous year. Corresponding risks associated with current exposure to desogestrel (4.28, 3.66 to 5.01), gestodene (3.64, 3.00 to 4.43), drospirenone (4.12, 3.43 to 4.96), and cyproterone (4.27, 3.57 to 5.11) were significantly higher than those for second generation contraceptives with levonorgestrel (2.38, 2.18 to 2.59), norethisterone (2.56, 2.15 to 3.06), and norgestimate (2.53, 2.17 to 2.96). The number of extra cases of VTE per year per 10,000 treated women was lowest for levonorgestrel (6, 95% confidence interval 5 to 7) and norgestimate (6, 5 to 8), and highest for desogestrel (14, 11 to 17) and cyproterone (14, 11 to 17).1
“This is the largest study to date to investigate risk of thrombosis for different types of combined oral contraceptive drugs using the two largest UK primary care databases,” said lead author Yana Vinogradova, MSc, a research statistician in the Faculty of Medicine & Health Sciences at the University of Nottingham, in a release accompanying the report. “We hope the results, in due course, will help doctors with prescribing decisions.”
Professor Julia Hippisley-Cox, MD, a co-author on the research paper and a general practitioner at the University, noted, “We have found a higher risk of thrombosis for some newer types of oral contraceptive pill in this research project. However, to put this in perspective, the risk is lower than the risk of thrombosis which naturally occurs during pregnancy.”
Hippisley-Cox said there is “no suggestion that women should stop or change their treatment without medical advice since this could have undesirable consequences such as an unplanned pregnancy.” Instead, patients with concerns should discuss alternatives with their providers at their next routine appointment, she stated.
Look at the risks
The UK researchers estimated that use of levonorgestrel and norgestimate resulted in six extra cases of VTE each year per 10,000 treated women ages 15-49 and seven extra cases for women ages 25-49. Desogestrel and cyproterone each contributed 14 additional cases of VTE each year per 10,000 treated women ages 15-49, and drospirenone, desogestrel, and cyproterone each contributed to an extra 17 cases of VTE each year per 10,000 women ages 25-49.
In an accompanying editorial, Susan Jick, DSc, MPH, director of the Boston Collaborative Drug Surveillance Program at Boston University School of Medicine and professor of epidemiology at the Boston University School of Public Health in Lexington, writes that the current study “addresses important questions about the risk of venous thromboembolism in women taking oral contraceptives, concluding that the risk is around twofold higher than the risk associated with older contraceptives.”2 Jick was lead author of one of two 2011 case-control studies that suggested that women without risk factors for VTE who use pills containing drospirenone have an increased risk for nonfatal VTE compared with those who use levonorgestrel pills.3,4
Valerie Beral, FRCOG, FMedSci, professor of epidemiology and co-director of the Cancer Epidemiology Unit at the University of Oxford in England, in a statement, said, “There is nothing new about these findings — they just confirm what we have known for more than two decades now. The MHRA [Medicines and Healthcare Products Regulatory Agency] have prescribing guidelines directly relevant to the issue, which already incorporate previous evidence, and which were updated quite recently.” (Review the February 2014 guidance at http://bit.ly/1F11uuw.)
Even though the relative risk of thrombosis with oral contraceptives is increased, pill users face a low absolute risk because VTE is a rare event.5 The incidence rate in reproductive-age women is half the rate reported for women of all ages.6 The VTE risk during pregnancy is 98.5 per 100,000 women-years, but rises to 511.2 per 100,000 women-years in the postpartum period.7
In a 1999 study of 46,000 women, half of whom were using oral contraceptives at recruitment, pills seem to have their main effect on mortality while they are being used and in the 10 years after use ceases.8 Ten or more years after use ceases, mortality in past users is similar to that in never users, data indicate.
What does the U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) say about use of combined pills and VTE?9
For women with acute DVT/pulmonary embolism (DVT/PE) or previous DVT/PE, who are not on anticoagulant therapy and have risk factors for recurrence, combined pills are classed as Category 4 (unacceptable risk). If women have previous DVT/PE with no risk factors for recurrence, use is classed as Category 3 (theoretical or proven risks usually outweigh the advantages of using the method).
In 2011, the Centers for Disease Control and Prevention updated its recommendations to state that postpartum women should not use combined hormonal contraceptives during the first 21 days after delivery because of high risk for VTE during this period. During days 21-42 postpartum, women without risk factors for VTE generally can initiate combined hormonal contraceptives. Women with risk factors for VTE, such as VTE or recent cesarean delivery, generally should not use these methods. After 42 days postpartum, no restrictions on the use of combined hormonal contraceptives based on postpartum status apply.10
Robert Hatcher, MD, MPH, professor emeritus of gynecology and obstetrics at Emory University School of Medicine in Atlanta, offers these comments about combined pill use:
First, tobacco smoking increases the risk of VTE, especially in young combined pill users who are heavy smokers.5 Smokers who are prescribed pills should be strongly encouraged to decrease or stop smoking.
Second, the risk of VTE with combined pills is greatest in the first 3-12 months of use and declines thereafter. For this reason, women starting pills or restarting after a period of no pill use should be taught the Pill warning signals, using the mnemonic ACHES. (See box in this issue.)
- Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: Nested case-control studies using the QResearch and CPRD databases. BMJ 2015; doi:10.1136/bmj.h2135.
- Jick SS. Fresh evidence confirms links between newer contraceptive pills and higher risk of venous thromboembolism. BMJ 2015; doi:10.1136/bmj.h2422.
- Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: Case-control study using United States claims data. BMJ 2011; 342:d2151.
- Parkin L, Sharples K, Hernandez RK, et al. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: Nested case-control study based on UK General Practice Research Database. BMJ 2011; 342:d2139.
- Nelson AL, Cwiak C. Combined oral contraceptives. In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology: 20th revised edition. New York: Ardent Media; 2011.
- Heinemann LA, Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception 2007; 75(5):328-336.
- Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: A 30-year population-based study. Ann Intern Med 2005; 143(10):697-706.
- Beral V, Hermon C, Kay C, et al. Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46,000 women from Royal College of General Practitioners’ oral contraception study. BMJ 1999; 318(7176):96-100.
- Centers for Disease Control and Prevention. U.S. medical eligibility criteria for contraceptive use. MMWR 2010; 59(RR04):1-6.
- Centers for Disease Control and Prevention (CDC). Update to CDC’s U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: Revised recommendations for the use of contraceptive methods during the postpartum period. MMWR 2011; 60(26):878-883.
