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4th generation progestins and thrombosis.


What is the recent literature on 4th generation progestins . In my facility my medical director had been advising that if our patients wants to be on this birth control to document that we counseled them on the slight higher risk of thrombosis. Is Slynd a good option than a POP ?


First, a word about the “generation” nomenclature. These terms were introduced in the early 1990s primarily for marketing purposes. At that time when the progestins desogestrel, norgestimate and gestodene were introduced, they were marketed as “third generation” pills implying that they were safer. Subsequently research showed that these pill formulations were associated with a slightly higher risk for venous thromboembolism.

“Fourth generation” is a term applied to products with drospirenone. Pills with this hormone are generally marketed to have better favorability for androgenic symptoms such as acne or hirsutism, but all pills, regardless of progestin, improve acne and hirsutism. These pills have also been associated with a slight increased risk of blood clots.

When assessing a patient’s risk for venous thromboembolism (VTE), other factors play a role including increasing age which confers a nearly 5-fold increase from age 25-50. Obesity increases risk threefold. Other factors include smoking and immobilization.

Here is a review of thromboembolism that can help guide your approach to counseling:

• All combined pills increase the risk of blood clots compared with people not on pills. The absolute risk is still very low and much lower than the risk of blood clots with pregnancy

→ a young, healthy person not on pills has an absolute risk of VTE of 1-5 / 10,000 woman-years

→ pregnancy increases the relative risks by 4-5 times. The absolute risk is 5-20 / 10,000-woman years and the postpartum period has a greater risk of 40-65 / 10,000-woman years. So, the overall impact of being pregnant / postpartum is a 5-10 x risk over baseline, which argues for the safety of any type of pill compared with pregnancy.

→ oral contraceptive pill users have relative risk increases of 2-3 over nonusers depending on type of pill.

Here is a summary of quoted relative risks from a table in

Users of norethindrone pills vs nonusers: 3.2

Users of levonorgestrel pills vs nonusers: 2.8

Users of desogestrel pills vs nonusers: 3.8

Users of drospirenone pills vs levonorgestrel pills: 1.65

Users of drospirenone pills vs desogestrel: 1.43

Given this information, I agree with your medical director, but it is also about framing the risk overall for that particular individual (re: weight and lifestyle) within the context of alternatives, including pregnancy and tolerability of different formulations for individuals. In general, I think patients should be as informed as possible to help them make the best decisions for themselves, noting that the increased risk is very small.

Regarding Slynd, my answer is yes, it appears to be a very good choice. It is a more forgiving progestin-only pill in terms of the schedule of ingesting and it appears quite effective. Whereas a user who is more than 3 hours late ingesting a norethindrone progestin only pill must use back up for the following two days, a Slynd users can make up a missed pill within a 24-hour window.

A multicenter phase III trial reported a perfect-use Pearl Index of 0.7 (95% CI 0.3-1.4), approaching that of traditional estrogen-progestin combined contraceptives, however larger data sets are needed. Data on real-use effectiveness is not yet available.

Depo Provera (DMPA):

The literature doesn’t recommend limiting DMPA use to only two years but the label includes a black box warning against long-term use. This is based on the decrease in bone mineral density (BMD) while using the method. It is well documented that upon cessation of the method, BMD returns. That is why most guidance says it is okay to use longer term.

Therefore, the American College of Obstetrics and Gynecology, the Centers for Disease Control and Prevention, the Society for Adolescent Health and Medicine (SAHM), the World Health Organization, and the Society of Obstetricians and Gynaecologists of Canada, believe that the advantages of DMPA use as a contraceptive generally outweigh the theoretical concerns regarding skeletal harm.

It is also important to note the following as said by Dr. Andy Kaunitz, an expert on DMPA:

“use of DMPA is not an indication for BMD testing (eg, dual-energy X-ray absorptiometry [DXA]) either before, during, or in follow-up of its administration.”

Please let me know if you have additional questions!

– Dr. Z

See disclaimer below

DISCLAIMER: This information is for educational purposes only and not intended to guide individual therapy. Answers should never substitute for consultation with a healthcare provider or counselor who can make decisions based on an individual’s history, desires, and circumstances. Always seek the advice of a clinician for any questions regarding health, medical condition, birth control method or other family planning or social issues. Under no circumstances should an individual use this information in lieu of, or to override, the judgment of a treating clinician. Dr. Zieman, or SageMed LLC, is not responsible, or liable, for errors, omissions, or any damage or loss incurred as a result of use of any birth control method or use or reliance on any material or information provided through this website.

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