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Women’s Health- contraception

Primary Care Corner with Geoffrey Modest MD: New vs old OCPs and thromboembolism

23 Jun, 15 | by EBM

By: Dr. Geoffrey Modest

The BMJ just published a large analysis of the relationship between combined oral contraceptives OCPs and the risk of venous thromboembolism VTE (see BMJ 2015;350:h2135). They analyzed 2 nested case-control studies from 2 different UK databases, with a combined input from 1340 general practices, assessing the first diagnosis of VTE in women aged 15-49 from 2001-2013, and comparing this group to 5 controls matched for age, practice, and calendar year.


–10562 cases of VTE. mean age 38, 27% smokers in the VTE cases and 21% in controls, obesity in 27% vs 16% in controls. established risk factors for VTE were 47% vs 26% in controls

–odds ratio for incident VTE and use of OCPs in the previous year, adjusted for smoking, alcohol, ethnic group, BMI, comorbidities, and other contraceptives:

–current exposure to any OCP was associated with increased risk of VTE [odds ratio OR 2.97 (2.78-3.17)] vs no OCP exposure over the previous year, with breakdown as follows.

–newer OCPs:

–desogestrel         OR 4.28  (3.66-5.01)

–gestodene            OR 3.64  (3.00-4.43)  –not available in the US

–drospirenone      OR 4.12(3.43-4.96)

–cyproterone        OR 4.27  (3.57-5.11)  –not available in the US

–older OCPs (second generation)

–levonorgestrel     OR 2.38 (2.18-2.59)

​–norethisterone    OR 2.56 (2.15-3.06)    –not available in the US

–norgestimate       OR 2.53 ( 2.17-2.96)  –actually a third generation OCP which is partly metabolized to levonorgestrel, but is less androgenic than levonorgestrel and is actually considered a second generation one in Denmark.

–this translates to: the number of extra cases of VTE per year per women

        –levonorgestrel was lowest at 6 (5-7), along with norgestimate at 6 (5-8)

        ​–desogestrel was highest at 14 (11-17), along with cyproterone at 14 (11-17)

–overall, the risk associated with gestodene was 1.5x higher than levonorgestrel (the most commonly used in the UK), and those of desogestrel, drospirenone, and cyproterone was about 1.8x higher

–desogestrel had a slightly higher odds ratio for VTE with higher doses of estrogen. norethisterone and gestodene actually had slightly higher VTE rates at the lower estrogen dosages (these were not significant, which seems to support the primary association being with the progestin in these women already on lowish doses of estrogen)

So, most, but not all, studies over the past 2 decades have often shown increased VTE risk in the 3rd and 4th generation OCPs. The current very large UK groups, given the high quality of reporting, provides more information, though it is retrospective and observational. In terms of bias, one might think that since there have been older studies showing increased VTE risk with the newer agents, there might have been preselection bias to avoiding these agents in women surmised to be at somewhat increased risk, leading to understating the actual risk.  Although I do not prescribe OCPs so often these past years, I must admit that I have been largely avoiding the newer agents because of the issue of increased VTE found in several of the earlier studies, and now confirmed here.​

Primary Care Corner with Geoffrey Modest MD: Efavirenz and hormonal contraception

23 Feb, 14 | by EBM

recent report suggesting that efavirenz decreases the efficacy of intradermal Jadelle implant (this is the successor to Norplant, with 2 thin, flexible silicone rods, each containing 75 mg of the synthetic progestin levonorgestrel).

here is the abstract (that is all i could find), from PubMed:

Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. AIDS. 2014 Jan 2. [Epub ahead of print] Implementing the Jadelle implant for women living with HIV in a resource-limited setting in sub-Saharan Africa: concerns for drug interactions leading to unintended pregnancies.

“An analysis of 570 HIV-infected women in Swaziland using the Jadelle implant showed that age, condom use, which provider placed the implant, and CD4 cell count had no effect on unintentional pregnancy rates. However, antiretroviral regimen at the time of pregnancy correlated with pregnancy outcomes (P <0.001). None of the women on nevirapine or lopinavir/ritonavir-based regimens (n = 208 and 13, respectively) became pregnant, whereas 15 women on efavirenz (n = 121; 12.4%) became pregnant.”

so, this is a double hit for efavirenz. there are reports that HIV regimens with efavirenz lead to lower progestin blood levels on women on combination oral contraceptives (and recommendations that condoms still be used for contraception, as well as prevention of sexually-transmitted diseases).  this report adds significantly to the prior concerns.  in addition, efavirenz is probably the most teratogenic of the HIV antiretrovirals. so, bottom line, prob best not to choose efavirenz-based therapy on women of child-bearing age…


Primary Care Corner with Dr. Geoffrey Modest: Morning After Pill INEFFECTIVE in Overweight!?

27 Nov, 13 | by EBM

a disturbing story today that morning-after pills may not be as effective in overweight women (see for story). basically, European health regulators found that a French morning after pill marketed as Norlevo had decreasing effectiveness in women over 165 pounds and was not effective at all in those over 176 pounds, prompting the Europeans to order a label change.  turns out that Plan B in the US is basically the same composition. there was a comment in Physician’s First Watch that “According to the CDC, the average American woman weighs 166.2 pounds, which may raise concern about the efficacy of this type of emergency contraception among many U.S. women. The battle to make emergency contraception available has been long and arduous. Hopefully, this recent information will not discourage users, as this may still be the best option available.”

a couple of comments:

1. it is pretty surprising to me that if the average US woman weighs in the “decreasing effectiveness” group, and that there are lots in the “not effective at all” group, that failure rates in the US would have been pretty apparent before this.

2. seems that BMI would be more useful than weight per se, since (i would assume) the issue is the amount of fat present, with its effects on hormone metabolism (ie and the amount of adipose tissue in a 6 foot tall woman weighing 176# is pretty different from a 5 footer of same weight)

2. there was a recent article in ObGyn journal (see  DOI: http://10.1097/AOG.0b013e31828317cc) which assessed efficacy of oral contraceptive pills, patches, and vaginal rings in 7500 women of varying BMIs followed 2-3 years.  no difference in failure rates in those with BMI <25 (8.5%), BMI 25-30 (11%), or BMI >30 (9%). this was an observational study with self-reported outcomes. dose of ethinyl estradiol in the pills ranged from 20-35 micrograms (though no information on whether the higher dose pills were taken more by the more overweight women). other observational studies have had mixed results.

so, quite concerning finding in Europe. i would assume that the Food and Drug Admin will assess this aggressively to see, for example, what the US experience is and if the morning after pill should have differing hormonal content based on BMI (or weight).


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