Researchers in a 2021 study conducted a randomized clinical trial and found that intramuscular progesterone, or a combination of intramuscular and vaginal progesterone, led to improved live birth rates compared to vaginal progesterone alone in medicated FETs.
When it’s time to transfer that frozen embryo, you need to prepare the endometrium for transfer! And for many, performing a “programmed FET” (or a medicated FET) is the way to go.
This involves suppression of the natural menstrual cycle and administration of estrogen and progesterone to stimulate the endometrium to prepare it for implantation (luteal phase support).
Progesterone can be administered by inserting a suppository into the vagina, or by injecting it into the muscle. The latter is more painful, but is considered a more consistent way of getting progesterone into the body.
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
💡 Reminder: Terms underlined with a dotted black line are linked to glossary entries. Clicking these does not count toward your paywall limit.
There have been multiple studies on whether the vaginal or intramuscular route is the better choice, and the data has been a bit scattered:
- Haddad et al. (2007) found a decrease in live birth rates with vaginal progesterone vs intramuscular (22.8% vs 34.5%) (retrospective study).
- Kaser et al. (2012) found a decrease in live birth rates with vaginal progesterone vs intramuscular (24.4% vs 39.1%) (retrospective study).
- Shapiro et al. (2014) found no difference with vaginal progesterone vs intramuscular (48.9% vs 49.1%) (retrospective study).
- Berger et al. (2012) found no difference with vaginal progesterone vs intramuscular (48.9% vs 49.1%) (retrospective study).
Because of the inconsistent data, Devine et al. (2021) conducted a prospective clinical trial with over 1000 medicated FETs between 2014 and 2017 at 14 Shady Grove Fertility Centers in the US.
After birth control and administration of estradiol, and levels were adequate, progesterone was given (Day 1), and embryos were transferred on Day 5. There were three arms to this study:
- Arm 1 (VP, 231 women): vaginal progesterone only (Endometrin, 200 mg twice a day starting in the morning of Day 1 and transfer on Day 5).
- Arm 2 (VP+IMP, 408 women): Vaginal progesterone like above, but also intramuscular progesterone (50 mg in oil, administered once every 3 days – so twice in total before transfer – once on Day 1 and once on Day 3, and then transfer on Day 5).
- Arm 3 (IMP, 421 women): Intramuscular progersterone (50 mg every evening, with the transfer on Day 6).
- Progesterone/estradiol was continued until 10 weeks of pregnancy or a negative pregnancy test.
Take note of the acronyms I’m using for each arm above (VP vs VP+IMP vs IMP), and let’s look at the results!
IMP and VP+IMP saw a higher clinical pregnancy (54% and 54%) compared to VP (37%).
IMP and VP+IMP saw a higher live birth (44% and 46%) compared to VP (27%).
These are some mighty big differences! The reason is that IMP reduced losses. Biochemical losses were doubled with VP alone (32%) compared to IMP (18%) and VP+IMP (13%), and clinical pregnancy losses were increased, although this was only statistically significant between VP and VP+IMP (27% vs 15%; IMP was 19%). When both the biochemical and clinical pregnancy losses were considered, half (50%) of pregnancies were lost with VP, but only 33% with IMP and 26% with VP+IMP.
The stats above are for the intention-to-treat analysis (ITT), an unbiased analysis of the whole dataset. The per-protocol analysis (which looks at only those who followed the protocol exactly, and excludes those who drop out of the study), was also significant and a bit more pronounced than the ITT analysis!
So vaginal progesterone alone was inferior in nearly every outcome looked at compared to intramuscular injection of progesterone. What’s interesting is that you don’t even need to do the shots every day! Taking it every third day (along with daily vaginal progesterone) is comparable!
They also looked at serum progesterone levels two weeks after FET (while they were still administrating their doses). These levels were lowest with the vaginal progesterone only group (7.4 ng/ml), in the middle with the vaginal + intramuscular group (11.2 ng/ml), and highest with the intramuscular only group (17.8 ng/ml). In fact, live birth was highest when the serum progesterone levels were 9 ng/ml or higher (48% of these women had a live birth), and lowest when these levels were <3 ng/ml (12%).
So it may be that the overall amount of progesterone is what matters.
In this study, only 2 administrations of vaginal progesterone were given which was done to encourage adherence to the protocol (among other reasons). Some people take 3 doses, or higher doses (>200 mg – although this isn’t approved by the FDA, but is in Europe), and if this increases the serum progesterone levels then it might be enough to see improved outcomes.
Regardless, this was a great study that opens up the possibility of taking one-third of the intramuscular shots (with combined vaginal delivery) instead of the daily injection, and this is probably a big relief to many!!
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
Related posts:
Pregnancy outcomes and factors linked to low levels of progesterone on day of FET
Study examines optimal timing for an FET after an IVF cycle
2 embryos or 1? The risks of a double embryo transfer for women under 35
Prolonged frozen embryo storage may result in lower success
Comparing pregnancy outcomes for letrozole, natural and medicated FETs
Pregnancy outcomes and complications with medicated, natural and mild stimulated FETs
Study finds no difference in live birth rates for embryos frozen up to 10 years
Study finds more flexible triggering timing for modified natural cycle FETs