The curse of the Empty Follicle Syndrome

Updated: Oct 26

Many frustrating situations may occur during an IVF cycle: from low response to having the cycle cancelled, from retrieving immature eggs that don’t fertilize to embryos that don’t develop properly.

But by far, one of the most dreaded scenarios is the one where you wake up from your egg retrieval anaesthesia only to be told your follicles were empty.

Wait, what??

“But I’ve seen them on a scan the day of the trigger: they were nice and plump and the tech measured and counted them!

I even had my Estrogen level measured and it totally indicated my follicles were actually hosting eggs.

HOW can this even be possible?!!”

Well, here’s a great question: IS it possible? Does the Empty Follicle Syndrome really exist or is it just an excuse? And if it does exist, are there any ways to prevent it from happening?

The Empty follicle syndrome (EFS), is a very disappointing condition in which no eggs are retrieved from mature follicles after ovulation induction in in vitro fertilization (IVF) cycles. The occurrence is pretty rare, but highly disappointing. EFS has been first recorded in 1986, and has been considered pretty controversial ever since.

Medical literature classifies Empty follicle syndrome in two categories: false and genuine.

Genuine EFS is defined as a failure to retrieve eggs from mature follicles, in spite of a normal follicular development (constant growth, satisfactory Estrogen levels on trigger day) and an optimal Beta HCG level measured on the day of egg retrieval (as proof the trigger shot has been properly administered and correctly timed)

False EFS includes all cases in which the above conditions have been met, and in which human error or pharmaceutical inaccuracy may be suspected.

To put it simple:

· did your scans show proper growth progression of your follicles throughout your stimulation?

· did you have an Estradiol level of at least 200 pg/ml per “mature” follicle on trigger day?

· was your trigger shot within the expiry date and properly stored before administration?

· was your egg collection timed correctly, 36 hours post trigger?

(I am not going to include the level of Beta HCG measured the day of egg retrieval, because clinics do not regularly do that, unless they participate in studies)

If your answer to all four questions above is YES, and you still got no eggs retrieved during that cycle, your case would more likely classify as False Empty Follicle Syndrome.

Basically, there is no way there were no eggs in there, and if none were collected, it most likely is due to a human error: improper administration of the HCG trigger, bad timing of the egg collection, incorrect flushing and/or collecting the follicle.

Frustrating as it is, there is some silver lining here: Empty Follicle Syndrome doesn’t appear to represent a permanent condition per se, because many cases occur sporadically. Therefore, chances are it was a fluke and you’ll get a better outcome on a future IVF cycle.


It was suggested that in some women, early oocyte atresia (follicular disintegration) may occur even in the presence of a normal hormonal response (good Estrogen level growth) or that some women may need longer exposure to Beta HCG in order for the egg to detach from the follicle. This theory was challenged by studies that showed employment of rescue protocols led to retrieval of follicles later in the same cycle.

It was also suggested that ovarian ageing may be one of the causes for Empty Follicle Syndrome, yet in a total of 34 case studies, published from January 1986 to February 2006, the average age of the reported patients with Genuine EFS was 33 years. Most of these patients had normal ovarian reserve, which refutes the theory of ovarian aging as cause for EFS.

The conclusion of the above-mentioned study seems to confirm what many of us suspected:


“This systematic review shows that most of the reported cases of EFS were actually avoidable and did not represent any potential pathology in the relevant patients and that the risk of GEFS is much smaller than was once thought. In fact, it can be reasonably argued whether such a syndrome really exists. Many of the case reports may represent premature ovulation that was not recognized at the time, which renders the incidence of the condition even rarer than previously estimated. Therefore, the whole concept of EFS may simply reflect a rare chance finding in any apparently normal cycle”(1)

So, what is there to be done in order to prevent Empty Follicle Syndrome?


· make sure your trigger date is decided based not only on size but also on Estrogen level. There is no news that the Estrogen level on trigger day is correlated with the number of eggs retrieved (2)

· discuss with your doctor the possibility of administering a dual trigger (Beta HCG and an antagonist) – the dual trigger is not only considered to reduce the incidence of EFS but is also recommended in older patients with diminished ovarian response and low response to stimulation meds (4)

· make sure your trigger is well within the expiry date and has been properly stored

· make sure your trigger and retrieval time are correctly timed (cca 36 h post trigger shot) because “The effect of HCG may be impaired either if oocyte retrieval is carried out too early (before 34 h from the injection), or too late (after 38 h, when the biggest follicles have already spontaneously re- leased the oocyte)” (3)

Most of all, do not despair, chances are you’ll do better next time, especially if all conditions are met.

Sources

(1) Stevenson, T. and Lashen, H., 2020. Empty Follicle Syndrome: The Reality Of A Controversial Syndrome, A Systematic Review. [online] Fertstert.org. Available at: <https://www.fertstert.org/article/S0015-0282(07)02949-4/pdf>

(2) Siddhartha, N., Reddy, N., Pandurangi, M., Tamizharasi, M., Radha, V. and Kanimozhi, K., 2020. Correlation Of Serum Estradiol Level On The Day Of Ovulation Trigger With The Reproductive Outcome Of Intracytoplasmic Sperm Injection.

(3) Revelli, A., Carosso, A., Grassi, G., Gennarelli, G., Canosa, S. and Benedetto, C., 2020. [online] Rbmojournal.com. Available at: <https://www.rbmojournal.com/article/S1472-6483(17)30238-9/pdf> [Accessed 24 October 2020].

(4) Chern, C., Li, J., Tsui, K., Wang, P., Wen, Z. and Lin, L., 2020. Dual-Trigger Improves The Outcomes Of In Vitro Fertilization Cycles In Older Patients With Diminished Ovarian Reserve: A Retrospective Cohort Study.