Empty Follicle Syndrome: An Uncommon but Frustrating Complication of In Vitro Fertilization

Empty Follicle SyndromeEmpty follicle syndrome (EFS) is a recently discovered condition that affects a small number women going through in vitro fertilization (IVF). IVF is a type of assisted reproductive technology. Simply put, IVF is a way to help a woman become pregnant who has been unable to become pregnant naturally.

If you are not using IVF, you probably don’t need to know about EFS, but if you are, this condition can be a frustrating and expensive complication. Each cycle of IVF takes a great deal of time and effort, and costs a lot of money. Women who experience EFS get half way through an IVF cycle and may have to stop and start over.

Some IVF Basics

To understand EFS, you need to know some IVF basics. EFS may become a more common problem as more and more women are trying IVF. According to the latest statistics from the Centers for Disease Control and Prevention (CDC), almost two percent of babies born in the United States are conceived using some form of assisted reproductive technology.

During IVF, a woman is given medications to stimulate egg production. Eggs are removed and placed with a sperm sample in a laboratory. If a sperm fertilizes an egg, the fertilized egg (embryo) is placed back inside the womb (uterus) to grow. In some cases, there may be more than one embryo placed. Here are the basic steps to prepare for an IVF cycle:

  • IVF begins with regulating and timing the menstrual and ovulation cycle.
  • Various hormone medications are used to stimulate ovulation and egg production.
  • Blood tests are done to measure the hormone estradiol, which signals ovulation.
  • Ultrasound images are done to look for enlarging (mature) follicles. Follicles are the fluid-filled sacs that form inside the ovary to support an egg.
  • When the blood tests and ultrasounds suggest the time is right, a final ovulation trigger is given about 36 hours before egg removal. This trigger is an injection of the hormone beta-human chorionic gonadotropin (hCG).
  • Levels of hCG are checked with a blood test on the day of egg retrieval.
  • If all the tests look good for egg retrieval, surgery is scheduled. Under a light anesthesia, using ultrasound imaging as a guide, a hollow needle is placed through the back of the vagina and up into the ovary to remove eggs from several mature follicles.

What Happens With EFS

In EFS, everything goes as planned, but no eggs are found after removing the contents of the follicles. They are empty. EFS was first described in 1986. It has remained a frustrating mystery since then. EFS may occur in up to seven percent of IVF cycles.

Two types of EFS have been described. False EFS may be caused by a failure of the hCG trigger. Genuine EFS may be caused by an actual failure of the egg maturation process despite normal hormone levels, follicle formation, and response to hCG. Studies agree that false EFS is more common that genuine EFS.

Possible causes of false EFS include:

  • Poor timing of the hCG injection (too soon or too early)
  • A weak batch of hCG medication
  • A higher than normal clearance of hCG by the liver (clearance may vary from person to person, throwing off the timing)

Possible causes of genuine EFS include:

  • Abnormal follicle formation that causes eggs to age too soon or not develop properly (follicle dysfunction)
  • A poor supply of eggs, or eggs that are too old
  • Unknown genetic causes

An aging egg supply is a probable cause because genuine EFS. EFS increases with age of the mother. If a woman has genuine EFS once, the chance of EFS occurring in another cycle is 20 percent. If the woman is over age 40, the chance of EFS occurring again is close to 60 percent.

Some researchers believe that genuine EFS is not a true syndrome at all. They contend that even in a normal cycle, without any hormone stimulation, not all follicles produce eggs. As many as 20 percent of normal follicles may be empty. So, even when several follicles are used, genuine EFS may be a normal and random occurrence.

What Can Be Done About EFS

EFS is unpredictable. By definition, everything looks on target until the follicles are found to be empty. One possible treatment for false EFS is to save the cycle by giving another hCG injection and repeating egg retrieval in about 36 hours. A different batch of hCG medication is used. This treatment works best if the blood level of hCG on the day of retrieval was not as high as it could be (not optimal). Under these conditions, the cycle can be saved in about 40 percent of cases.

False EFS should not occur again during a repeat cycle of IVF. Genuine EFS is more likely to be a recurrent problem, especially in older woman.

One way to prevent EFS during a repeat IVF cycle is to add another triggering hormone along with hCG before egg retrieval. The hormone is called GnRH and this process is called dual triggering. Dual triggering is a relatively new technique, so the success rate in not known yet.

Key Takeaways

  • EFS is a rare complication of IVF.
  • EFS is frustrating for doctors and for patients because it can cancel an expensive and time-consuming IVF cycle.
  • The most common cause of false EFS is poor timing or poor concentration of the hCG injection.
  • Genuine EFS is less common but may reoccur during future cycles. The chances of reoccurrence increase with age.
  • A cycle lost to false EFS may be saved by repeat hCG injection.
  • If a cycle is lost to genuine EFS, EFS may be prevented with a dual trigger injection during a repeat cycle.

If you are thinking about trying IVF, talk to your doctor about the risk of EFS. Ask how your IVF clinic deals with this problem and how often they see it. Ask what they do to prevent it or save a cycle. The more you know, the better you will be able to deal with this rare but frustrating IVF complication.

Christopher Iliades
Dr. Chris Iliades is a medical doctor with 20 years of experience in clinical medicine and clinical research. Chris has been a full time medical writer and journalist since 2004. His byline appears in over 1,000 articles online including EverydayHealth, The Clinical Advisor, and Healthgrades. He has also written for print media including Cruising World Magazine, MD News, and The Johns Hopkins Children's Center Magazine. Chris lives with his wife and close to his three children and four grandchildren in the Boston area.

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