Minimal stimulation IVF protocols have existed for decades. In fact, in 1978, the first successful IVF pregnancy was the result of a natural cycle—no stimulation medications were used. The development of conventional IVF protocols that relied heavily on stimulation medications soon followed.
To understand the advantages of Mini IVF, it is important to understand the key points of conventional IVF.
A conventional IVF cycle typically consists of three stages:
To maximize the number of eggs being produced (and to inhibit the natural selection of a single follicle), most IVF clinics require patients to undergo a preparation stage before the cycle starts. Preparation may involve combination birth control pills, estrogen pills or patches, GnRH agonist (Lupron) injections, and/or testosterone topical gel or patches. There is no uniform consensus regarding which type of medical intervention is optimal. The primary purpose of the preparation stage is to prevent a lead follicle from developing, thereby increasing the likelihood of follicles growing at a relatively similar rate. When one or more follicles grow at a faster rate than the majority during the stimulation stage, the physician will typically let them grow past the point of viability—i.e., “sacrifice” these dominant follicles—to give the remaining follicles a chance to mature.
Physicians at some IVF clinics believe that a preparation stage improves egg quality and optimizes outcomes. Physicians at other IVF clinics skip this stage entirely, believing that preparation has no impact on egg quality.
The stimulation stage involves daily injections of IVF medication (such as Follistim, Gonal-F, or Menopur) at daily doses of 225 IU or more to stimulate the follicles to grow. IVF clinics follow a range of different protocols regarding dosage and administration. Some IVF clinics may require patients to receive injections twice a day (in the morning and night), or they may prescribe very high daily doses (e.g., 450 IU) to maximize egg production. Again, there is no uniform consensus regarding which protocol works best. Generally, the goal for a conventional IVF stimulation protocol is to promote the development of 10-15 eggs; at some IVF centers, 20-30 eggs is not unusual.
Many IVF clinics adhere to the philosophy that more is better; however, the clinical evidence does not support this philosophy. The administration of high doses of IVF medication to maximize egg production leads to an increased risk of side-effects and other complications. In addition, it is well accepted that the majority of the eggs retrieved will not develop into normal embryos.
Premature ovulation, or ovulation before the egg is mature, is an inherent risk with conventional IVF. To prevent this, physicians may use a GnRH agonist protocol, which involves the use of Lupron for both the preparation and stimulation stages. During the preparation stage, Lupron stimulates FSH and LH production. During the stimulation stage, Lupron shuts down the pituitary gland’s production of FSH and LH, which in turn can prevent a premature LH surge and ovulation. A newer protocol, the GnRH antagonist protocol, uses a GnRH antagonist (e.g., Ganirelix) towards the end of the cycle to temporarily inactivate the pituitary gland’s production of LH and FSH.
Prior to retrieval, human chorionic gonadotropin (HCG) is given as a trigger to release the egg and initiate the ovulation process. The use of HCG is meant to mimic what happens naturally when the body is ready to ovulate and the pituitary gland produces a surge of LH: the hormonal surge releases the egg from the follicle wall into the follicle, the follicle ruptures and releases the egg 38-40 hours later. Some IVF clinics may use a GnRH agonist such as Lupron or a combination of HCG and Lupron as a trigger. Because Lupron remains in the body for only a few hours and primarily affects more mature eggs, it may decrease the risk of Ovarian Hyperstimulation Syndrome (OHSS). General anesthesia is used to sedate the patient for the retrieval procedure, which requires the presence of an anesthesiologist.
Twenty years ago, physicians in Japan reassessed the viability of minimal stimulation protocols, revolutionizing IVF treatment by developing what is now known as Mini-IVF or Japanese IVF.
Mini-IVF follows what is known as a Clomid hyperstimulation protocol. Patients are administered Clomid as a daily oral pill in conjunction with a limited number of HCG injections (approximately 3-6 injections). Clomid stimulates the natural production of FSH, which lessens the need for stimulation medication. Clomid also suppresses the LH surge, which minimizes the risk of premature ovulation and eliminates the need for continued injections of Lupron to control premature ovulation. Because fewer follicles are stimulated in a Mini-IVF protocol, egg retrievals are a significantly less complicated and less uncomfortable process, and can be performed under local anesthesia. Eliminating the use of general anesthesia reduces general-anesthesia-related costs as well as numerous associated side-effects and complications.
Mini-IVF also incorporates the use of intracytoplasmic sperm injection (ICSI). To minimize the risks of complications due to multiple gestations, single embryo transfers are performed. Because a single embryo transfer of a Day 3 embryo is associated with lower odds of success compared to multiple embryo transfers, embryos are cultured to the blastocyst stage. Transfer of a single blastocyst yields equivalent success rates as transferring 2-3 Day 3 embryos.
Due to concerns about the negative effects of Clomid on the uterine environment, Mini IVF protocol involves “vitrification,” a rapid freezing technique, which allows the embryo to be transferred to the uterus at a later date. Vitrification has up to a 99% success rate and has since been universally adopted as the freezing technique of choice.
The pioneering Mini IVF research done in Japanese has led to several important discoveries:
IVF clinics specializing in minimal stimulation techniques have been able to achieve success rates comparable to those seen at conventional IVF clinics. Mini-IVF has the added advantage of reducing the side-effects and complications that are associated with general anesthesia and high doses of IVF medication.