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Teramoto's protocol

Cancellation rate

Pregnancy rates


Home : Teramoto

Teramoto minimal stimulation IVF cycles

Teramoto, a reproductive endocrinologist in Japan, reported retrospectively on his impressive series of 44,345 patients treated with minimal stimulation IVF or mini-IVF at Kato Ladies Clinic in Tokyo, Japan in 2007.  His approach to minimal stimulation IVF has been transplanted to the United States and is growing in popularity.  Anyone considering undergoing mini-IVF should first better understand the basis for it.  Teramoto’s protocol is based both on reproductive physiology and on solving certain obstacles to simplifying IVF that are unique to Japan.  The obstacles to a simplified form of IVF are different in the United States than in Japan and a slightly different approach may be both more effective and less expensive.  

Individuals considering different approaches to advanced reproductive technologies need to better understand the advantages and disadvantages involved with each procedure as well as the reported success ratesWe are not aware of any direct comparison of Teramoto minimal stimulation IVF to traditional IVF, Fauser style minimal stimulation IVF or any of the variations of IVM.

Teramoto pre-treats some patients with oral contraceptives with or without estradiol which appears to improve results in younger patients.  He then treats patients with clomiphene citrate (Clomid or Serophene).   An important innovation in his protocol is to treat patients with clomiphene from day 3 of their menstrual cycle until ovulation is triggered.   This appears to be very successful in preventing a premature LH surge.  An LH surge is a physiological event that is supposed to occur when the (single) egg is ready to ovulate.  If it occurs too early, you will either loose the egg before retrieval or the egg will be damaged (possibly the egg starts ageing too soon) and IVF will not work.  Premature LH surges are a major cause of cycle cancellation (up to 20% of the time) with natural cycle IVF.  Teramoto also monitors LH levels and if an LH surge occurs, he undertakes an “emergency” IVF retrieval.  Teramoto is very effective in avoiding uncontrolled LH surges (only 5% of cycle are lost or require emergency retrievals).  A key objective of the Teramoto protocol is to limit injectable medications, since in Japan, injections (including SQ) generally are only given in the doctor’s office.  (Nevertheless, some patients in his series received 150 units of gonadotropins every other day from day 8 of a patient’s cycle administered during an office visit.)  Ovulation is triggered by the patient taking nasal GnRH (a drug like Lupron) to induce a spontaneous LH surge.   Teramoto suggests that this is better than triggering ovulation in preparation for IVF with HCG, but the primary benefit is likely avoiding a timed injection.  (LH surges in the natural cycle have been shown to be quite diverse in their patterns and in some patients may be suboptimal.) The retrieval is done 32 to 35 hours later.  Embryo transfer is on day 2  and progesterone is used to support the last part of the cycle.   (Some patients in his series had transfers after embryos were frozen and defrosted.)  Our approach to mini-IVF builds on the Teramoto protocol (and the Fauser protocol), but avoids or improves upon those features that were designed to solve particular problems in Japan.  

An important premise of the Teramoto protocol is that when fewer eggs are obtained for IVF they are likely to be of better quality then when a large number are obtained.  This assertion has not been well studied.  The chromosomal normality of eggs was looked at in good prognosis patients in a comparison between the Fauser mini- IVF (late start mild stimulation IVF) and a slightly more aggressive ovulation induction type IVF which favored mild stimulation.  The premise suggests that there should be no difference between the pregnancy rates using mild or traditional stimulation.  This does not appear to be true.  In the United States, mild stimulation of this sort is rarely used, but the pregnancy rate in US national reporting data is significantly higher than European reporting data which usually employ a milder ovulation induction (even when corrected for the number of embryos transferred).

The Teramoto series reports on a very large number of older patients (in the context of IVF).  For example, there are 463 women aged 44 to 47 who underwent 4736 IVF cycles in his series (an average of more than 10 cycles each).   The live birth rate for these women with the Teramoto protocol was 2 live births for each 1000 cycles initiated.   In the United States many of these women would have utilized donor eggs rather than a long term trial of IVF.  The large number of older patients is not due to the effectiveness of the Teramoto protocol for this subset of patients, but rather to the fact that donor eggs are not available in Japan.   (For the informed patient in this age group who wishes to undertake IVF, we would recommend Mini-stim IVF™ over traditional IVF.

The biggest problem with the Teramoto protocol and minimal stimulation IVF is the cancellation rate for cycles.  Once a cycle is started, it may be cancelled for inadequate response, a premature LH surge, no eggs obtained on retrieval, no eggs fertilized, or no growth in fertilized embryos.  For traditional IVF, the LH surge is controlled, most retrievals obtain eggs, most embryos grow enough to be transferred, and about 95% of cycles have fertilizations.  Thus the cancellation rate is primarily for poor response and only about 18% (US data 2003) of started cycles do not have a transfer.  

On average in Teramoto’s series, 30 to 50% of started cycles did not have a fresh transfer.  (Some may have had a transfer after cryopreservation and defrost.)    This is similar to the Fauser paper, in which the cancellation rate was 40%.  The cancellation rate (no fresh transfer/ fresh cycle start) based on his published data varies by age.

Age -->

27-29

30-32

33-35

36-38

39-41

42-44

45-47

% cancel

32.3

30.3

29.3

32.3

37.7

41.6

52.4

This high cancellation rate makes it more difficult to compare pregnancy rates.  It makes sense to talk about the (ongoing or delivered fresh) pregnancy rates per initiated cycle, per retrieval or per transfer.  The numbers are quite different.  For example, for women aged 27 to 29, Teramoto had a fresh pregnancy rate of 14.6% per initiated cycle, 15.1% per retrieval, and 21.5% per transfer. 

The table below lists fresh pregnancy rates for Teramoto’s series for the different age bands used in his paper.  Note that pregnancy rates are highest in the youngest patients and decline with age just like they do in traditional IVF.  Similarly, the pregnancy rates reflect a generic sub-fertility that begins in the 36-38 age group.  The pattern mirrors that of traditional IVF.

Age -->

27-29

30-32

33-35

36-38

39-41

42-44

45-47

% pregnancy per initiated cycle

14.6

13.5

10.5

7.4

3.1

1.0

0.08

% pregnancy per retrieval

15.1

14.0

11.4

7.5

3.2

1.0

0.08

% pregnancy per transfer

21.5

19.4

14.9

10.9

5.0

1.6

0.2

 

It is important to understand that data presented in this way has a slightly different focus than as presented by Teramoto, who may have been more concerned with the pregnancy rate per patient rather than the pregnancy rate per cycle.  Although we agree that it is desirable to think in terms of doing multiple cycles in order to achieve a tangible pregnancy per patient, in order to compare therapies it is more helpful to compare pregnancy rates per cycle.

We believe that minimal stimulation IVF will play an important role in the provision of advanced reproductive technologies in the future.  Its primary advantages are ease of use and lower cost.  However, there is no magic bullet.  Minimal stimulation IVF is not the best approach for everyone.  It may be a poor approach for some patients.  Learning more about this technique and your provider’s approach to it is the correct next step for you to take.  The Teramoto approach is only one way to do minimal stimulation IVF and his approach was specifically designed for Japan.  We think minimal stimulation IVF can be better adapted to United States practice with more effectiveness and greater ease of use.