Natural Cycle IVF: Follicle Physiology and Treatment Costs

Minimal Simulation and Natural Cycle In Vitro Fertilization, Allahbadia, G and Nitzschke, M, 2015

Natural Cycle IVF: Follicle Physiology and Treatment Costs (von Wolf, M)

Dr Daiter’s summary of this chapter

The author describes follicular endocrine changes in natural cycle IVF and conventional IVF in an attempt to explain why the implantation potential of oocytes from natural cycle IVF appears to be greater than the implantation potential of oocytes from conventional IVF cycles.  He looks at the higher intrafollicular concentrations of androgens and anti-Mullerian hormone in natural cycle IVF versus conventional IVF and proposes that these differences may be due to the suppression of LH in conventional IVF protocols that use GnRH agonists and antagonists.  The author also describes what he feels is the most cost effective IVF treatment protocol per pregnancy.

The technical discussion of the hormone milieu within developing follicles is beyond the scope and purpose of this website.  Suffice it to say, there may be reason to believe that the follicular fluid contains elements that  limit the ability of the eggs to implant efficiently, which may be a completely different mechanism that lowers pregnancy rates in conventional IVF versus natural cycle IVF (per embryo) than the commonly held believe that it is the endometrial window of receptivity that is reduced in conventional IVF cycles.

In terms of their natural cycle IVF protocol, it is noted that a completely drug free cycle is not practical, but rather that the protocol should include:

  1. As few consultations as possible prior to the egg aspiration
  2. High yield of oocytes (eggs) and the highest possible transfer rate per treatment cycle
  3. Simple and almost painless follicle aspiration
  4. Lowest treatment cost per successful pregnancy outcome

To maintain pregnancy rates while reducing consultations and diagnostic tests, patients receive Clomiphene 25 mg/day (Clomiphene at 50 mg/day is thought to have negative effects on endometrial function and may form cysts that persist into the following cycle) starting on cycle day (CD) 6 or 7 and continued until 24 hours prior to ovulation induction with hCG, the initial consultation occurs on CD 10 +/- 2 (ultrasound to measure follicle sizes and endometrial stripe, serum E2 and LH determined) and often allows for calculating the expected time of ovulation (otherwise a second consultation may be required), 5,000 IU hCG given 36 hours prior to egg retrieval once the follicle is greater than or equal to 15mm and the E2 is greater than 700 pmol/L.  This protocol had few side effects, a high embryo transfer per cycle ratio, and Clomiphene did not reduce pregnancy rates compared to drug free natural cycle IVF.

In natural cycle IVF protocols the follicle aspiration in monofollicular cycles benefit from follicle flushing (although flushing was not shown to increase oocyte yield in studies of conventional IVF ).  In their study of 164 aspirations during monofollicular IVF cycles, follicles were aspirated and then flushed three times each with 2 mL flushing medium with heparin, and the total egg yield per aspiration was 45% in the initial aspiration, 21% in the first flush, 10% in the second flush and 4% in the third flush (by flushing the egg yield increased significantly from 45% to 80%).  The number of MII eggs per aspirate was similar in all four samples (92%, 91%, 94% and 100%) and the total transfer rate increased significantly from 20% to 38% with flushing.

Luteal phase support is not thought to be needed if the follicle is just aspirated, but if there is flushing of the follicles then the granulosa cells within the follicle may become disrupted and luteal support with progesterone and possibly estrogen is suggested.

Monofollicular aspiration does not need anesthesia.  When the author studied the pain intensity from natural cycle IVF follicle aspiration with a 19G aspiration needle in relation to venous blood sampling roughly 45% of patients stated the discomfort was the same, 25% said the discomfort was slightly less, 15% said the discomfort was much less, 10% said the discomfort was slightly more and 5% said the discomfort was much more.  Therefore, 95% of patients said the discomfort was at most slightly more uncomfortable than a venous blood draw.

This center’s pregnancy rate per cycle for all patients (up to 42 years old) was 14%.   When this center compared their “treatment costs per pregnancy” for natural cycle IVF to conventional IVF, based on their findings of a pregnancy rate of 30% in fresh cycles and 20% in cryo cycles for conventional IVF (low rates compared to most of New Jersey USA), natural cycle IVF was cheaper than conventional IVF in low responders as well as in normal responders but the occurrence of pregnancy takes longer on average in natural cycle IVF.

Dr. Eric Daiter’s review of this chapter
The author’s IVF center is in Berne, Switzerland.

This chapter makes a number of good points to consider.  The initial part of the chapter describes research on the hormones within the developing follicles, comparing follicles from natural cycle IVF to conventional IVF, and finds several differences that are thought to relate to impaired implantation for embryos developed through conventional IVF.  This seems like a developing area of clinical research that could become very interesting.

The author presents a protocol for natural cycle IVF using a low dose of Clomiphene (25 mg/day), which is thought to have less of a damaging effect on the endometrium than 50 mg/day (or more).  Unfortunately, many patients will not respond to this low dose of Clomiphene but it is useful for those patients that do respond.  The dose also limits the patient’s ability to trigger her own ovulation (mount an LH surge) so there is more control of the cycle.

The authors make the valuable point that follicle flushing is important in natural cycle IVF even though it does not seem to be helpful in conventional IVF.  If follicle flushing is performed then luteal support with progesterone and possibly estrogen is warranted.

The author provides support from his own center’s clinical data that anesthesia is not often required since the discomfort of aspirating and flushing one follicle compares favorably to a venous blood draw for 95% of patients.

The cost analysis may not relate directly to a cost analysis in the USA since the prices and the success (pregnancy rates) are not the same, but it does illustrate that the costs per pregnancy in Switzerland are equal or less for natural cycle IVF.  The time to pregnancy is somewhat longer for natural cycle IVF since multiple cycles may be required.


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