From natural to mild IVF cycle

Prof Tomaz Tomazevic

Universitty Clinical centre Ljubljana Slovenia

ISMAAR : renewed the interest for natural cycle and mild approaches in asssisted reproduction .

Proposal of terminology Aim Methodology

Natural cycle Single oocyte No medication

Modified natural cycle IVF

Single oocyte hCG only

GnRH ant &FSH

Mild stimulation IVF 2-7 oocytes Low dose FSH& antagonist

Conventional high

Stimulation IVF

> 8 oocytes Agonist or antag.

& high dose FSH

In the frame of this terminology we are presenting and discussing our experiences with modified natural and mild IVF

1. Our data on 1167 IVF / ICSI attempts in modified natural cycle ( only HCG)- 1994-2004

2. Our data on 2068 frozen thawed embryo replacements (FER) in natural and in modified natural cycle - 1994 -2008

3. Our data on 246 mild stimulated cycles 2009 -2011

What are live birth rates in a modified natural IVF cycle-Ljubljana IVF : Ljubljana IVF 1994- 2004 . (avg. 4-5 previous stimulated cycles)

No of Cycles 1167• Oocytes retrieved 943/1167 80%• ET/positive puncture 613/943 65%• Optimal ET / positive puncture 411/943 44%• Live birth / cycle 86/1167 7%

• Live birth / ET 86/613 14%• Live birth / optimal ET 71/345 21%• Live birth / suboptimal ET 15/255 6%

• Live birth / woman 86 /522 16%

Factors associated with success Indications ? Female vs. male infertility in modified natural IVF cycle

Female Male

Cycles 772 395

Oocytes retrieved 81% 80%

ET/oocyte retrieved

66% 58%

Clinical pr./cycle 12% 4%

Cinical pr. /ET 21% 8%

0%

2%

4%6%

8%

10%

12%14%

16%

18%

LB/ET

LB/CY

P<0.001

ICSI for severe male Clinical Pr./212 cycles 3%, Live birth / cycle 3%

Factors associated with success. Influence of maternal age on embryo development, clinical pregnancy and live birth rate . From RBM Online 2007,15:230-236

Maternal age <39 years ≥ 39 years

No of natural cycles . 286 111

Oocytes retrieved/cycle % 77 75

Embryo tranfer/ cycle % 57 52

Blastocyst development % 55 29 (P<0,001)

Pregnancy /blastocyst ET % 39 24

Pregnancy /morula ET % 13 3

Pregnancy/ lower stage ET % 0 0

Pregnancy/embryo transfer % 26 9

Live birth / ET % 23 3 (P<0001)

Spontaneous abortion / Preg% 14 60 (P<0,05)

Live birth/ Cycle % 11 2(P<0001)

Poor responders ? Normal vs. poor response in previously stimulated cycles and success in a modified natutral IVF cycle ? From data published in RBM Online 2007,15:230-236

0ocytes in previous

stimulated cycles

≥5oocytes

(Normal)

≤4 oocytes

(Poor)

Natural IVF Cycles 192 133

Ocyte retrieved %

83% 66% P<0.001

ET/cycle % 61% 45% P<0.01

Optimal ET/ cycle 33% 18%

P<0,03

Clinical pregnancy /cycle

15% 7%

P<0.03

0%

5%

10%

15%

20%

normal poor

LB/ET

LB/cy

p<0.05

First or last line treatment? Number of previous IVF attempts and success of modified natural IVF cycle for female infertility ?

p<0.05

0%

5%

10%

15%

20%

25%

1 to 3 4 to 9 10 to 20

LB/ET LB/cy

No of Attempt 1 to 3 4 to 9 10 to 20

No of cycles 205 354 84

Oocytes retrieved

170 287 84

ET / cycle 58% 54% 59%

Clinical pr./ ET

27% 23% 12%

Clinical pr./ cycle

16% 11% 7%

Natural cycle for endometrial preparation ?Live birth / FER in 1077 natural cycles and 991 modified natural cycles for endometrial preparation.

No of ETs Live birth /ET

Natural 1077 19 %

Modified Natural

991 17 %

375 deliveries after 2068 frozen thawed blastocyst transfers in the natural cycle - Ljubljana IVF 1997- 2009

0%5%

10%15%20%25%

1emb

2emb

LB/ET-NC

LB/ET- MNC

Variables – avg. - range 248 modified natural IVF cycles (day of HCG)

223 natural FER cycle

(day before LH surge)

E2 nmol/l (272 pg/ml)

Range 0.4-1.2 nmo/l

0,56± 0,1 0,56 ± 0,13 NS.

Dominant follicle (mm) Range 16-22

18.7 ±1,44 18,90 ±1,4 NS.

Endometrium (mm)

6-12 mm

8,2 ± 2,3 8,80 ± 1,50 NS.

Characteristics of natural cyle monitoring ? Very important individual variability of hormonal,and ultrasonic monitoring variables just before HCG in 248 modified natural IVF cycles and one day before spontaneous LH surge in 223 natural FER cycles has been noticed.

Influence of E2 concentrations on the day of HCG administration on embyro development, clinical pregnancy and live birth rate . From RBM Online 2007,15:230-236

E2 nmol/l 04-0.49 0.5-1.25

Natural cycles 180 217

Φ Follicle (16-22mm) 18.7 ± 1.5 18.5 ± 1.4

Oocytes retrieved % 77 76

ET/ cycle %

58 54

Blastocyst develop. % 47 57

Pregn/blastocyst ET % 37 37

Pregn /morula ET % 13 6

Pregn/ lower stage % 0 0

Sp. abortion / Preg % 21 17

Live birth/ET % 19 18

Live birth/ Cycle %

11 10

0%

5%

10%

15%

20%

E20.4-049

E2 0.5-1.25

Livebirth/ET%

Livebirth/cy%

Low vs high NS

Summary of recent data on modified natural cycle IVF - presented by Jehoshua Dor.

Philips* Tomazevic* Trokoudes ** Pelinck ** Total

No of cycles 242 286 138 844 1510

No of ET 52% 57% 32% 37% 43%

Cancellations 47% 7% 26% 17% 20%

No fertilization

19% 19% 5% 28% 23%

Clinical preg./ET

19% 26% 53% 27% 26%

Clinical preg./Cy

10 % 15 % 17% 10% 11%

* Use of hCG only, * *use of gonadotropins (day 7) and antagonists

Mild stimulation a compromise between conventionally stimulated and modified natural cycle

Mild stimulation starting on day 5 + antag

Conventional stimul. starting on day 2 +antag

Modified natural cycle stim. starting on day 7 +antag

Our experience with mild stimulation -2009-2011

• Mild stimulated cycles 246

• Positive puncture 236 96 %

• ET /PP 200 85 %

• Embryo Freeezing / ET 32 16 %

• Pregnant 68 34.5 %

• Live birth & ongoing pr. /ET 54 26.5 %

• Live birth & ongoing pr. /Cycle 54 21,5 %

• LB/Day ET day 5 ( 182- 91%) 52 28,6%

• LB/Day ET day 3 ( 18 - 9% ) 2 11 %

• LB/Blastocyst ET day 5 ( 150 -82% ) 51 34 %

• LB/Morula ET day 5 ( 32 -18% ) 1 3 %

• Twins / Live birth & ongoing preg. 9 17 %

Conclusions

• The use of natural cycle IVF with respect to appropriate indications female infertility and age <36 years could provide relatively good results with low costs of treatment. Dilemma of using it as a first or a last line treatment is still open

• Complementary use of stimulated and unstimulated cycles could possibly reduce costs in allow better cumulative success rate. In the modern ara it is difficult to implement natural cycle .

• Natural and modified natural in our hands represent a gold standard for transfer of frozen thawed embryos

• Dilemma between conventionally stimulated and natural cycle can sucessfully be solved by a compromise i.e by using a mild stimulation protocol starting on day 5.

Thank You