Natural cycle IVF involves IVF without using gonadotropins to stimulate the ovaries. It has the benefits of being lower cost, having fewer health risks than conventional IVF like OHSS, and higher patient satisfaction due to less intervention. The success rate per cycle is around 15%, though it may take more cycles to achieve pregnancy than with conventional IVF. It requires regular menstrual cycles and a flexible clinic staff and patients due to the need for frequent monitoring. It is a good option for those who do not want ovarian stimulation or have contraindications to stimulation.

1. NATURAL CYCLE IVF
Dr. Markus Nitzschke

2. DEFINITION
WHY NATURAL CYCLE IVF?
HOW IS IT DONE?
WHAT IS THE SUCCESS RATE? : Efficiency
PATIENT SATISFACTION
WHEN? : Indications
COSTS

3. WHY NATURAL CYCLE IVF

4. OHSS
moderate: 1-7%
severe: 0,5%
OHSS
moderate: 1-7%
severe: 0,5%
Ovarian
Torsion: 0,1%
Ovarian
Torsion: 0,1%
Multiple
Pregnancy
Multiple
Pregnancy
Risks of conventional IVF:
Kjellberg et al., 2006, Hum Reprod
Delvigne et al. 2002, Hum Reprod. Update

5. Egg Quality
Baart et al., 2007, Hum Reprod

6. Embryo selection
Baart et al., 2007, Hum Reprod
Verproest et al. 2008, Hum Reprod
Rubio et al. 2010, Hum Reprod
Conventional
Minimal Type of cycle Aneuploid Embryos
Convencional
IVF
63% Baart et al
Mini - IVF 45% Baart et al
No stimulation 36% Verpoest et al

7. Endometrium
Ovulation
Horcajadas et al., Mol Hum Reprod, 2005

8. Gonadotropin free IVF with SET?
ADVANTAGES: INCONVENIENCES:
 High embryo quality
 Better endometrial receptivity
 Reduced risk of OHSS
 Less multiple pregnancies
 More “patient friendly”(?)
 Lower costs (?)
 Long learning curve
 Team has to be flexible
 Higher % of cancellation/cycle
 Less benefit(?)

9.  Conventional-IVF
 Low dose-IVF
 Mild-IVF
 Minimal-Stimulation-IVF
 Late Start Minimal Stimulation-IVF
 Natural Cycle-IVF
 Modified Natural Cycle-IVF
 IVF-NAT
 ……………………..
DEFINITION

11. A clinically understandable definition
IVF with gonadotropins
IVF without gonadotropins
Conventional IVF: High dosages of gonadotropins
Mini-IVF: less dosage of gonadotropins
+/- aromatase inhibitors or SERM
Natural Cycle IVF: IVF without medication
Modified Natural Cycle IVF: Similar to Natural Cycle IVF,
but using medication to control LH

12. IVF WITHOUT GONADOTROPINS
Modified Natural Cycle IVF
= IVF Naturelle

13. The problem: premature ovulation
1) Plan egg retrieval according to the natural hormonal pattern?
2) Premature ovulation induction (HCG o GnRHa)?
3) GnRH-Antagonists?
4) Prostaglandin inhibitors (NSAIDs) ?
5) Clomifen Citrate (CC) ?
Possible solutions:
5) Clomifen Citrate (CC) ?5) Clomifen Citrate (CC) ?

14. Concept:
- The anti-estrogenic effect of CC can be used to control LH instead of
GnRH Antagonists
(Teramoto and Kato, 2007, RBMOnline)
CLOMIFEN CITRATE (CC)CLOMIFEN CITRATE (CC)
How does it work?
- In healthy women with normal ovarian reserve, LH is triggered on
the hypothalamus level when the blood E2 concentration stays 2 –
3 days over 200 pg/mL.
- CC is blocking the E2 receptors on the hypothalamus and is able
to delay LH surge in this way.

15. Clomifen citrate to control LH rise + ovulation induction :
⇒ 50mg Clomid from D7-8 until ovulation induction
⇒ Hormonal blood test D10: E2 + LH
⇒ If E2 < 300 pg/mL D10, repeat E2 + LH until E2 > 300 pg/mL
⇒ Alternative: TVS D10 => Monitor follicle until 19 - 21 mm
⇒ Ovulation induction HCG or GnRH Agonist
⇒ Program ER 36h after trigger
⇒ Embryo transfer 2 – 3 days after egg retrieval
⇒ Luteal phase support: 200 mg progesteron vaginally every 12h
Protocol

16. IVF Naturelle -
the basic concept
Less controls
Monthly egg retrievals without anaesthesia
Low risk of complications
Low cost
Efficient

17. Aanesen et al., RBMonline, 2010
Modified NC-IVF - Sweden
Less controls

18. 1 2 3 4 5 6 7 8 9 10 11 12 ........36h-OR........ET….......OR+14
OR=oocyte retrieval LH-surge/GnRha/HCG HCG-Test
IVF Naturelle - Switzerland
Monitoring (E2, LH)/Ultrasound X (X)
Von Wolff, 2011-2013 not published data
Less controls
Cycle day
1,2 controls x cycle

19. Easy egg retrieval without complications
• > 1000 egg retrievals: without complications
• No cancellation because of pain
Bern, Switzerland:
 Without anaesthesia
 Very thin needle (19G)
 Fast procedure (< 5min)

20. IVF Naturelle - Efficiency
Premature ovulation
(Control of ovulation)
Premature ovulation
(Control of ovulation)
Immature oocytesImmature oocytes
Pregnancy rate / transferPregnancy rate / transfer
Pregnancy rate / initiated cyclePregnancy rate / initiated cycle

21. Premature ovulation/immature oocytes
Nº Cycles ER
Premature
ovulation
ER with
oocyte
Immature
oocytes
Fahy, 1995 79 65 17% 83%
Nargund, 2001 181 174 82%
Ingerslev, 2001 114 74 32,4% 87,8% 11,6%
Lenton, 2007 534 495 8,7% 81%
Aanesen, 2010 129 89 13,2% 85%
Kawachiya, 2011 962 934 3,6% 75,3% 2,6%
Von Wolff, 2013* 103 91 6,8% 77,7% 2,9%
ER: egg retrieval
* < 42 years. Protocol with clomifen citrate

22. Natural Cycle IVF – Pregnancy rate
Cycles ER ET/cycle
Implantation
rate
Clinical
PR/cycle
Multiple
pregnancy
rate
Fahy, 1995 79 65 14% 9%
Nargund, 2001. 181 174 68% 24% 13,2%
Ingerslev, 2001 114 74 39% 14% 3,5% 0%
Lenton, 2007. 495 495 57% 15% 8%
Aanesen, 2010 129 89 46,5% 27% 12,4% 0%
Kawachiya, 2011 962 934 46,8% 39,1% 14,7% (NV)
Von Wolff 2013* 103 91 54% 25% 14% 0%
*(Natural Cycle IVF, Bern)
(< 42 years, 1.2 follicle controls pre cycle)
.

23. Natural Cycle IVF – Cumulative pregnancy rate
Nargund et al., Hum Reprod 2001
3,49 cycles per patient
Mean age : 34
Regular cycles
46%

24. COSTS
Nargund et al., 2001, Hum Reprod; Berna
Conventional IVF Modified Natural Cycle
Time of treatment 1-2 months 3-4 months
Pregnancy rate 30-40% 30-40%
Costs/life birth
(only treatment costs)
≈$6.000,-
70% less
(40% less, Bern)
OHSS 2-4% 0%
Multiple pregnancy 17% ≈0%
The INeS study- Bensdorp 2009

25. Study in Bern, Switzerland:
How painful was the egg retrieval compared with drawing blood?
Much
less
A bit
less
The
same
A bit
more
Much
more

26. Study in Bern, Switzerland:
Which of the following interventions was less stressful during Conventional
IVF or during Natural Cycle IVF?
Conventional IVF
The
same Natural IVF
Follicle control Egg retrieval Transfer

27. WHEN
Indications (our opinion):
 Patients who do not want or tolerate
hormonal stimulation
 Moral or religious reasons (no
generation of more than one embryo)
 History of OHSS
 Low responders to ovarian stimulation
 Low ovarian reserve
 Patients with low economic resources
Relative contraindications (our
opinion)
 PCOS with dis-ovulation
 Irregular menstrual cycles
 Anovulation because of GnRH
deficit
 Difficult access to ovaries

28. CONCLUSIONS
Natural Cycle IVF offers pregnancy rates up to 15%/cycle
Nevertheless, this technique requires:
Low cost Less risks Higher satisfaction
A specialization of the clinic
A bit more time to
achieve the pregnancy
Regular menstrual cycles
Higher flexibility of patients and
staff of the clinic

29. THANK YOU FOR YOUR INTEREST