NATURAL CYCLE IVF

Dr. Markus Nitzschke

DEFINITION

WHY NATURAL CYCLE IVF?

HOW IS IT DONE?

WHAT IS THE SUCCESS RATE? : Efficiency

PATIENT SATISFACTION

WHEN? : Indications

COSTS

WHY NATURAL CYCLE IVF

OHSS moderate: 1-7%

severe: 0,5%

Ovarian Torsion: 0,1%

Multiple Pregnancy

Risks of conventional IVF:

Kjellberg et al., 2006, Hum Reprod

Delvigne et al. 2002, Hum Reprod. Update

Egg Quality

Baart et al., 2007, Hum Reprod

Embryo selection

Baart et al., 2007, Hum ReprodVerproest et al. 2008, Hum ReprodRubio et al. 2010, Hum Reprod

Conventional

Minimal Type of cycle Aneuploid EmbryosConvencional IVF

63% Baart et al

Mini - IVF 45% Baart et al

No stimulation 36% Verpoest et al

Endometrium

Ovulation

Horcajadas et al., Mol Hum Reprod, 2005

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(?)

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

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

IVF WITHOUT GONADOTROPINS

Modified Natural Cycle IVF = IVF Naturelle

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) ?

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)

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.

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

IVF Naturelle -the basic concept

Less controls

Monthly egg retrievals without anaesthesia

Low risk of complications

Low cost

Efficient

Aanesen et al., RBMonline, 2010

Modified NC-IVF - Sweden

Less controls

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

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)

IVF Naturelle - Efficiency

Premature ovulation(Control of ovulation)

Immature oocytes

Pregnancy rate / transfer

Pregnancy rate / initiated cycle

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

Natural Cycle IVF – Pregnancy rateCycles ER ET/cycle Implantation

rateClinical

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)

.

Natural Cycle IVF – Cumulative pregnancy rate

Nargund et al., Hum Reprod 2001

3,49 cycles per patientMean age : 34Regular cycles

46%

COSTS

Nargund et al., 2001, Hum Reprod; Berna

Conventional IVF Modified Natural CycleTime of treatment 1-2 months 3-4 monthsPregnancy 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

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

Study in Bern, Switzerland:

Which of the following interventions was less stressful during Conventional IVF or during Natural Cycle IVF?

Conventional IVFThe

same Natural IVF

Follicle control Egg retrieval Transfer

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

CONCLUSIONSNatural 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

THANK YOU FOR YOUR INTEREST