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NATURAL CYCLE IVF
Dr. Markus Nitzschke
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DEFINITION
WHY NATURAL CYCLE IVF?
HOW IS IT DONE?
WHAT IS THE SUCCESS RATE? : Efficiency
PATIENT SATISFACTION
WHEN? : Indications
COSTS
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WHY NATURAL CYCLE IVF
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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
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Egg Quality
Baart et al., 2007, Hum Reprod
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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
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Endometrium
Ovulation
Horcajadas et al., Mol Hum Reprod, 2005
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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(?)
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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
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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
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IVF WITHOUT GONADOTROPINS
Modified Natural Cycle IVF = IVF Naturelle
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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) ?
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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.
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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
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IVF Naturelle -the basic concept
Less controls
Monthly egg retrievals without anaesthesia
Low risk of complications
Low cost
Efficient
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Aanesen et al., RBMonline, 2010
Modified NC-IVF - Sweden
Less controls
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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
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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)
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IVF Naturelle - Efficiency
Premature ovulation(Control of ovulation)
Immature oocytes
Pregnancy rate / transfer
Pregnancy rate / initiated cycle
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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
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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)
.
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Natural Cycle IVF – Cumulative pregnancy rate
Nargund et al., Hum Reprod 2001
3,49 cycles per patientMean age : 34Regular cycles
46%
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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
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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
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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
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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
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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
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THANK YOU FOR YOUR INTEREST