Seeking the strategy against treatment...
Transcript of Seeking the strategy against treatment...
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Seeking the strategy against
treatment failure
Edson Borges Jr.
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Sucesso na FIV - ICSI
Como definir ?
• Obtenção de óvulos maduros?
• Fecundação?
• Embriões de boa qualidade?
• Implantação?
• Gestação?
• Nascimento?
• Bebê e mãe saudáveis após tratamento!
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Resultados globales de FIV/ICSI en Brasil el 2014
* aspiraciones/ciclos iniciados ** xxx/aspiraciones
96,8 % *
65,2 % **
23,8 % ** 19,8 % **
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50,7 49,7 48,3 49,2 46,8 45,9 46 44,2 43,3 41,837 36
40
31,1 31,3 33,9
34,4 35,2 35,1 35 36,9 35,9 36,7 37,9 38,7 40,1
39 39
39,9
42,741,3 43,5
14,9 15,1 16,6 15,8 16,3 18,2 17,2 17,9 18 18,124 25
20,126,2 23,4 22,6
0%
20%
40%
60%
80%
100%
00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15
≤34 35 - 39 ≥40
Frecuencia de transferencias embrionaria (FIV/ICSI) de acuerdo a la edad de la mujer - RLA 2000 - 2015
Frec
uen
cia
de
tran
sfer
enci
as e
mb
rio
nar
ias
66,1%
49,3%
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Sucesso na FIV - ICSI
Paciente
Estimula- ção
Ovariana
Monitori-zação
Trigger
Suporte de fase lútea
Freeze all x transfer a
fresco
Sêmen
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Paciente
Monitori-zação
Trigger
Suporte de fase lútea
Freeze all x transfer a
fresco
Sêmen
Estimulação Ovariana
Sucesso na FIV / ICSI
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O que sabemos:
Estimulação ovariana: pobre resposta
• Redução progressiva e mais acelerada dos folículos após 35-37 anos • 10% das mulheres < 40 anos têm redução prematura dos folículos • 10-24% dos ciclos de FIV • Causas prováveis: cromossômicas adquiridas, alterações genéticas,
iatrogênicas
Porém: SEM CAUSA APARENTE na maioria das vezes
0%
5%
10%
15%
20%
25%
30%
35%
40%
<23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 >47
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The present study shows that: The definition of poor responders is still subjective
Estimulação ovariana: pobre resposta
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Clique para adicionar um texto.
Estimulação ovariana: pobre resposta
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Estimulação ovariana: pobre resposta
“Taxa de produção folicular”
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AUMENTAR O NÚMERO DE OVÓCITOS / EMBRIÕES
E quando a resposta é muito pobre / sem resposta?
• Aumento das Gns não aumenta o recrutamento folicular • Terapias complementares ?? – sem comprovação • Paciente quer continuar tratamento • Doação de ovócitos: alternativa descartada
Estimulação ovariana: pobre resposta
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There is insufficient evidence to support the routine use of any particular intervention either: • pituitary down regulation, • ovarian stimulation or • adjuvant therapy
Estimulação ovariana: pobre resposta
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Dinâmica de recrutamento folicular
Estimulação ovariana: pobre resposta
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Dupla estimulação
• Maior possibilidade de obtenção de ovócitos / embriões • Menor tempo de tratamento • Menos estresse a paciente • Melhores resultados comparados a estímulos independentes?
Estimulação ovariana: pobre resposta
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Estimulação ovariana: pobre resposta
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CONCEITOS:
Ibuprofeno: prevenir ruptura folicular
MPA: para estimulações mais longas, evitando punção durante a menstruação
Citrato de clomifeno (CC) e letrozole (Let): ações sinérgicas
• CC (anti-estrogênico): aumento FSH hipofisário por diminuir ação estrogênica • Let (inibidor da aromatase): liberação hipotalâmica/hipofisária do feedback
negativo dos estrógenos e aumenta os andrógeno foliculares
Estimulação ovariana: pobre resposta
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Pacientes (pelo menos 2 critérios): • > 40 anos • Tratamentos prévios < 3 ovócitos • < 5 folículos antrais • FSH 10-19 mUI/mL • Cirurgia ovariana prévia
Estimulação ovariana: pobre resposta
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CONCLUSÃO: Protocolo a ser utilizado para pacientes com: • falhas recorrentes de obtenção de ovócitos ou • pacientes sem embriões viáveis em estímulos ovulatórios convencionais
Estimulação ovariana: pobre resposta
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Estimulação ovariana: pobre resposta
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Estimulação ovariana: pobre resposta
Pacientes : • HAM < 1,5 ng/mL • Tratamentos prévios < 3 ovócitos • < 6 folículos antrais ou < 5 ovócitos • PGT-A
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Estimulação ovariana: pobre resposta
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Estimulação ovariana: pobre resposta
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Brigg R, Hum Rep 2015; 30:81-87 Sunkara SK, et al. Hum Rep 2011; 26:1768-1774
Estímulos com > 15 ovócitos: resultados mantidos
Estimulação ovariana: hiper-resposta
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STUDY DESIGN, SIZE, DURATION: • Retrospective population-based registry study (The National Quality Registry of Assisted
Reproduction, Q-IVF) • 39.387 women / 77.956 fresh IVF cycles in the period 2007–2013 • 36.270 consecutive transfers of frozen/thawed embryos in the period 2007–2014
Estimulação ovariana: hiper-resposta
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SUMMARY ANSWER: • Cumulative delivery rate per aspiration increases up to 20 oocytes retrieved and
then evens out • The incidence of severe OHSS increases more rapidly from around 18 oocytes • Thromboembolic events, although rare, occurs in particular if 15 or more oocytes
are retrieved.
Estimulação ovariana: hiper-resposta
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Conclusion(s): • One fresh cycle with high oocyte yield is an optimal way to
plan IVF treatment.
• With modern cryopreservation methods, the concept of ‘‘one-and-done’’ could safely achieve >2 live births with just one stimulation cycle in almost a quarter of patients.
Estimulação ovariana: hiper-resposta
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Study design, size, duration: • This is the largest multi-center analysis using individual patient data, conducted
in 15 tertiary referral Hospitals in Europe.
• The study included women undergoing their first ovarian stimulation cycle for
IVF/ICSI in an antagonist protocol from 2009 to 2014.
• All patients were followed up for at least 2 years until using all their fresh and frozen embryos
Human Reprod 2017
Estimulação ovariana: hiper-resposta
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Main results and the role of chance: • Cumulative live birth rates steadily increased with the number of oocytes,
reaching even 70% when >25 oocytes were retrieved. • No plateau in cumulative live birth rates was observed but a moderate
increase of 5.1% in average was detected beyond 27 oocytes.
Human Reprod 2017
Estimulação ovariana: hiper-resposta
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Razões das diferenças de resultados: • Vários tipos e resultados de programas de criopreservação • Dados mais antigos Vantagens: • Maior número ovócitos recuperados = maior número de
blastocistos euplóides (Labarta E et al. Biomed Res Int, 2017)
Estimulação ovariana: hiper-resposta
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Paciente
Estimula-ção
Ovariana
Trigger
Suporte de fase lútea
Freeze all x transfer a
fresco
Sêmen Monitori-
zação
Sucesso na FIV / ICSI
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Progesterona: controvérsia?
Monitorização
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Elevação precoce da P4 antes do trigger com hCG
Monitorização
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Diferença da P4 que afeta o resultado?
Monitorização
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Patient(s): 10,280 patients undergoing their first IVF cycle. Main Outcome Measure(s): The ratio of exogenous LH-to-FSH throughout stimulation and association with absolute serum P level >1.5 ng/mL on the day of hCG administration.
P4 e estímulo ovulatório
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• Quando e quanto ser considerado aumento de P4? • Valor único ou diferença?
• Valor único ou tempo de exposição?
• Variação conforme o estímulo ovulatório?
• Freeze all ??
Monitorização
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Paciente
Estimula-ção Ovariana
Monitoriza-ção
Suporte de fase lútea
Freeze all x transfer a
fresco
Sêmen
Trigger
Sucesso na FIV / ICSI
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Trigger com hCG: golden standard
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Trigger
LH vs. hCG vs. GnRH
Casper R.F., Fertil Steril vol 103, No. 4, April 2015
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No. de folículos > 11 mm no dia do hCG pode predizer SHEO grave
Trigger - SHEO
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GnRHa trigger: LH-like luteal - mais fisiológico
• Leuprolide acetate: 1,0 - 2,0 mg
• Triptorelin: 0,1 - 0,2 mg
• Buserelin: 0,5 mg
Trigger - GnRH
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Trigger - hCG
• Daily monitoring of serum progesterone concentrations
• Once progesterone concentrations drop below 30 nmol/l (10 ng/mL)
• Administration of a rescue bolus of hCG (1.500 UI)
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Trigger - nível de LH
LH dia trigger
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LH início ciclo
Trigger - nível de LH
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• Resposta sub-ótima: LH < 15 mUI/mL 8-12 hs após o GnRH trigger • Leuprolide 2,0 mg + 1.000-3.000 UI hCG
Dual trigger: resposta inadequada
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7,0%
10,57%
25,0%
17,95%
13,91%
Limiting GnRH-agonist trigger alone to patients with a trigger day LH > 0.5 would have reduced the rate of suboptimal response.
Dual trigger: resposta inadequada
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• Resposta sub-ótima: LH < 15 mUI/mL ~ 10 hs após o GnRH trigger • Triptorrelina 0,1 mg + 1.000-5.000 UI hCG
Dual trigger: resposta inadequada
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Dual trigger: resposta inadequada
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Dual trigger: resposta inadequada
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A lower basal LH level (LH < 2.27 mIU/mL) is a useful predictor of a suboptimal response to GnRH-a trigger.
Dual trigger: resposta inadequada
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Dual trigger: pobre resposta
• 1350 patients undergoing 1389 ICSI cycles. Poor responders: Bologna criteria • Patients triggered with 5000 IU hCG alone (328 cycles) were compared with those
undergoing dual triggering with 5000 IU hCG + 0.1 mg gonadotrophin-releasing hormone agonist (GnRHa) (386 cycles).
• And patients triggered with 10,000 IU hCG (363 cycles) were compared with those
undergoing dual triggering with 10,000 IU hCG plus 0.1 mg GnRHa (312 cycles)
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Dual trigger: pobre resposta
Dual trigger: Higher number of oocytes collected, number of mature oocytes (P < 0.001), oocyte retrieval rate and percentage of mature oocytes(P < 0.001).
v
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Conclusion(s): The messenger RNA (mRNA) expression of reproduction-related genes in granulosa cells (GCs) from patients receiving the double trigger may explain and suggested improved oocyte and embryo quality related to the double triggering group.
Dual trigger
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Cuidados para uma recuperação oocitária inadequada
Fatores de risco:
• Mulheres magras e com longo tempo de uso ACO
• Mulheres com ciclos menstruais irregulares
• Estimulações longas, com altas doses de Gns
• LH quase indetectável no início do ciclo
• Valores baixos de LH no dia do trigger
Considerações no uso do GnRH trigger
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Diferentes abordagens
• Hiperestímulo: GnRH trigger + freeze all
• Pobre resposta ou resposta inadequada: dual trigger
• Resposta adequada e trigger com GnRH: suporte
modificado de fase lútea
Considerações no uso do GnRH trigger
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Paciente
Estimula-ção
Ovariana
Monitori- zação
Trigger
Freeze all x transfer a
fresco
Sêmen
Suporte de fase lútea
Sucesso na FIV / ICSI
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Suporte da Fase Lútea
Papel da PROGESTERONA
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Papel da PROGESTERONA
Suporte da Fase Lútea
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Cochrane 2010 and 2014: GnRH agonist trigger previne SHEO em detrimento as taxas de bebes nascidos
Modificação no suporte convencional da fase lúlea é mandatório para a manutenção de bons resultados após transferência de embrião a fresco
Suporte da Fase Lútea
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Trigger com agonista GnRH em ciclos de antagonistas necessita especial atenção no suporte da fase lútea
Bolus HCG OPU-day
Intense Progesterone-
Estradiol Luteal support
Suporte da Fase Lútea
• hCG : 1.500 IU no dia da punção dos ovócitos
• E2 oral ou transdérmico: (200 mcg E2 trans / 4 mg oral) + PROG vaginal (600 – 800 mg/dia) iniciados no dia da punção ovócitos
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Suporte modificado de fase lútea não elimina o risco de SHEO
SHEO tardio: gestação múltipla
Suporte da Fase Lútea
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Paciente
Estimula-ção
Ovariana
Monitori- zação
Trigger
Suporte de fase lútea
Sêmen
Freeze all x transfer a
fresco
Sucesso na FIV / ICSI
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Freeze all
Estimulação ovariana
Transferência embrionária
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Freeze all
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The live-birth rate did not differ significantly between fresh-embryo transfer and frozen-embryo transfer among ovulatory women
Transfer of frozen embryos did not result in significantly higher rates of ongoing pregnancy or live birth than the transfer of fresh embryos, among women without PO.
n engl j med 378;2 nejm.org January 11, 2018
n engl j med 378;2 nejm.org January 11, 2018
Freeze all
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Evans J, et al HR Update. 2014; 20(6):808-821
Freeze all
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• Ciclos com transferência de embriões “a fresco”
• Número de ovócitos recuperados > 20 vs. 10 – 15 ovócitos
• Piores resultados obstétricos e perinatais
Freeze all
Pre-term birth
Low birthweight
Early pre-term birth
Very low birthweight
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Acharya KS, et al. Fertil Steril. 2015 Out;104(4):873-8
Freeze all
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Freeze all
• Data Sources from Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE and CINAHL (1984–2016)
• Studies comparing obstetric and perinatal outcomes in singleton pregnancies
conceived through IVF using either fresh or frozen thawed embryos
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Freeze all
Frozen-thawed embryos:
o lower relative risk (RR) of preterm delivery (0.90; 95% CI 0.84–0.97),
o low birth weight (0.72; 95% CI 0.67–0.77) and small for gestational age (0.61; 95% CI 0.56–0.67)
o increased risk (RR) of hypertensive disorders of pregnancy (1.29; 95% CI 1.07–1.56),
o large for gestational age (1.54; 95% CI 1.48–1.61) and
o high birth weight (1.85; 95% CI 1.46–2.33).
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• A segmentação do ciclo (crio + transfer em ciclo subsequente) pode não ser aceitável para todas os envolvidos devido a considerações legais, éticas ou econômicas.
• A criopreservação pode produzir alterações moleculares en genes chaves e
transcriptos, que ainda não são detectáveis pelos métodos diagnósticos atuais, com consequências de longo prazo ainda desconhecidas para as crianças nascidas provenientes de embriões congelados/descongelados (Kopeika et al.,2015).
Freeze all
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Freeze-all
Tranfer Freeze-
only
Freeze all
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Paciente
Estimula-ção
Ovariana
Monitori- zação
Trigger
Suporte de fase lútea
Freeze all x transfer a
fresco
Sêmen
Sucesso na FIV / ICSI
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Sêmen
Patient(s): A total 1,030 ART cycles evaluated from 2011 to 2015. Intervention(s): Group I, abstinence period 2–7 days, and group II, abstinence period >7 days, were compared. Two subgroups Ia (2–4 days) and Ib (5–7 days) were also compared with group II.
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Sêmen
Conclusion(s): An abstinence period of more than 7 days may impact ART outcomes adversely when compared with an abstinence period of 2–7 days.
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In total 2204 patients were included in seven RCTs.
Sêmen
RR 1.24, 95% CI 1.07 –1.43, P < 0.003
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Sêmen
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Hábitos
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• Sperm concentration: negatively influenced by BMI and alcohol consumption and positively influenced by cereal consumption and number of meals per day
• Motility: negatively influenced by BMI, alcohol consumption, and smoking habit, and positively influenced by the consumption of fruits and cereals
• Morphology: not affected by any food consumption or
social habit
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• Alcohol: negative influence on the fertilization rate
• Read met and weight-loss diet: negative influence
on implantation rate and decrease the chance of pregnacy
• Miscarriage: not affected
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2659 embryos – 269 ICSI cycles • Embryo quality at the cleavage stage: negative influence by alcohol
and smoking; positive influence by ceral, vegetables and fruits
• Blastocyst: negative influence by consumption of red meat, weight-loss diet, alcohol and cigarrete; positive influence by consumption of fruits and fish.
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• Read meat and BMI: negatite influence on implantancion
and pregnancy
• Weight-loss diet: negative influence on implantation
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21 estudos, 13.077 homens da população geral e em investigação
de infertilidade
Estudo da relação entre BMI e incidência de
oligozoospermia / azoospermia
Comparados com homens com peso normal:
Sobpeso: OR= 1,15 (0,93-1,43)
Sobrepeso: OR= 1,11 (1,01-1,21)
Obeso: OR= 1,28 (1,06-1,55)
Obeso mórbido: OR= 2,04 (1,59-2,62)