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IVM Overview and Introduction

VIEWS: 4 PAGES: 60

									WORLD IVM EXPERIENCE


         Milton K. H. Leong, M.D.

                IVF Centre

  Hong Kong Sanatorium & Hospital, China
     LEARNING OBJECTIVES
At the conclusion of this presentation, participants
    should be able to:

1.   Describe the indications IVM
2.   Outline the various IVM approaches undertaken
     currently.
3.   Evaluate the IVM outcomes with regard to the
     treatment success rates and the babies born as a
     result of IVM treatment.
DISCLOSURE

Milton K. H. Leong, MD

        None
                Development of IVM
• It was first demonstrated in 1935 that the
  immature oocytes have the ability to resume
  meiosis spontaneously when removed from the
  follicle.
  –   Pincus G, Enzmann EV. J. Exp. Med. 62, 665-675 (1935)


• Edwards showed that in-vitro matured human
  oocytes could be fertilized.
  –   Edwards RG, Bavister BD, Steptoe PC. Nature. 221(5181), 632-5 (1969).
• the immature human oocytes retrieved during
  gynecologic surgery in an oocyte donation
  program resulted in the first IVM pregnancy in
  1991.
  –   Cha et al., Fertil Steril 55; 109-13 (1991).




• 1994-first IVM pregnancy with a patient’s
  own oocytes.
  –   Trounson A, Wood C, Kausche A. Fertil Steril 62; 353-62 (1994)
          Development of the follicle
             Stage                Follicle size (mm)

             Primordial           0.03           -     0.04
             Primary              0.05           -     0.06
             Secondary            0.07           -     0.11
             Preantral            0.12           -     0.20
             Early antral (*)     0.21           -     0.40
             Antral (* +)         0.41           -     16.00
             Preovulatory (+)     16.10          -     20.00

              + IVF * IVM




Gougeon, Hum Reprod 1986;1:81-7
              Target patient group
• Women with high AFC;
    – PCOS
    – PCO with regular cycles


• The most significant factor which
  determines the success of IVM treatment
  is the AFC of the woman
(Tan, 2002. Am. J. Obstet. Gynecol. 186; 684-9)
                Patient selection for IVM




Suikkari 2007; Best Practice & Res Clin Obstet Gynecol 21; 145-155
     promising outcomes are also
  reported in “regular cycling” women




Better prognosis if AF basale count > 7

Suikkari 2007; Best Practice & Res Clin Obstet Gynecol 21; 145-155
  Common Indications for IVM
• failure after > 6 cycles of ovulation
  induction
• women having IVF with high AFC
• repeated poor embryo quality in previous
  IVF cycles for no obvious reason
• repeated poor responders to ovarian
  stimulation
                  however
• low implantation rates when compared to
  conventional stimulated cycles.

  – asynchrony in the cytoplasmic and nuclear
    maturation of the oocyte
  – asynchrony in the endometrium
  – culture conditions
    Various approaches to improve
       implantation rates in IVM
   Clinical                Laboratory
• Gonadotropin priming   • Culture conditions
  – None
  – hCG
  – FSH / FSH+hCG
• Metformin
• IVF / ICSI
              HCG Priming
• Theoretically;

  – Promote invitro maturation
  – Improve pregnancy rates
      IVM following hCG priming
•   Cycles of IVM                25
•   Age (yrs)                    35.4  4.7
•   Oocytes retrieved            10.3  5.4
•   Maturation rate (%)           84
•   Fertilization rate (%)        87
•   Cleavage rate (%)             95
•   Embryos transferred          2.9  0.6
•   Clinical pregnancies - no (%) 10 (40)

                                         Chian et al
                               New Engl J Med 1999; 341:1624-6
90
80
70
60       + HCG
50       - HCG

40                                            *p < 0.05
30
20
10
 0
     0           12        24            36               48

                  hours of culture         Chian et al
                                     Hum Reprod 2000; 165-170
Response to LH in granulosa cells from follicles < 8 mm
from ovulatory women (with normal ovaries or PCO
compared to anovulatory women with PCO)


                                                                 Fold increase in steroid
                                                             accumulation in response to LH
                                                                      above control

                       Patients                                Estradiol               Progesterone

    Ovulatory (normal and ovPCO)                           1.0 (5.0 - 3.9);            1.0 (0.3 - 2.5);
                                                              (n = 46)a                   (n = 42)c
    Anovulatory (anovPCO)                                 1.4 (0.7 - 25.4);            1.3 (0.3 - 7.0);
                                                             (n = 17)b                    (n = 20)d

    a   vs b, P<0.0003
    c   vs d, P<0.03


    Willis et al., Journal of Clinical Endocrinology and Metabolism 1998; 83:3984-91
      Duration between HCG
 administration and oocyte retrieval
• When the durations of 35 hours vs. 38 hours
  between hCG administration and the oocyte
  retrieval were compared, the 38 h group yielded
  significantly higher number of mature oocytes.

• In-vitro maturation rate after 24 h in the culture
  was significantly higher, and the clinical
  pregnancy rate in the 38 h group was higher
  compared to the 35 h group in the unstimulated
  cycles, 40.9% vs. 25%.

Son et al. Fertil Steril 88(Suppl. 1), S24-S25 (2007).
   Clinical outcome in hCG-primed IVM cycles with (Group 1) and
     without (Group 2) MII-stage oocytes on the day of retrieval


                Groups                       Group 1 (n=48)             Group 2 (n=46)              P
 No. of oocytes collected (mean +            922 (19.2 + 8.4)           854 (18.6 + 9.9)            NS
 SEM)
 No. of MII-stage oocytes collected (%)         135         (14.6)            0

 No. of oocytes cultured                           787                        854                   NS

 No. of oocytes matured in vitro (%)            500         (63.5)         535        (62.6)        NS

 Total no. of oocytes matured (%)               635         (68.8)         535        (62.6)        NS

 No. of oocytes fertilized (%)                  456         (71.8)         419        (78.3)        NS

 No. of oocytes cleaved (%)                     396         (86.8)         377        (90.0)        NS

 No. of oocytes transferred (mean)              178             (3.7)      173             (3.8)    NS

 No. of pregnancies (%)                          23         (47.9)           13       (28.3)       <0.05




Son WY et al. RBM Online. (2008), in press
        Hormonal Priming
Regular cycling      PCOS
 • Beneficial         • Beneficial
   •Wynn 1998           •Mikkelsen 2001

 • No difference      • No difference
   •Trounson 1998       •Lin 2003
   •Suikkari 2000       •Chian 2000
   •Mikkelsen 2005
              FSH Priming
• Results are conflicting

• Potential benefits:
  – Larger ovarian size
  – Easier retrieval
  – Higher E2 levels
  – More maturational competence

            May improve endometrium
  Overview of IVM treatment cycle
• Withdrawal bleed
• U/S scan day 2-4 to identify if PCO and
  measure AFC
• Repeat u/s scan on day of hCG to measure
  endometrial thickness
• s/c hCG 10,000 IU when ET 6-8 mm, largest
  follicle 10-12 mm and oocyte retrieval 38 hours
  later
Transvaginal U/S-guided oocyte retrieval

 •   vaginal vault cleansed with sterile water
 •   i.v. sedation sedation with fentanyl and L.A.
 •   19 G single single-lumen needle
 •   reduced aspiration pressure (7.5 kPa)
 •   multiple punctures
 •   10 ml culture tubes with 2ml warm 0.9% saline
     with 2 IU heparin
  In-vitro maturation of oocytes
• GV oocytes cultured in IVM medium
  supplemented with 75mIU/ml FSH + LH for 24 -
  48 hrs, checked every 12 hours all MII oocytes
  undergo ICSI
• ET day 2 or 3 following ICSI
• Patients receive estradiol-17ß (micronized)
  immediately following OR and progesteron
  following ICSI
       Endometrial Priming



Endometrium is           Dyssynchrony between phase
exposed to lower          of endometrium – matured
                                   oocyte
E2 levels


      Endometrial preparation is necessary
       Endometrial preparation
   Endometrial thickness on day of oocyte retrieval

  <6 mm       10 - 12 mg       estradiol-17ß (micronized)


  6 - 8 mm    8 - 10 mg        estradiol-17ß (micronized)

  >8   mm      6 mg             estradiol-17ß (micronized)


Progesterone support (50 mg I/M or 200mg tid, pv)
started following ICSI
  Timing of Oocyte Retrieval


                     Dominant follicle


Early atretic   Still competent to
follicles       Embryonic development


                Can be used in IVM

                But; TIMING ?
   Timing of Oocyte Collection
• Russell et al. (1999)

 When the leading follicle > 13 mm


            • Less oocytes
            • Less fertilization
            • Fewer embryos
   Timing of Oocyte Collection
• Cobo et al. (1999)

  When the leading follicle < 10 mm


                Higher blastocyst formation
                    Metformin in IVM
• 56 women, 70 cycles
• Metformin, 500 mg bid for 12 weeks before the IVM
  treatment
• HMG for 5 days and hCG 10,000 IU, 36 h prior to OPU
• number of immature oocytes, oocyte maturation,
  fertilization and cleavage rates in were comparable to
  the control group
• significantly higher implantation and clinical pregnancy
  rates were obtained in the metformin-treated group
  (15.3% and 38.2% respectively) compared to the
  controls (6.2% and 16.7%)




Wei Z et al. Fertil Steril 2007 Nov 15
IVM outcomes
Outcome of IVM cycles from literature in women with PCO/PCOS.

Authors (year)           No. of    Indication   No. of ET         Gn      Maturation   Fertilization   Implantatio   Pregnancy   Miscarriage
                         cycles                    cycles       Priming   Rate (%)      Rate (%)           n          Rate/ET     Rate (%)
                                                at cleavage                                             Rate (%)        (%)
                                                    stage
Chian et al (1999)         25       PCOS            25           HCG         84             87             32           40           20
Cha et al (2000)           94       PCOS            85           None        75.1          67.9            6.9         27.1         26.1
Chian et al (2000)         11       PCOS            11           None        69.1          83.9           24.8         27.3           0
                           13                       13           HCG         84.3          90.7           16.6         38.5          40
Mikkelsen and              12       PCOS            9            None        44.0          69.0            0            0           57.1
Lindenberg (2001)          24                       21           FSH         59.0          70.0           21.6         33.3

Child et al (2002)        107      PCO/PCO          107          HCG         76.0          78.0            9.5         26.2         26.1
                                      S
Lin et al (2003)           35       PCOS            35         FSH+HCG       76.5          75.8            9.5         31.4         13.0
                           33                       33           HCG         71.9          69.5           11.3         36.4
Chian (2004)              254      PCO/PCO          NA           HCG         78.8          69.2           11.1         24.0         NA
                                      S
Soderstrom-Anttila et   PCO: 13    PCO: 13        9 (IVF)        None        60.6          35.0           13.3         22.2          0
al (2005)                    7         7         5 (ICSI)                    49.2          72.4            0            0            -
                        PCOS: 18   PCOS: 18      17 (IVF)                    54.3          82.5           34.5         52.9         33.3
                            10         10        9 (ICSI)                    53.2          70.0           12.5         22.2         50.0
Cha et al (2005)          203       PCOS            187          None        NA            NA              5.5         21.9         36.8
Torre et al (2007)        138       PCOS            NA           HCG         61.7           62            10.9         24.5*        42.3
Son et al (2007)          415      PCO/PCO          415          HCG         74.0          80.1            9.7         28.4         NA
                          106         S             106          HCG         78.2          80.5           26.8         51.9         21.8
                                                (blastocyst)
Outcome of IVM cycles from the literature in women with normal
ovaries and regular cycles.

Authors      No. of cycles    No. of      Gn       Mean no.     Maturat   Fertilization   Implanta   CPR/ET   M/C
(year)                       ET cycles   Priming   of oocytes    ion      Rate (%)          tion      (%)     Rate
                                 at                retrieved     Rate                     Rate (%)            (%)
                             cleavage                            (%)
                               stage
Child et     56 (normal)        50       HCG       5.1 ± 3.7      79.5        67.7          1.5        4      50
al. (2001)    53 (PCO)          52       HCG       10 ± 5.1      75.9*       71.6*          8.9       23.1    25
             68 (PCOS)          67       HCG       11.3 ± 9                                 9.6       29.9    50

Mikkelsen        132            83       None         3.9        60.1        72.9           NA         18     NA
et al.
(2001)

Soderstrom     92 (IVF)      58 (IVF)    None      6.3 ± 3.4     66.9        35.9           22.6       31     33.3
-Anttila      100 (ICSI)     86 (ICSI)             6.5 ± 3.6     54.5        67.1            15        21     16.7
et al.
(2005)



  * PCO and PCOS groups pooled together.
IVM for other indications
            IVM oocyte donation
•   12 oocyte donors (29.7 yrs; AFC 29.7)
•   oocyte retrieval days 9-18 of unstimulated cycle
•   mean of 12.8 GV oocytes retrieved
•   8.67 mature oocytes and 5.9 fertilized oocytes
•   3.9 embryos transferred
•   implantation rate 19.1%; 6/12 clinical
    pregnancy – 4 delivered
                                             Holzer et al
                                  Fertil Steril 2007; 88: 62-67
IVM +/- natural cycle IVF and PGD
• 35 yr old with RM failed 2 IUI and 2 IVF
• IVM offered because of PCO; 1 M II and 14 GV oocytes;
  ICSI performed
• 8 embryos, 6 biopsied, 1 embryo from MII oocyte and 1
  from GV oocyte chromosomally normal for 6 autosomes
  and X and Y chromosome
• 2 ET – one blastocyst from MII oocyte and one morula
  from GV oocyte
• ß-hCG 399 IU 14 days after ET and livebirth in May 2005

                                                   Ao et al
                                    Fertil Steril 2006;85:1510-12
          IVM as a Rescue
• Some cycles are cancelled due to
  – Risk of OHSS
  – Poor pesponse
                             Can IVM be a rescue ?



          these oocytes can be matured in-vitro
                        IVM as a rescue


                                    Risk of OHSS
                             10,000 IU HCG


Immature oocyte retriaval                          + IVM
                     Leading follicle = 12-14 mm


                          47 % CLINICAL PREGNANCY
                                             No OHSS
 Lim et al. Fertil Steril 2002
         IVM as a rescue
• In POOR RESPONSE = E2 < 1000 pg/ml
                   < 4 mature oocytes

             Poor responders        no HCG

                   Immature oocyte retrieval + IVM

                           37,5 % Pregnancy rate

                               Liu et al. Fertil Steril 2003
IVM for Fertility Preservation
        Fertility preservation for
              young women

• Best option; embryo cryopreservation, after
  ovarian stimulation followed by oocyte retrieval
  and fertilization of oocytes by sperm; IVF or ICSI


• Probably second best;
  oocyte cryopreservation after ovarian
  stimulation followed by oocyte retrieval
Ovarian stimulation is not suitable
for certain cancer patients;
no sufficient time and/or ovarian
stimulation contraindicated
Solution ?

  Trial: Retrieval of immature oocytes from
  unstimulated ovaries, and maturation in-vitro
  followed by cryopreservation of oocytes by
  vitrification
  Viability and pregnancy outcome of vitrified
                  IVM oocytes
No. of patients                                                 20
Mean age                                                    30.8 + 0.9
No. of mature oocytes retrieved                                 6
No. of immature oocytes retrieved                              290
Mean oocyte maturation rate                                 67.3 + 4.9
No. of oocytes vitrified and thawed                            215
No. of oocytes survived (mean % + SEM; range)   148 (67.5 + 5.8; range 23.5 -100.0)
No. of oocytes fertilized (mean % + SEM)                  96 (64.2 + 4.5)
No. of embryos transferred (median; range)              64 (4; range 1 - 6)
No. of implantations (mean % + SEM)                        4 (9.6 + 5.4)
No. of pregnancies (%)                                       4 (20.0)
No. of clinical pregnancies (%)                              4 (20.0)
No. of ongoing pregnancies (%)                                 0 (0)
No. of live births (%)                                       4 (20.0)
Mean birth weight (grams)                                     3486

Chian et al, 2008, Fertil Steril, in press
                                                 Fertility preservation
                                             strategies offered for women
                                                  at MRC with cancer


                              Chemotherapy                           Chemotherapy can be
                            cannot be delayed
 Ovarian wedge                                                       delayed and hormonal
                             and/or hormonal
  resection or                                                           stimulation not
                               stimulation
 oophorectomy                                                           contraindicated
                             contraindicated


                             Immature oocyte
                                retrieval
                                                                       Ovarian stimulation
                                                                         mature oocyte
Immature oocyte                                                             retrieval
                                      IVM
  retrieval from
 ovarian tissue


                     Male partner                               Male partner
                                            No male partner                       No male partner
                      available                                  available
                                               available
                        (ICSI)
 Ovarian tissue
cryopreservation
                       Embryo                                     Embryo
                                                 Ooycte                                 Ooycte
                   cryopreservation                           cryopreservation
                                              vitrification                          vitrification
Obstetric and perinatal
 outcomes of the IVM
     pregnancies
        Outcome of IVM, IVF, ICSI and
             normal pregnancies

• obstetrical and perinatal outcome of 432 babies
  (55 IVM, 217 IVF, 160 ICSI) compared with
  1,296 age-matched spontaneous pregnancies
  (controls) delivered at a single hospital (MUHC)




                                     Buckett et al.
                            Obstet Gynecol 2007; 110:885-91
                   Perinatal outcome
                              IVM     IVF     ICSI   Controls   p-value

Twin pregnancy rate          12.0%   16.0%   14.0%     1.3%     p<0.001

Triplet pregnancy rate       4.0%     2.0%    3.0%     0        p<0.001

Mean birthweight (g)         2,812   2,826   2,801   3,289      p<0.001

Mean gestational age (wks)     37      37      36       39      p<0.001

Mean Apgar scores at 1 min      8       8       8          8      n/s

Mean Apgar scores at 5 min      9       9       9          9      n/s

Mean cord pH                 7.29     7.30    7.30     7.29       n/s
     Congenital abnormalities following
                IVM (n=55)
Major malformations                  2
• ompalocele                         1
• small ventricuoloseptal defect     1

Minor malformations                  3
• patent ductus arteriosus           1
• congenital hip dislocation         2
        Relative risk for any congenital
      abnormality compared with controls

                     RR         95% CI


IVM                 1.19       0.35 – 3.25


IVF                 1.01       0.52 – 1.90


ICSI                1.41       0.72 – 2.68
  Pregnancy outcomes per clinical
 pregnancy after IVM, IVF and ICSI
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
      Live Birth (p<0.05)   Miscarriage   Ectopic     Late Pregnancy     Miscarriage in
                             (p<0.005)                     Loss           PCOS (NS)


                                    IVM   IVF       ICSI                 Buckett et al
                                                                       Fertil Steril 2007
   Pregnancy Outcome in IVM

• Mikkelsen et al. (2005) ----- 47 IVM babies
  – 2 twins
  – 1 NT            Normal karyotype
  – 2 preterm deliveries
  – 1 stillbirth (42 weeks)
  – 1 chromozomal abnormality
   Pregnancy Outcome in IVM
• Malformation:
  – Cha, Fertil. Steril. 2005    5,3% major
                                malformation rate


• Later neuromotor development:
  – Soderstrom-Anttila, Hum. Reprod. 2006

  ))) Minor developmental delay at first year
  ))) No Difference in the second year
Deliveries and ongoing pregnancies
  (facts and educated guesses)


Countries        Deliveries and ongoing
                       pregnancies
Scandinavia                150
Italy                       77
France                     40
Germany                    20
Rest of Europe             33
Total Europe              320
 Deliveries and ongoing pregnancies
   (facts and educated guesses)

Countries           Deliveries and ongoing
                          pregnancies
Middle East                    21
Japan                         100
Vietnam                        26
China (incl. HK)               60
Korea (Cha Hosp.)              57
Korea (Maria Cl.)            ≈ 400
Rest of Asia                   15
Total Asia                    679
Deliveries and ongoing pregnancies
  (facts and educated guesses)


Countries      Deliveries and ongoing
                     pregnancies
Canada                   120
USA                       5
Australia                5
Total                   130
Deliveries and ongoing pregnancies
  (facts and educated guesses)


Countries             Deliveries and ongoing
                            pregnancies
Asia                            679
Europe                          320
North America                  125
Australia                       5
Grand Total                   1129

   - one year ago !
Korea       455
Taiwan       20
Colombia     7
Canada      131
Finland      52
Turkey       8
China        58
Japan        51
Vietnam      42
Hong Kong    18
Denmark      34
Italy        56
UK           8
Total       930
                Conclusions

• IVM simplifies treatment, reduces costs and
  eliminates OHSS
• IVM successful in women with high AFC
• hCG increases final number of MII oocytes and
  rate of maturation
• IVM may be helpful in women with repeated poor
  embryo quality in previous IVF cycles for no
  obvious reason, or repeated poor responders to
  ovarian stimulation
                Conclusions
• IVM produces CPR/C of 35%, and up to 48% in
  selected cases, in women up to 35 .
• obstetric and perinatal outcomes of IVM
  pregnancies comparable with IVF and ICSI
• IVM may be useful for oocyte donation or PGD
• IVM may offer a chance for fertility preservation to
  young women with cancer and undergoing
  cytotoxic treatment.
• IVM may not replace standard IVF but appears to
  play increasingly important role in ART
 Acknolwedge
Dr. Ezgi Demirtas

Reproductive Centre

 McGill University

								
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