In vitro fertilization and embryo transfer "IVF"; Overview on the Story FROM A TO Z ……

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5. Ahmed Mowafy 2015

6. 1931
Aldous Huxley published a science fiction novel called
“Brave New World”. In this novel , Huxley realistically
described the technique of IVF near we know now. in
1937, The New England Journal of Medicine describes
this as “note worthy !!“.
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7. 1958
Carl Gemzell obtained the first pregnancies following
treatment with human pituitary gonadotrophin (hPG) and
human menopausal gonadotrophin (hMG),
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8. 1958 – 1959
Min Chang succeeded in growing rabbit embryos derived
from oocytes fertilized in vitro, and in 1959 achieved a
live birth by transfer of an in-vitro-fertilized oocyte.
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9. 1961
Palmer from France described the first retrieval of
oocytes by laparoscopy.
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10. 1973
The first IVF pregnancy was reported by the Monash
research team of Professors Carl Wood and John
Leeton in Melbourne, Australia. Unfortunately, this
resulted in early miscarriage
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11. 1978
Louise Brown the first ever IVF baby occurred in
Oldham, England on July 25, 1978. This birth was the
result of the collaborative work of Patrick Steptoe and
Robert Edwards
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12. Louise Brown
Louise Joy Brown, the first test-tube baby 1978
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13. 1983
• First pregnancy after oocyte donation
• The first vaginal egg retrieval using an abdominal
ultrasound
1984
• First surrogacy embryo transfer baby born in
California, USA
• First report on pregnancy following translaparoscopic
gamete intrafallopian transfer “GIFT” A H M E D M O W A F Y 2 0 1 5

14. 1985
Human pregnancy by in vitro fertilization (IVF) using
sperm aspirated from the epididymis
1986
First report on pregnancy after translaparoscopic
zygote intrafallopian transfer “ZIFT”
1989
First report on biopsy of human preimplantation embryos
and sexing by DNA amplification A H M E D M O W A F Y 2 0 1 5

15. 1992
• The first pregnancy after intracytoplasmic sperm
injection “ICSI”
• Successful in-vitro fertilization and embryo transfer
after treatment with recombinant human FSH
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20. (Centres for Disease Control and Prevention, 2013. National Summary and Fertility Clinic Reports.
Atlanta, GA, 2013.) A H M E D M O W A F Y 2 0 1 5

21. Congenital absent or secondary to surgery which cannot
be corrected by surgery and when surgery fails.
In patients with polycystic ovarian disease (PCOS) and
other ovulatory problems.
Patients with endometriosis, often have tubal
involvement and ovarian cysts (endometrioma).
Mullerian anomalies that requires a surrogate mother
(prohibited in Moslem countries).
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22. due to poor quality semen parameters;
Azoospermia, oligozoospermia, asthenozoospermia,
anti-sperm antibody etc.
When woman's ovarian function is diminished with age.
In many cases, this reduced function can be
overcome through the use of IVF
after failure of ovulation induction and IUI.
Hostile cervical mucus which cannot be treated by IUI.
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23. 1.preimplantation genetic diagnosis (PGD) to rule out
presence of genetic disorders, Gender selection
2.Pregenetic screening (PGS)
3.egg donation and surrogacy "; where the woman
providing the egg is not the same who will carry the
pregnancy to term. (Prohibited in Muslims countries)
4.Fertility preservation: oocyte, sperm and embryo
cryopreservation for further use , oocyte
cryopreservation can be used for women who are
likely to lose their ovarian reserve due to undergoing
chemotherapy
5.same-sex couples, single and unmarried parents
(ethical debate)
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27. Oocytes and sperms
are placed into the fallopian tube. The procedure is
applicable in patients who have normal fallopian tubes.
The fertilized oocytes in the pronuclear stage (zygotes)
are placed into the fallopian tube. It has the same
indications as GIFT. In this case the male and female
pronuclei are seen in the cytoplasm.
The embryos (zygotes after cleavage) are placed into
the fallopian tube.
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28. The oocytes and sperms are placed into the pelvic
cavity.
A hole is made in the zona pellucida and 3-6
spermatozoa are introduced into the subzonal space.
A single sperm or spermatid is injected into the
cytoplasm of the oocyte under the control of the
microscope.
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34. 1. The questions your patient is going to ask (FAQs)
2. The NBs you should tell your patients about
3. Instructions in the consent
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35. 1. What would be the success rate of my ICSI?
• 32.2% for women aged under 35
• 27.7% for women aged between 35–37
• 20.8% for women aged between 38–39
• 13.6% for women aged between 40–42
• 5.0% for women aged between 43–44
• 1.9% for women aged 45 and over
( Human fertilization and embryology authority HFEA 2010 )
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36. 1. What would be the success rate of my ICSI?
( Human fertilization and embryology authority HFEA 2010 )
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37. 2. The Cost ?!!
• Argentina 4600$
• Austria 2500 EUR
• India 3000 – 3500 $.
• Kenya 4000$
• Malaysia 5000$
• UAE 6000$
• USA 7000 $
• Israel 5000 $
• UK 6000$
8000 – 12000 L.E
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38. 2. The Cost ?!!
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39. 3. For how long should I stay in bed after embryo
transfer?
Actually : no role.
The recommended time is
20-30 minutes of bed rest after ET.
(Marieke J et al, Ultrasonographic Evidence that
Bedrest after Embryo Transfer Is Useless Gynecol Obstet
Invest 2009;68:122-126)
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40. 4. Does ICSI increase the liability of congenital
defects?
• No ↑ the risk of CM.
( K. Paul Katayama et al, 2011 Meta-analysis genetics
Journal of Assisted Reproduction and genetics..)
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41.  Alarm the patient of warning symptoms :
• rapid weight gain
• dyspnea
• palpitation
• vomiting
= Risk of OHSS
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42.  For PCOS patients:
• ↑ Risk of OHSS.
• ↑ Duration of stimulation phase.
• The value of weight loss.
• Better chance for embryo vitrification
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43.  For poor responders:
• ↓ success rate.
• Cancellation:
• Poor response.
• Poor quality oocytes.
• Failure of fertilization
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44.  Remind your patient with:
• The time of B-HCG.
• The schedule of follow up visits after +ve pregnancy
test.
• The higher possibility of multiple pregnancy.
• The possible need for fetal reduction
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52. 1. Detailed history and clinical examination
2. Ovarian reserve testing
3. Uterine cavity exam
4. (mock) embryo transfer
5. Semen analysis
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53. • Duration of infertility
• Age of the patients
• Assessment of cause of infertility
• Body mass index “BMI”
• Previous investigations
• Previous surgical operations
• Previous diagnostic procedures (laparoscopy,
hysteroscopy …etc)
• Previous trials of ICSI
• Special habbits (smoking, alcolism, caffeine intake
..etc)
• Basic trans-vaginal ultrasound
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54. a. Passive tests
• Anti Mullerian Hormone (AMH)
• Follicle Stimulating Hormone (FSH) - early follicular
phase
• estradiol level- early follicular phase
• Basal FSH/ LH ratios
• FSH and estradiol
• Inhibin B level- early follicular phase
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55. a. Passive tests
• Antral Follicular Count (AFC)
• Ovarain Volume
• Ovarian blood flow
• Ovarian biopsy
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56. b. Dynamic tests
• Chlomiphene citrate challenge test (CCCT)
• Exogenous FSH Ovarian Response Test (EFORT)
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66. AMH Based COH
• < 0.5 --------------> don’t stimulate.
• 0.5 – 1 ------------ > don’t use long protocol.
• > 1 -------------- > use for long protocol.
• AMH (>4 ) ----> care for OHSS.
• Serum frozen immediately to avoid low levels.
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67. • 3D trans-vaginal ultrasonography
• Office hysteroscopy
• Saline infusion sonohysterography (SIS)
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68. • To assess the cervix and to make sure there are no
abnormalities such as tumors, cysts or anything else
that could possibly halt embryo transfer
• To determine the depth of your uterine cavity and
the technique most likely to successfully place the
embryos into your uterus.
• To determine what type and size of catheter he
should use during the actual embryo transfer
process.
• Insertion of a catheter, “Wallace catheter”, into
the cervix and uterus as in actual embryo transfer
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69. • As a part of your initial fertility evaluation
• Semen is tested before IVF. If semen abnormalities
are identified, consultation with andrologist.
• To determine the method of sperm collection
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70. • Infectious disease screening including HIV,HBV
• Prolactin , T3 ,T4 , TSH , DHEAS
• Genetic studies
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74. I. GnRH agonist drugs
Short Acting :
• Triptorelin acetate (Decapeptyl)
• Leuprolide acetate (Lucrin)
• Buserelin acetate (Superfact)
 Long Acting :
• Goserelin acetate( Zoladex)
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75. I. GnRH agonist drugs
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76. I. GnRH agonist drugs
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77. II. GnRH antagonist drugs
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78. II. GnRH antagonist drugs
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79. I. Urinary gonadotrophins
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80. I. Urinary gonadotrophins
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81. II. Recombinant gonadotrophins
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82. II. Recombinant gonadotrophins
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83. Preparation Trade name Route price company
Progesterone Cyclogest 200 mg
Cyclogest 400 mg
Vaginal pessaries
Vaginal pessaries
90 LE
125 LE
Activis UK
Prontogest 200 mg
Prontogest 400 mg
Prontogest
Vaginal pessaries
Vaginal pessaries
ampoules
72 LE
102 LE
82.5 LE
Marcyrl co
Crinone 8% Vaginal gel 236 LE Merck
sharp co
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85. 1. COCS
2. Anti oxidants
3. Folic Acid
4. Low dose Aspirin
5. Metformin
6. Vasodilators ; sildenafil , L-Arginine
7. Growth hormone
8. DHEA
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87.  COCS
 In the cycle preceding the IVF cycle
 Regulation of the cycle if irregular.
 prevent ovarian cysts, which sometimes develop
during GnRH analog therapy.
 Improved response to gonadotropins
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88.  Metformin
 Increases the sensitivity of body tissue to insulin
effects
 decreases high levels of testosterone.
 May reduce 1st trimester pregnancy loss in women
with PCOS.
 reduces the incidence of gestational DM.
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89.  Anti-Oxidants
 Prevent oxidative damage to embryos
 May improves fertilization and implantation rate
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90.  Vasodilators ; sildenafil , L-arginine
 increase blood flow in uterus and stimulate the
development of endometrium may improve
endometrial receptivity
 DHEA , Growth hormone
 May have a role in poor responders
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94. 1. Pre-stimulation preparation
2. Down regulation of pituitary hormones
3. Ovarian stimulation
4. Monitoring follicle development with ultrasound and
serum hormone levels
5. Final oocytes maturation and hCG administration
6. Transvaginal ultrasound-guided oocyte retrieval
7. Fertilization in vitro
8. Embryo transfer
9. Luteal phase support
10.Pregnancy test and early pregnancy follow-upA H M E D M O W A F Y 2 0 1 5

95. 
• Stop (smoking – alcohol)
• Reduce caffeine intake
limiting caffeine intake to 200 mg per day. (One cup of
coffee contains 100 mg caffeine)
• Increase Fluid Intake
A daily intake of 8 glasses of water daily is advised.
• Well balanced diet
• Reduction of body weigh (in obese patients)
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96. 
• Folic acid
• multivitamins ( vitamin B12 – vitamin E )
• Anti-oxidants
• Low dose aspirin 75-81 mg
• Others : DHEA , sildenafil
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97. 
• COCs: in the cycle prior to the ART cycle
 ensures that GnRH analog therapy will start at the proper
time if you have irregular cycles.
 prevent ovarian cysts, which sometimes develop during
GnRH analog therapy
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99. • To avoid premature ovulation (premature LH surge)
which indicates cancellation of the cycle.
• Prevents spontaneous ovulation and allows complete
control of the cycle by exogenous hormones only.
• Drains the pituitary from its hormones leading to
initial flare up effect followed by prolonged
suppression
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102. International Society for Mild Approaches in Assisted Reproduction (ISMAAR), 2007
1. Natural cycle
Unstimulated,
spontaneous cycle
Single
oocyte
No medication
2. Modified natural
cycle
Semi-natural,
controlled natural cycle
IVF
Single
oocyte
hCG only
GnRHan and FSH/HMG
add-back
3. Mild
Soft, minimal
stimulation, ‘friendly’
IVF
2-7
oocytes
Low dose FSH/HMG,
oral compounds and
GnRHan
4. Conventional Standard, routine, COS
> 8
oocytes
GnRHa or antagonist
conventional
FSH/HMG dose
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104. • Dose adjusted based on US and E2 monitoring
• Usually requires 10-12 days of stimulation
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106.  HCG induces final follicular maturation.
 When:
At least 3 follicles >18 mm .
 E2: 150 pg/ml per >15mm follicles. .
Endometrium: Thickness >8mm, Triple line
 IM injection of HCG 10,000 IU administered 34-36 h
before the scheduled time of oocyte retrieval
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107.  Do not trigger ovulation with the intention of fresh
ET in women who have:
 E2>3500 pm/l
 or >20 follicles on US (NICE, 2013)
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108.  The egg retrieval is performed at a time usually
between 34 and 36 hours after hCG injection.
 Egg retrieval is usually accomplished by transvaginal
ultrasound aspiration.
 It is done under short general anesthesia, and is 20
to 30 minutes procedure.
 In some circumstances, one or both ovaries may not
be accessible by transvaginal ultrasound. Laparoscopy
may then be used .
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109.  The eggs are aspirated (removed) from the follicles
through the needle connected to a suction device.
 Usually around 10-15 oocytes are aspirated
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111.  After the eggs are retrieved, they are examined in
the laboratory for maturity and quality.
 Mature eggs are placed in an IVF culture medium and
transferred to an incubator to await fertilization by
the sperms
 Shortly before or after the oocyte collection the
male partner will be asked to give a sperm sample.
 Intra-cytoplasmic sperm injection (ICSI) is
performed.
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112.  Fertilization check is performed the next day
approximately 18 hours after sperm injection or
insemination of the eggs.
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114.  Embryo transfer may be performed on day 2, 3 or 5
post fertilization.
 One or more embryos suspended in a drop of culture
medium are drawn into a transfer catheter, a long,
thin sterile tube with a syringe on one end.
 The physician gently guides the tip of the transfer
catheter through the cervix and places the fluid
containing the embryos into the uterine cavity under
guidance of trans-abdominal ultrasound on a full
bladder
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115.  Precautions and instructions for successful embryo
transfer:
1. Avoiding the use of a tenaculum:
2. Removal of the cervical mucus plug:
3. Ultrasound-guided transfer: improves the placement
of the catheter tip with respect to the endometrial
surface.
4. Be sure that is no uterine bleeding
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116.  Precautions and instructions for successful embryo
transfer:
5. Do not touch the fundus: Since embryo transfer is
often a blind shot, contact between the catheter and
the uterine walls may result in trauma.
6. Keeping catheter stationary for at least one minute
7. Giving antiprostaglandins to prevent contractions:
The insertion of a cannula into the uterus may cause
contractions, and can hinder implantation.
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117. SART/ASRM Guidelines for the Number of Embryos Transferred (2008)
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118. SART/ASRM Guidelines for the Number of Embryos Transferred (2008)
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119. SART/ASRM Guidelines elective single embryo transfer (2012)
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120. SART/ASRM Guidelines elective single embryo transfer (2012)
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122.  Day 5 (blstocyst) embryo transfer
1. Synchronizing embryo replacement with the
endometrium
2. Enhance embryo selection
3. Higher implantation rate
4. Decrease the number of embryos transferred ;
Decrease multiple gestations
5. Longer time in culture provides opportunity for
Preimplantation Genetic Diagnosis (PGD)
6. Lower incidence of ectopic pregnancy
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123.  Day 5 (blstocyst) embryo transfer
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124. SART/ASRM Guidelines Blastocyst culture and transfer in clinical-assisted
reproduction (2013)
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125. SART/ASRM Guidelines Blastocyst culture and transfer in clinical-assisted
reproduction (2013)
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128. Luteal phase supplementation , after controlled ovarian
stimulation for IVF, has been a routine practice in IVF/
ET because stimulated IVF cycles are associated with a
defective luteal phase in almost all patients .
Pabuccu R, Akar ME. Curr Opin Obstet Gynecol. 2005;17:277–81.
 Why ?
 due to removal of large quantities of granulosa cells
during the oocyte retrieval
 prolonged pituitary recovery that followed the
GnRH agonist downregulation
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129.  When ?
 A window for progesterone start time between the
night after oocyte retrieval and day 5. (A systematic review
and meta analysis. ASRM 2014)
 Till 5 weeks after conception (7th week of
gestation)
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130.  How ?
 Progesterone
 Oral Route: Significantly associated with lower
imlantation and pregnancy rate , higher miscarriage
rate or both. ( fert. Sterility 1999, Human reproduction 1999)
 Intra-muscular route
 Vaginal route
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131.  How ?
 Progesterone
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132.  How ?
 Progesterone
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133.  How ?
 Progesterone
 IM Versus vaginal Route:
Intramuscular Progesterone in oil (50 mg/day)
generates circulating Progesterone concentrations at
or above the physiological range.
Vaginally administered Progesterone yields lower
serum levels, but nonetheless achieves endometrial
tissue concentrations up to 30-fold greater than
those achieved with IM Progesterone
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134.  How ?
 Others
 Estrogen and progesterone (COCs)
Controversy
 GnRH agonist
 hCG
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135.  How ?
ASRM Guidelines for progesterone supplementation in LP (2008)
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136.  How ?
ASRM Guidelines for progesterone supplementation in LP (2008)
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137. B-hCG is done after 14 days of embryo transfer
The theoretical LMP can be considered as:
 IVF and ICSI: Reduction of 14 days (2 weeks) to
the day of egg collection.
 Replacement of frozen-thawed embryo (3 days):
Reduction of 17 days to the day of embryo
replacement.
 Replacement of frozen-thawed embryo (blastocyst):
Reduction of 19 days to the day of embryo
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140. Ahmed Mowafy 2015

141. International Society for Mild Approaches in Assisted Reproduction (ISMAAR), 2007
1. Natural cycle
Unstimulated,
spontaneous cycle
Single
oocyte
No medication
2. Modified natural
cycle
Semi-natural,
controlled natural cycle
IVF
Single
oocyte
hCG only
GnRHan and FSH/HMG
add-back
3. Mild
Soft, minimal
stimulation, ‘friendly’
IVF
2-7
oocytes
Low dose FSH/HMG,
oral compounds and
GnRHan
4. Conventional Standard, routine, COS
> 8
oocytes
GnRHa or antagonist
conventional
FSH/HMG dose
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142. >> According to ovarian reserve
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144. I.GnRH agonist protocols
 Types :
1.Long GnRH agonist protocol
2.Short GnRH agonist protocol
3.Ultra short GnRH agonist protocol
 Effects :
1. Flare effect: Within 12 h and lasting 24-48 h :
5 fold increase of FSH 10 fold rise in LH & 4
fold elevation in E2.
2. down-regulation of pituitary hormones with
suppression of the pituitary Gnt synthesis &
liberation >> Arrest of follicular development
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145. I.GnRH agonist protocols
 Types :
1.Long GnRH agonist protocol
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146. I.GnRH agonist protocols
 Types :
1.Long GnRH agonist protocol
 GnRH agonist From middle of the luteal phase
(D19-21)
 Gonadotrophins while GnRH agonist therapy is
maintained.
 Criteria of suppression:
i.Hormonal: E2 <50 pg/ml ,Progesterone < 1 ng/m
, LH <5 IU
ii.US: No ovarian cysts , endometrial thickness
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147. I.GnRH agonist protocols
 Types :
2. Short GnRH agonist protocol (flare protocol)
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148. I.GnRH agonist protocols
 Types :
3. Ultra short GnRH agonist protocol
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149. I.GnRH agonist protocols
 Types :
 Ultra Long GnRH agonist protocol
 GnRH could be given for three months before
the start of hMG.
 May be used in patients with severe
endometriosis before the start of the
treatment
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150. II. GnRH antagonist protocols
 Types :
1.Small daily dose (LubecK)
2.Single dose (French)
 Effects :
Inhibition of LH & FSH immediately without the
initial flare up effect.
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151. II. GnRH antagonist protocols
 Types :
1.Small daily dose (LubecK)
 HMG or FSH: From day 2 or 3 of the cycle
 Cetrorelix or Ganirelix: 0.25 mg daily SC: from
stimulation day 5 or 6 (fixed protocol) or leading
follicle14 mm (Flexible protocol) onwards until the
day of HCG
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152. II. GnRH antagonist protocols
 Types :
1.Small daily dose (LubecK)
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153. II. GnRH antagonist protocols
 Types :
2. Single dose (French)
 HMG or FSH: from day 2 or 3 of the cycle
 Cetrorelix: single dose, 3 mg SC, on stimulation
day 7
 HCG is given when the follicles are mature by
U/S &/or E2
 GnRha single dose can be given instead of HCG to
reduce incidence of OHSS
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154. II. GnRH antagonist protocols
 Types :
2. Single dose (French)
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155. A H M E D M O W A F Y 2 0 1 5

156. >> According to ovarian reserve
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157. >> According to ovarian reserve
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162. Ahmed Mowafy 2015

163. 1. Semen analysis and preparation
2. Oocyte collection and denudation
3. Incubation for 30 – 120 min
4. Intracytoplasmic sperm injection
5. Incubation and embryo grading
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164.  Normal semen parameters
WHO 2010A H M E D M O W A F Y 2 0 1 5

165.  Ways to Collect Semen
I.Ejaculation
II.Surgical
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166.  Ways to Collect Semen
I.Ejaculation
1.Masturbation, directing the semen into a clean
sample cup
2.Coitus interruptus - withdrawing the penis from
the partner just before ejaculating
3.Coitus - by using a special silicon condom that
does not contain any spermicides
4.Assisted ejaculation – electro-ejaculation used in
paralegics
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167.  Ways to Collect Semen
II. Surgical
1.PESA =percutaneous epididymal sperm aspiration
2.MESA =microsurgical epididymal sperm aspiration
3.TESA =testicular sperm aspiration
4.TESE =testicular sperm extraction
5.Micro TESE = microsurgical testicular sperm
extraction
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168.  Cases with retrograde ejaculation :
semen is ejaculated into the bladder. The acidity
of the urine will kill sperms quickly. Alkalination of
the urine is very important in order to recover live
motile sperms
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169.  Sperm preparation :
1. Simple Wash
2. Swim-Up
3. Swim-Down
4. Migration-Sedimentation
5. Density Gradient Centrifugation
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170.  Oocyte Denudation :
1. Mechanical
2. Chemical
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171.  Oocyte Denudation :
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172.  Oocyte grading :
1. Empty zona “EZ”
2. Germinal vesicle “GV”
3. Metaphase I “M I”
4. Metaphase II “M II”
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173.  Oocyte grading :
Empty zona “EZ” Germinal Vesicle “GV”
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174.  Oocyte grading :
Metaphase I “M I” Metaphase II “M II”
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175. A H M E D M O W A F Y 2 0 1 5

176. A H M E D M O W A F Y 2 0 1 5

177.  embryo grading :
One-cell embryo embryo containing four
on day 1 cells on day 2
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178.  embryo grading :
eight-cell embryo day 5 blastocyst stage
on day 3
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181. Ahmed Mowafy 2015

182. 
The IMSI process involves the assessment of sperm, at
very high magnification, using an inverted microscope.
This digitally enhanced microscope provides a much
greater magnifying power (about 6000x magnification)
compared to the one normally used in ICSI (200x).
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183. 
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184. 
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185. 
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186. 
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187. 
• It is a micro-surgical procedure on pre-embryos
before embryo transfer
• Performed by making a small hall in the zona or
outer shell of pre-embryos
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188. 
• Indications include :
1.More than 3 failed IVF trials
2.Poor embryos growth and morphology (less than 6
cells on day 3)
3.Thickening of the zona (more than 17 mm)
4.Cytoplasmic fragmentation (more than 20%)
5.Advanced maternal age ( more than 37 years
old)
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189. 
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190. 
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191. 
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192. 
Used in :
1.Sex selection
2.Diagnosis of aneuploidy
3.Diagnosis of balanced translocations
4.Single gene defect
Commonly, more than 100 diseases can be
detected through testing, including (Hemophilia A,
Muscular dystrophy, Tay-Sachs disease, Cystic
fibrosis and Down Syndrome)
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193. 
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194. 
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