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Recent
advances on
Treatment of
female
infertility
Presenter- Dr. Asmita Poudel
MPH-2022 1
48
Introduction
• Infertility is a disease of the reproductive system defined by the
failure to achieve a clinical pregnancy after 12 months or more of
regular unprotected sexual intercourse (and there is no other
reason, such as breastfeeding or postpartum amenorrhea)
………………………………(WHO)
• Infertility can be primary or secondary.
• Primary infertility is when a pregnancy has never been achieved by
a person, and secondary infertility is when at least one prior
pregnancy has been achieved
2
Introduction(2)
• In the male reproductive system, infertility is most commonly caused
by problems in the ejection of semen, absence or low levels of
sperm, or abnormal morphology and motility of the sperm.
• In the female reproductive system, infertility may be caused by a
range of abnormalities of the ovaries, uterus, fallopian tubes, and the
endocrine system.
• Risk factors- Age, Smoking, Weight, Sexual history, Alcohol
• Diagnosis- Physical examination, Blood tests, Hormone test,
Laparoscopy, Hysteroscopy, Ultrasound scans
3
Statement of the problem
• 48 million couples and 186 million individuals live with infertility, half
of these couples are living in Sub-Saharan Africa (SSA) and South
Asia globally. (WHO)
• The use of assisted reproductive technology (ART) by infertile
couples is increasing by 5% to 10% per year.
• Nearly 2% of live births in the U.S. are a result of assisted
reproductive technology. (CDC, 2017)
• According to the article published in journal of Karnali academy of
health sciences the problem was highest among the females of 26-
30 years (51%) The most common causes of female infertility were
ovarian cyst (37%) and heavy bleeding (18.7%), uterine fibroids
(9%), Pelvic inflammation (9%) and Thyroid disease (21.8%) 4
Treatment for
female infertility
• Ovulation induction
• Surgery
• Artificial insemination (IUI)
• Assisted reproductive
technologies (ART) including in-
vitro fertilisation (IVF) and
intracytoplasmic sperm injection
(ICSI)
5
6
SURGERY
7
INTRAUTERINE INSEMINATION
8
9
• In 1978 the world witnessed the
birth of first “test tube baby”-
louise Brown, now 45yrs old.
• Since this time there have been
explosive innovations and
advances in assisted
reproductive technologies (ART)
10
11
RECENT ADVANCES
Advances in ICSI Pulse driven ICSI
Medical advancement long acting gonadotropins, salivary estrdiol
concentration, selfoperated endovaginal
telemonitoring, e-therapy
Technological advancement Novel lab-on-a-chip concept, time lapse
monitoring system, robotic ICSI
Scientific advancement fertility preservation (cryopreservation, oocyte
vitrification, ovarian tissue cryopreservation,
ovarian transposition)
Invitro gametogenesis concept of stem cells
Reproductive genetics preimplantation genetic diagnosis and
screening
Medical Advancements
• Conventional- Controlled ovarian stimulation involves multiple
injections of gonadotropins and serial visits to the fertility clinic for
the conduct of transvaginal ultrasound evaluations and the
measurement of circulating hormone levels.
• COH is complex, time sensitive, and intensive.
1. Recently- Various strategies intent on reducing the number of
injections by utilizing long-acting gonadotropins( eg named
corifollitropin alfa (Elonva) or FSH‐CTP ) are available and are
gaining increased acceptance
2. Emerging strategy- to measure salivary estradiol levels may help
decrease the need for blood draws during COH. 12
Medical Advancements (2)
3. Recent advancements in portable lower cost ultrasound devices to
simplify follicular and endometrial monitoring(eg self-operated
endovaginal telemonitoring).
4. Screening of patients for psychological issues as well as offering
counseling and coping interventions such as e-therapy as an
integral part of IVF.
• These approaches may greatly simplify COH by rendering it less
invasive and by decreasing the time commitment required.
13
14
15
• Results: The clinical results showed similar conception rates and ongoing pregnancy rates, Similar
numbers of follicles, embryos available at transfer, top quality embryos (SOET: non-SOET) indicating
non-inferiority of SOET monitoring.
• Regarding patient-reported outcomes, a significantly higher contentedness of patient and partner, a
higher feeling of empowerment, discretion and more active partner participation as well as a trend
towards less stress were observed in the S versus the NS group.
• In the economic analysis, the use of SOET led to reduced productivity loss, lower transportation costs,
and lower sonogram and consultation costs but higher personnel cost than NS
Laboratory advancement
1. The novel IVF lab-on-a-chip concept
Automation and miniaturization of the IVF laboratory
Advantages of Automated IVF: standardization of workflows,
reduction in errors, reduction in cost, reduction in contamination
• Has the potential to revolutionize IVF by enabling the automation of
virtually all of the steps involved in a single system.
• Microfuidic sperm-sorting devices and automated sperm analyzers
are already being introduced into routine IVF practice
16
Laboratory advancement(2)
2. Time lapse monitoring system
• Traditional embryo assessment- based on time point evaluation
• Time lapse monitoring system allows complete observation of
embryo development.
• Introduction of imaging systems allows us to assess embryos in a
different way through their morphokinetics.
• Morphokinetics comprise of cell-division patterns and time points
• Out of various time lapse systems two most frequently used are
Primo vision and embryoscope system
17
Laboratory advancement(3)
• The embryoscope is a highly sophisticated instrument containing an
incubator, a microscope and a computer
• Consist of a digital inverted microscope that takes a picture of the
embryos at the interval of every 15 to 20 minutes
• These images can be reviewed at any time by our embryologists without removing
the embryos from the incubator.
• This is simple way to document and save all the stages of embryo
development
• Embryo culture is fully automated with use of time-lapse incubators
18
19
Laboratory advancement(4)
3. Robotic ICSI
• Aim of robotic ICSI: to standardize how clinical ICSI is performed
• It includes a cell holding device, motion control and computer vision
algorithms
• This system performs visual tracking of a single sperm, robotic
immobilization of sperm, aspiration of sperm with picoliter volume
and insertion of sperm into an oocyte with a high degree of
reproducibility
• Requires minimal human involvement( requiring only a few computer
mouse clicks) 20
21
Scientific advancements
• Fertility preservation in women with cancers or women who want to
postpone pregnancy
• Young patient with cancer should be referred for fertility preservation
counseling quickly
• Oocyte vitrification, oocyte maturation in vitro techniques,
• ovarian tissue cryopreservation, invitro follicle growth, derivation of
germ cells from stem cells will become established in next decade
22
Scientific advancements(2)
1. Cryopreservation
• Involves freezing unfertilised eggs or embryo and storing them for
later use
• social (non-medical) or medical reasons
• cryopreserved using either slow freezing or vitrification
• Traditional slow-freezing protocols requires expensive
equipment and is time-consuming where as Vitrification requires
high cooling rates combined with a high concentration of
cryoprotectant
23
Scientific advancements(3)
2. Oocyte vitrification
• First live birth with oocyte cryopreservation after vitrification was
reported in 1999.
• It has paved the way for establishment of donor oocyte bank and
social egg freezing
• Establishment of a first commercial donor egg bank – 2007
• The frequency of this procedure has steadily increased since
January 2013 when the American Society of Reproductive Medicine
(ASRM) announced that oocyte cryopreservation was no longer
experimental
24
Scientific advancements(4)
• The success rate has improved by replacing slow freezing with ultra-rapid
vitrification and utilisation of Intracytoplasmic sperm injection (ICSI) for
fertilising frozen-thawed oocytes.
• Success rate with oocyte cryopreservation using slow freezing were lower
than that of IVF with fresh oocytes
• Oocyte vitrification was more successful than with slow freezing
• Over the past 10yrs, oocyte cryopreservation using vitrification technology
has resulted in pregnancy outcomes similar to that of IVF with fresh
oocytes.
• Recently in 2018, the ASRM practice committee accepted social egg
freezing as ethically permissible and termed it as “planned oocyte
cryopreservation” (“Planned OC”) 25
26
Conclusion: It is too early to draw any final conclusions on outcomes of OC in
medical OC and planned OC; however, preliminary data supports that utilization
of OC in both groups result in preservation of fertility and subsequent live births
in patients who return to use their cryopreserved eggs. Higher oocyte yield, with
fewer ovarian stimulation cycles, and higher live birth rates are seen in patients
who seek OC at younger ages, reinforcing the importance of age on fertility
preservation..
Scientific advancements(5)
3. Ovarian tissue cryopreservation (OTC)
• removes the egg-producing portion of the ovary, called the ovarian cortex,
before a patient's treatment, freeze it, and store it.
• The tissue can be transplanted years later, if transplantation is successful
and the patient is producing eggs, pregnancy can occur naturally or
through in vitro fertilization (IVF).
• The first transplantation procedure of previously frozen ovarian tissue took
place in 1999.
• The most recent guideline published by the American Society for
Reproductive Medicine (ASRM) states that OTC is an “acceptable fertility
preservation technique and is no longer considered experimental”- 2019
27
28
Results :To date, out of 1026 total women, 812 (79.1%) had their tissue stored. Sixty-eight
(6.6%) patients died from their primary disease. Twentyfour (2.3%) women performed 33 OTTs
between December 2011 and January 2022. Restoration of menstruation was observed in 15
out of 17 menopausal women. Six pregnancies were achieved, two hesitated in abortion and
four in the birth of healthy babies.
Conclusion: OTC is the only fertility preservation technique applicable in pre-
pubertal/pediatrics and in adult patients when stimulation for oocytes/embryos cryopreservation
is not possible. The reported data can help future patients and physicians in their discussions
and decisions about the need and possibilities of preserving ovarian function.
Scientific advancements(6)
4. Ovarian transposition
• A procedure used to help keep a woman fertile by preventing
damage to the ovaries during radiation therapy.
• Before radiation therapy begins, one or both ovaries and fallopian
tubes are separated from the uterus and attached to the wall of the
abdomen away from where the radiation will be given.
• Medial transposition (behind the uterus)
• Lateral transposition (up to the pelvic side wall at least 3cm from the
upper border of the radiation field)
29
Common locations for ovarian transposition: laterally within the pelvis, in lower paracolic gutters (green circle), anterior to
psoas muscles (blue circle) and in intraabdominal paracolic gutters (pink circle). References: Sella T et al. (2005) Imaging of
transposed ovaries in patients with cervical carcinoma. AJR 184:1602-1610
30
31
Conclusions: In women with cervical cancer, ovarian transposition offers a
significant preservation of the ovarian function. Despite an expected incidence of
ovarian cyst formation, it carries almost no risk for metastases to the transposed
ovaries
Invitro gametogenesis
• Most revolutionary concept in modern reproductive science
• led to the creation of functional gametes in rodent models
• Appliction of stem cells in infertility
• Several researchers in Eunice kennedy shriver National institute of
child health and human development, US(Jan 2017) and Hospital
university La fe, (Sep 2014) have confirmed the presence of ovarian
stem cells, as well as bone marrow derived stem cells that have
been able to colonize the ovaries and have folliculogensis.
32
First baby born using innovative stem cell
in vitro fertilization technique
• https://time.com/3849127/baby-stem-cells-augment-ivf/
• Zain Rajani was born on April 13, 2015 by taking an ovarian tissue sample from his
mother, Natasha Rajani
• Born using an in vitro fertilization technique called AUGMENT- mitochondria replacement
therapy
• Her tissue sample was analysed in order to identify egg stem cells.
• Once the egg stem cells were identified, they were removed from the tissue and purified.
• The purification process allowed for the extraction of the mitochondria, organells that
provide energy for cell
• The introduction of mitochondria provided a more reliable source of energy for the egg
cells and helped produce a healthy embryo for Natasha, resulting in baby Zain.
33
Invitro gametogenesis…..
Artificial gametes
• https://www.technologyreview.com/2022/08/23/1056921/lab-made-human-sex-cell/
• Imagine two men making a baby. Or two women. Or an infertile couple. Or an older
woman whose eggs are no longer viable. None of these people could have a baby today
without the help of an egg or sperm donor.
• But in future, it may be possible for them to reproduce using only, their own genetic
material, using an emerging technology invitro gametogenesis.
• Researchers are learning how to reprogram adult human cells like skin cells to become
lab-created egg and sperm cells
• In 2016, Japanese scientists proved that the concept could be successfully carried out in
mice.
• Now some experts, like Dr. John Zhang, the founder and CEO of New Hope Fertility
Center in Manhattan, say it's just "a matter of time" before the method is also made to
work in humans.
34
Invitro gametogenesis…..
Reproductive genetics
• Preimplantation genetic diagnosis or preimplantation genetic
screening
Involves obtaining one or more cells from the developing embryo
and evaluating the genetic composition of this cells for either a
specific genetic defect known to exist in the parents or to screen for
the presence of embryo aneuploidy.
Goal: to identify genetic defects in embryos created through IVF
before transferring them into uterus, thus decreasing abortions and
birth with genetic abnormalities
35
36
Three parent baby
• A human offspring produced
from the genetic material of
one man and two women
through the use of assisted
reproductive technologies,
specifically mitochondrial
replacement therapy (MRT)
and three-person in vitro
fertilization (IVF)
37
Reproductive genetics…
Three parent baby(2)
• https://time.com/4509565/worlds-first-baby-born-with-dna-from-three-parents/
• A baby boy born in April, 2016 to Jordanian parents.
• The mother carries genes for Leigh syndrome, a rare genetic disorder characterized by the
degeneration of the central nervous system; the brain, spinal cord, and optic nerve. Although she is
healthy, her first two children died because of Leigh syndrome
• Doctors at the center carried out a ‘spindle nuclear transfer’, where they removed the nucleus from
one of her eggs and inserted it into a donor egg which had had its nucleus removed. The resulting
egg was then fertilized with the father’s sperm. An embryo was then implanted in the mother – and,
nine months later, their baby son was born.
• When the boy was tested for Leigh syndrome, reseachers found less than 1% of his mitochondria
(tiny structures found in cells) carried the mutation. He will continue to be monitored by doctors to
make sure the levels remain as low.
• May 6, 2022 – this procedure now legal in two countries: the U.K. and Australia. 38
In the context of Nepal……
• First IVF Service in Om Hospital & Research was inaugurated on
10th July 2004.
• The IVF, ICSI program was established by the initiation of Dr. Bhola
Rizal and his Team.
• The first test-tube baby of Nepal, Om Mani Tamang was born on
March 3, 2005 and opened the doors to IVF treatment in Nepal
which flourishing.
39
In the context of Nepal……
• Fertility Society of Nepal (FESON) urged the government to plan a
policy on IVF technology to make it cost effective.
• FESON says that there are around 15-20 percent infertile couples in
Nepal, of which 85 percent can be treated with medication. The
remaining 15 percent require IVF technology intervention.
• 12 centers in Nepal, seven in Kathmandu and the rest outside.
• With the introduction of IVF technology in Nepal, around 70 percent
of Nepali couples have stopped going to India
• https://kathmandupost.com/national/2018/06/03/calls-to-make-in-
vitro-fertilisation-affordable
40
41
Conclusions:
The success rates of ART
treatment in this study were
comparable to the international
estimates. More research on
treatment outcomes by all ART
service providers in Nepal is
needed to provide better
evidence on utilization and
efficacy of ART treatment in
fertility centres across the
country.
Surrogacy
• Surrogacy is a fertility treatment in which a
woman carries and delivers pregnancy for
another couple.
• It is an arrangement, often supported by
legal agreement, to bear a child for
another person.
Traditional surrogacy
Gestational surrogacy
Altruistic Surrogacy
Commercial Surrogacy
42
THE RISE AND FALL OF SURROGACY
IN NEPAL
• Nepal may just be one of the shortest lived destinations on the international
surrogacy list
• Nepal was a popular Asian destination following India’s 2013 limited ban on
international surrogacy for single and same sex couples, and Thailand’s ban on
commercial surrogacy.
• In September 2014 the Nepalese Cabinet permitted international surrogacy
(expanding on the 2014 National Health Policy which permitted surrogacy for
Nepalese citizens) provided Nepalese were not donating sperm or eggs or acting
as surrogates. This led to an influx of Indian women into Nepal to act as
surrogates.
• The practice was formally banned by a Cabinet decision on September 18, 2015,
using the Supreme Court decision after it was found that the practice was
commercialized.
• https://blogs.canterbury.ac.nz/surrogacy/the-rise-and-fall-of-surrogacy-in-
nepal/2015
43
44
Legal System addressing infertility in
Nepal
• The long practice of 1963 civil code has now been replaced by
Civil Act (Muluki Ain), 2017 that does not consider women's
infertility as a ground for divorce .
45
Conclusion
• Infertile couples also experience a lot of adverse psychological effect
associated with infertility. Therefore, infertility needs to be seen as a public
health problem rather than a purely medical condition.
• Management of infertility should be included in the national policy
guideline and should commit action and resources towards low cost IVF
and infertility treatment service
• Moreover, the introduction of innovative technologies into clinical practice
must be rooted in science and supported by well-designed clinical trials.
• Given the rapid evolution of scientific, technological and reproductive
genetics, it is imperative that public and regulatory bodies be engaged in
establishing a framework for the ethical evaluation of emerging
technologies. 46
References
1. https://www.who.int/news-room/fact-sheets/detail/infertility
2. https://www.mayoclinic.org/diseases-conditions/female-infertility/symptoms-causes/syc-
20354308
3. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/infertility-in-women
4. https://www.singlecare.com/blog/news/infertility-statistics/
5. https://hegdefertility.com/blog/what-are-the-recent-advancement-in-infertility-treatments/
6. https://www.expresshealthcare.in/news/recent-advances-and-trends-in-ivf-
technology/437247/
7. https://link.springer.com/content/pdf/10.1007/s43032-021-00829-3.pdf?pdf=button
8. https://slas-technology.org/action/showPdf?pii=S2472-6303%2822%2901196-7
9. https://www.sciencedirect.com/science/article/abs/pii/S1472648321002790
10. https://hsci.harvard.edu/examining-ethics-embryonic-stem-cell-research
47
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RECENT ADVANCES ON TREATMENT OF FEMALE INFERTILITY.pptx

  • 2. Introduction • Infertility is a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse (and there is no other reason, such as breastfeeding or postpartum amenorrhea) ………………………………(WHO) • Infertility can be primary or secondary. • Primary infertility is when a pregnancy has never been achieved by a person, and secondary infertility is when at least one prior pregnancy has been achieved 2
  • 3. Introduction(2) • In the male reproductive system, infertility is most commonly caused by problems in the ejection of semen, absence or low levels of sperm, or abnormal morphology and motility of the sperm. • In the female reproductive system, infertility may be caused by a range of abnormalities of the ovaries, uterus, fallopian tubes, and the endocrine system. • Risk factors- Age, Smoking, Weight, Sexual history, Alcohol • Diagnosis- Physical examination, Blood tests, Hormone test, Laparoscopy, Hysteroscopy, Ultrasound scans 3
  • 4. Statement of the problem • 48 million couples and 186 million individuals live with infertility, half of these couples are living in Sub-Saharan Africa (SSA) and South Asia globally. (WHO) • The use of assisted reproductive technology (ART) by infertile couples is increasing by 5% to 10% per year. • Nearly 2% of live births in the U.S. are a result of assisted reproductive technology. (CDC, 2017) • According to the article published in journal of Karnali academy of health sciences the problem was highest among the females of 26- 30 years (51%) The most common causes of female infertility were ovarian cyst (37%) and heavy bleeding (18.7%), uterine fibroids (9%), Pelvic inflammation (9%) and Thyroid disease (21.8%) 4
  • 5. Treatment for female infertility • Ovulation induction • Surgery • Artificial insemination (IUI) • Assisted reproductive technologies (ART) including in- vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) 5
  • 8. 8
  • 9. 9
  • 10. • In 1978 the world witnessed the birth of first “test tube baby”- louise Brown, now 45yrs old. • Since this time there have been explosive innovations and advances in assisted reproductive technologies (ART) 10
  • 11. 11 RECENT ADVANCES Advances in ICSI Pulse driven ICSI Medical advancement long acting gonadotropins, salivary estrdiol concentration, selfoperated endovaginal telemonitoring, e-therapy Technological advancement Novel lab-on-a-chip concept, time lapse monitoring system, robotic ICSI Scientific advancement fertility preservation (cryopreservation, oocyte vitrification, ovarian tissue cryopreservation, ovarian transposition) Invitro gametogenesis concept of stem cells Reproductive genetics preimplantation genetic diagnosis and screening
  • 12. Medical Advancements • Conventional- Controlled ovarian stimulation involves multiple injections of gonadotropins and serial visits to the fertility clinic for the conduct of transvaginal ultrasound evaluations and the measurement of circulating hormone levels. • COH is complex, time sensitive, and intensive. 1. Recently- Various strategies intent on reducing the number of injections by utilizing long-acting gonadotropins( eg named corifollitropin alfa (Elonva) or FSH‐CTP ) are available and are gaining increased acceptance 2. Emerging strategy- to measure salivary estradiol levels may help decrease the need for blood draws during COH. 12
  • 13. Medical Advancements (2) 3. Recent advancements in portable lower cost ultrasound devices to simplify follicular and endometrial monitoring(eg self-operated endovaginal telemonitoring). 4. Screening of patients for psychological issues as well as offering counseling and coping interventions such as e-therapy as an integral part of IVF. • These approaches may greatly simplify COH by rendering it less invasive and by decreasing the time commitment required. 13
  • 14. 14
  • 15. 15 • Results: The clinical results showed similar conception rates and ongoing pregnancy rates, Similar numbers of follicles, embryos available at transfer, top quality embryos (SOET: non-SOET) indicating non-inferiority of SOET monitoring. • Regarding patient-reported outcomes, a significantly higher contentedness of patient and partner, a higher feeling of empowerment, discretion and more active partner participation as well as a trend towards less stress were observed in the S versus the NS group. • In the economic analysis, the use of SOET led to reduced productivity loss, lower transportation costs, and lower sonogram and consultation costs but higher personnel cost than NS
  • 16. Laboratory advancement 1. The novel IVF lab-on-a-chip concept Automation and miniaturization of the IVF laboratory Advantages of Automated IVF: standardization of workflows, reduction in errors, reduction in cost, reduction in contamination • Has the potential to revolutionize IVF by enabling the automation of virtually all of the steps involved in a single system. • Microfuidic sperm-sorting devices and automated sperm analyzers are already being introduced into routine IVF practice 16
  • 17. Laboratory advancement(2) 2. Time lapse monitoring system • Traditional embryo assessment- based on time point evaluation • Time lapse monitoring system allows complete observation of embryo development. • Introduction of imaging systems allows us to assess embryos in a different way through their morphokinetics. • Morphokinetics comprise of cell-division patterns and time points • Out of various time lapse systems two most frequently used are Primo vision and embryoscope system 17
  • 18. Laboratory advancement(3) • The embryoscope is a highly sophisticated instrument containing an incubator, a microscope and a computer • Consist of a digital inverted microscope that takes a picture of the embryos at the interval of every 15 to 20 minutes • These images can be reviewed at any time by our embryologists without removing the embryos from the incubator. • This is simple way to document and save all the stages of embryo development • Embryo culture is fully automated with use of time-lapse incubators 18
  • 19. 19
  • 20. Laboratory advancement(4) 3. Robotic ICSI • Aim of robotic ICSI: to standardize how clinical ICSI is performed • It includes a cell holding device, motion control and computer vision algorithms • This system performs visual tracking of a single sperm, robotic immobilization of sperm, aspiration of sperm with picoliter volume and insertion of sperm into an oocyte with a high degree of reproducibility • Requires minimal human involvement( requiring only a few computer mouse clicks) 20
  • 21. 21
  • 22. Scientific advancements • Fertility preservation in women with cancers or women who want to postpone pregnancy • Young patient with cancer should be referred for fertility preservation counseling quickly • Oocyte vitrification, oocyte maturation in vitro techniques, • ovarian tissue cryopreservation, invitro follicle growth, derivation of germ cells from stem cells will become established in next decade 22
  • 23. Scientific advancements(2) 1. Cryopreservation • Involves freezing unfertilised eggs or embryo and storing them for later use • social (non-medical) or medical reasons • cryopreserved using either slow freezing or vitrification • Traditional slow-freezing protocols requires expensive equipment and is time-consuming where as Vitrification requires high cooling rates combined with a high concentration of cryoprotectant 23
  • 24. Scientific advancements(3) 2. Oocyte vitrification • First live birth with oocyte cryopreservation after vitrification was reported in 1999. • It has paved the way for establishment of donor oocyte bank and social egg freezing • Establishment of a first commercial donor egg bank – 2007 • The frequency of this procedure has steadily increased since January 2013 when the American Society of Reproductive Medicine (ASRM) announced that oocyte cryopreservation was no longer experimental 24
  • 25. Scientific advancements(4) • The success rate has improved by replacing slow freezing with ultra-rapid vitrification and utilisation of Intracytoplasmic sperm injection (ICSI) for fertilising frozen-thawed oocytes. • Success rate with oocyte cryopreservation using slow freezing were lower than that of IVF with fresh oocytes • Oocyte vitrification was more successful than with slow freezing • Over the past 10yrs, oocyte cryopreservation using vitrification technology has resulted in pregnancy outcomes similar to that of IVF with fresh oocytes. • Recently in 2018, the ASRM practice committee accepted social egg freezing as ethically permissible and termed it as “planned oocyte cryopreservation” (“Planned OC”) 25
  • 26. 26 Conclusion: It is too early to draw any final conclusions on outcomes of OC in medical OC and planned OC; however, preliminary data supports that utilization of OC in both groups result in preservation of fertility and subsequent live births in patients who return to use their cryopreserved eggs. Higher oocyte yield, with fewer ovarian stimulation cycles, and higher live birth rates are seen in patients who seek OC at younger ages, reinforcing the importance of age on fertility preservation..
  • 27. Scientific advancements(5) 3. Ovarian tissue cryopreservation (OTC) • removes the egg-producing portion of the ovary, called the ovarian cortex, before a patient's treatment, freeze it, and store it. • The tissue can be transplanted years later, if transplantation is successful and the patient is producing eggs, pregnancy can occur naturally or through in vitro fertilization (IVF). • The first transplantation procedure of previously frozen ovarian tissue took place in 1999. • The most recent guideline published by the American Society for Reproductive Medicine (ASRM) states that OTC is an “acceptable fertility preservation technique and is no longer considered experimental”- 2019 27
  • 28. 28 Results :To date, out of 1026 total women, 812 (79.1%) had their tissue stored. Sixty-eight (6.6%) patients died from their primary disease. Twentyfour (2.3%) women performed 33 OTTs between December 2011 and January 2022. Restoration of menstruation was observed in 15 out of 17 menopausal women. Six pregnancies were achieved, two hesitated in abortion and four in the birth of healthy babies. Conclusion: OTC is the only fertility preservation technique applicable in pre- pubertal/pediatrics and in adult patients when stimulation for oocytes/embryos cryopreservation is not possible. The reported data can help future patients and physicians in their discussions and decisions about the need and possibilities of preserving ovarian function.
  • 29. Scientific advancements(6) 4. Ovarian transposition • A procedure used to help keep a woman fertile by preventing damage to the ovaries during radiation therapy. • Before radiation therapy begins, one or both ovaries and fallopian tubes are separated from the uterus and attached to the wall of the abdomen away from where the radiation will be given. • Medial transposition (behind the uterus) • Lateral transposition (up to the pelvic side wall at least 3cm from the upper border of the radiation field) 29
  • 30. Common locations for ovarian transposition: laterally within the pelvis, in lower paracolic gutters (green circle), anterior to psoas muscles (blue circle) and in intraabdominal paracolic gutters (pink circle). References: Sella T et al. (2005) Imaging of transposed ovaries in patients with cervical carcinoma. AJR 184:1602-1610 30
  • 31. 31 Conclusions: In women with cervical cancer, ovarian transposition offers a significant preservation of the ovarian function. Despite an expected incidence of ovarian cyst formation, it carries almost no risk for metastases to the transposed ovaries
  • 32. Invitro gametogenesis • Most revolutionary concept in modern reproductive science • led to the creation of functional gametes in rodent models • Appliction of stem cells in infertility • Several researchers in Eunice kennedy shriver National institute of child health and human development, US(Jan 2017) and Hospital university La fe, (Sep 2014) have confirmed the presence of ovarian stem cells, as well as bone marrow derived stem cells that have been able to colonize the ovaries and have folliculogensis. 32
  • 33. First baby born using innovative stem cell in vitro fertilization technique • https://time.com/3849127/baby-stem-cells-augment-ivf/ • Zain Rajani was born on April 13, 2015 by taking an ovarian tissue sample from his mother, Natasha Rajani • Born using an in vitro fertilization technique called AUGMENT- mitochondria replacement therapy • Her tissue sample was analysed in order to identify egg stem cells. • Once the egg stem cells were identified, they were removed from the tissue and purified. • The purification process allowed for the extraction of the mitochondria, organells that provide energy for cell • The introduction of mitochondria provided a more reliable source of energy for the egg cells and helped produce a healthy embryo for Natasha, resulting in baby Zain. 33 Invitro gametogenesis…..
  • 34. Artificial gametes • https://www.technologyreview.com/2022/08/23/1056921/lab-made-human-sex-cell/ • Imagine two men making a baby. Or two women. Or an infertile couple. Or an older woman whose eggs are no longer viable. None of these people could have a baby today without the help of an egg or sperm donor. • But in future, it may be possible for them to reproduce using only, their own genetic material, using an emerging technology invitro gametogenesis. • Researchers are learning how to reprogram adult human cells like skin cells to become lab-created egg and sperm cells • In 2016, Japanese scientists proved that the concept could be successfully carried out in mice. • Now some experts, like Dr. John Zhang, the founder and CEO of New Hope Fertility Center in Manhattan, say it's just "a matter of time" before the method is also made to work in humans. 34 Invitro gametogenesis…..
  • 35. Reproductive genetics • Preimplantation genetic diagnosis or preimplantation genetic screening Involves obtaining one or more cells from the developing embryo and evaluating the genetic composition of this cells for either a specific genetic defect known to exist in the parents or to screen for the presence of embryo aneuploidy. Goal: to identify genetic defects in embryos created through IVF before transferring them into uterus, thus decreasing abortions and birth with genetic abnormalities 35
  • 36. 36
  • 37. Three parent baby • A human offspring produced from the genetic material of one man and two women through the use of assisted reproductive technologies, specifically mitochondrial replacement therapy (MRT) and three-person in vitro fertilization (IVF) 37 Reproductive genetics…
  • 38. Three parent baby(2) • https://time.com/4509565/worlds-first-baby-born-with-dna-from-three-parents/ • A baby boy born in April, 2016 to Jordanian parents. • The mother carries genes for Leigh syndrome, a rare genetic disorder characterized by the degeneration of the central nervous system; the brain, spinal cord, and optic nerve. Although she is healthy, her first two children died because of Leigh syndrome • Doctors at the center carried out a ‘spindle nuclear transfer’, where they removed the nucleus from one of her eggs and inserted it into a donor egg which had had its nucleus removed. The resulting egg was then fertilized with the father’s sperm. An embryo was then implanted in the mother – and, nine months later, their baby son was born. • When the boy was tested for Leigh syndrome, reseachers found less than 1% of his mitochondria (tiny structures found in cells) carried the mutation. He will continue to be monitored by doctors to make sure the levels remain as low. • May 6, 2022 – this procedure now legal in two countries: the U.K. and Australia. 38
  • 39. In the context of Nepal…… • First IVF Service in Om Hospital & Research was inaugurated on 10th July 2004. • The IVF, ICSI program was established by the initiation of Dr. Bhola Rizal and his Team. • The first test-tube baby of Nepal, Om Mani Tamang was born on March 3, 2005 and opened the doors to IVF treatment in Nepal which flourishing. 39
  • 40. In the context of Nepal…… • Fertility Society of Nepal (FESON) urged the government to plan a policy on IVF technology to make it cost effective. • FESON says that there are around 15-20 percent infertile couples in Nepal, of which 85 percent can be treated with medication. The remaining 15 percent require IVF technology intervention. • 12 centers in Nepal, seven in Kathmandu and the rest outside. • With the introduction of IVF technology in Nepal, around 70 percent of Nepali couples have stopped going to India • https://kathmandupost.com/national/2018/06/03/calls-to-make-in- vitro-fertilisation-affordable 40
  • 41. 41 Conclusions: The success rates of ART treatment in this study were comparable to the international estimates. More research on treatment outcomes by all ART service providers in Nepal is needed to provide better evidence on utilization and efficacy of ART treatment in fertility centres across the country.
  • 42. Surrogacy • Surrogacy is a fertility treatment in which a woman carries and delivers pregnancy for another couple. • It is an arrangement, often supported by legal agreement, to bear a child for another person. Traditional surrogacy Gestational surrogacy Altruistic Surrogacy Commercial Surrogacy 42
  • 43. THE RISE AND FALL OF SURROGACY IN NEPAL • Nepal may just be one of the shortest lived destinations on the international surrogacy list • Nepal was a popular Asian destination following India’s 2013 limited ban on international surrogacy for single and same sex couples, and Thailand’s ban on commercial surrogacy. • In September 2014 the Nepalese Cabinet permitted international surrogacy (expanding on the 2014 National Health Policy which permitted surrogacy for Nepalese citizens) provided Nepalese were not donating sperm or eggs or acting as surrogates. This led to an influx of Indian women into Nepal to act as surrogates. • The practice was formally banned by a Cabinet decision on September 18, 2015, using the Supreme Court decision after it was found that the practice was commercialized. • https://blogs.canterbury.ac.nz/surrogacy/the-rise-and-fall-of-surrogacy-in- nepal/2015 43
  • 44. 44
  • 45. Legal System addressing infertility in Nepal • The long practice of 1963 civil code has now been replaced by Civil Act (Muluki Ain), 2017 that does not consider women's infertility as a ground for divorce . 45
  • 46. Conclusion • Infertile couples also experience a lot of adverse psychological effect associated with infertility. Therefore, infertility needs to be seen as a public health problem rather than a purely medical condition. • Management of infertility should be included in the national policy guideline and should commit action and resources towards low cost IVF and infertility treatment service • Moreover, the introduction of innovative technologies into clinical practice must be rooted in science and supported by well-designed clinical trials. • Given the rapid evolution of scientific, technological and reproductive genetics, it is imperative that public and regulatory bodies be engaged in establishing a framework for the ethical evaluation of emerging technologies. 46
  • 47. References 1. https://www.who.int/news-room/fact-sheets/detail/infertility 2. https://www.mayoclinic.org/diseases-conditions/female-infertility/symptoms-causes/syc- 20354308 3. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/infertility-in-women 4. https://www.singlecare.com/blog/news/infertility-statistics/ 5. https://hegdefertility.com/blog/what-are-the-recent-advancement-in-infertility-treatments/ 6. https://www.expresshealthcare.in/news/recent-advances-and-trends-in-ivf- technology/437247/ 7. https://link.springer.com/content/pdf/10.1007/s43032-021-00829-3.pdf?pdf=button 8. https://slas-technology.org/action/showPdf?pii=S2472-6303%2822%2901196-7 9. https://www.sciencedirect.com/science/article/abs/pii/S1472648321002790 10. https://hsci.harvard.edu/examining-ethics-embryonic-stem-cell-research 47
  • 48. 48

Notas do Editor

  1. Laparoscopy – a ‘keyhole’ surgical procedure in which an instrument is inserted through a small incision in the abdomen so that the reproductive organs can be examined Hysteroscopy: In this test, a device called a hysteroscope (a flexible, thin device with a camera) is inserted into the vagina and through the cervix. The healthcare provider moves it into the uterus to view the inside of the organ. Ultrasound scans – to check for the presence of fibroids.
  2. Age. The quality and quantity of egg decline Smoking. Besides damaging your cervix and fallopian tubes, smoking increases your risk of miscarriage and ectopic pregnancy Weight Being overweight or significantly underweight may affect ovulation. Getting to a healthy body mass index (BMI) might increase likelihood of pregnancy Sexual historySexually transmitted infections such as chlamydia and gonorrhea can damage the fallopian tubes. Alcohol Excess alcohol consumption can reduce fertility.
  3. Among the cases of infertility around the world, 40% lies within women, 30% within men, 20% within men and women and 10% unknown causes. Hospital-based descriptive cross-sectional study had been carried out in infertility centre Kathmandu Nepal. 165 married couple with infertility problem availing the infertility treatment was selected.
  4. OI is most common procedure carried out among infertile couple approaching at infertility clinic as anovulatory infertility is most common cause of infertility Clomiphene citrate, letrozole,gonadotropins, injections of FSH Risk of ART Ovarian hyperstimulation syndrome (OHSS) an increased incidence of multiple pregnancies an increased risk of premature labour and low birth weight an increased risk of caesarean delivery Steps in human reproduction One of the two ovaries releases a mature egg. The egg is picked up by the fallopian tube. Sperm swim up the cervix, through the uterus and into the fallopian tube to reach the egg for fertilization. The fertilized egg travels down the fallopian tube to the uterus. The fertilized egg attaches (implants) to the inside of the uterus and grows
  5. Indications for surgrey are due to disorders of reproductive system Tubal disorders such as blocked fallopian tubes→ caused by untreated (STIs) or complications of unsafe abortion Uterine disorders→inflammatory in nature (endometriosis), congenital in nature (septate uterus), or benign in nature (fibroids); Disorders of the ovaries→ such as polycystic ovarian syndrome
  6. (IUI) is a procedure in which processed sperm sample is placed inside a woman’s uterus at or just before the time of ovulationOBJECTIVE-is to increase the number of motile sperm that reaches the egg in the fallopian tubes to facilitate fertilization.can be used in combination with OI. If pregnancy isnot achieved IVF or ICSi may be needed PROCESS- couple of minutes with minor discomfort. The clinician inserts a small catheter into the uterine cavity through the cervix and releases the processed sperm sample.the patient is able to resume normal daily activities. ​
  7. produce 10 to 15 eggs rather than the one which normally matures every month. When the eggs are ‘ready’ they are retrieved in an ultrasound-guided procedure. the collected eggs are then mixed with sperm Two to 5 days later an embryo is transferred to the woman’s uterus using a thin tube that is inserted through the cervix. If there are more embryos than needed, these can be frozen for future use.
  8. ICSI each egg is injected with a single sperm. difference IVF and ICSI-In IVF, the egg and sperm (of which there are many) are left in a laboratory dish to fertilize on their own. In ICSI, the selected sperm is directly injected into the egg..yields satisfactory results and helps reduce problems with abnormal fertilization caused by eggs and sperm – such as fertilization by multiple sperm and the inability of the sperm to penetrate the eggs
  9. As opposed to conventional ICSI, pulse-driven ICSI employs piezoelectric pulses to puncture the egg shell and membrane thus Oocyte deformation during ICSI is avoided and the release of sperm into the egg is done more readily and securely.
  10. A single dose of long‐acting FSH is able to keep the circulating FSH level above the threshold necessary to support multi‐follicular growth for an entire week.. A single injection of long‐acting FSH can replace seven daily FSH injections during the first week of controlled ovarian stimulation and can make assisted reproduction more patient friendly.
  11. Studies showed that 20–25% of the women experience severe symptoms of anxiety or depression after unsuccessful assisted reproductive technology (ART) treatment, which can reduce quality of life but could also have a negative impact on continuation of treatment
  12. SOET patients were shown how to make video images, and how to upload and send them to the centre. They were given a laptop on which only the communication software and the imaging software were installed, a vaginal sonography probe with USB connection recordings were made by the patients by manually sweeping the probe. ovary, uterus, Videos were downloaded and opened in the imaging software in order to perform 2D-measurements of the follicles. All measurements were performed by the principal investigators. Video images could be stopped, played forward or backward using two callipers in order to measure each follicle at its largest diameters. Using the report function of the website, the patient then obtained instruction concerning hormonal dose continuation or adjustment and planning of the subsequent sonogram.. At any time, direct communication by e-mail or telephone was possible in both directions, creating a direct line between the centre (midwives, doctor) and the patient
  13. -The basic steps in the IVF laboratory include: 1. identifcation and separation of sperm and oocytes 2. fertilization 3. embryo culture 4. embryo selection for transfer 5. cryopreservation of surplus embryos and gametes- automation of these individual steps by way of new technologies
  14. AI integrates with Time-Lapsing Imaging (TLI) technology to generate images
  15. The Conventional Way provides brief snap-shot” at defined time points to minimise disturbances to culture conditions.thus, embryologists can only select embryos with little information. Time lapse- allows best embryo for transfer with undisturbed culture condition- which leads to improved success rate and pregnamcy rate
  16. microscope equipped with- holding pipette and an injection pipette. The holding pipette maintains the position of the oocyte using negative pressure during microinjection. The injection pipette is used to aspirate sperm into the oocyte. this process occurs within a confined microliter volume with the embryologist required to consistently refocus and micromanipulate within this miniscule 3D space
  17. Social egg freezing may benefit some women because  they may not be able to find a partner when they are younger, but may want to preserve their chances of conceiving if they marry later celebrities
  18. The practice of freezing eggs and sperm was introduced in 2014 ICSI was discovered in 1997 Under slow cooling conditions, it is possible to prevent intracellular ice formation  Vitrification does not produce any ice crystals during cooling and warming.
  19. Individuals undergoing gender affirmation surgery may also wish to preserve ovarian tissue. Patients with cancer(undergoing gonadotoxic chemotherapy) or do not want to undergo ovarian stimulation.
  20. Ovarian transposition was first established in 1952 by Batten to reduce the exposure of the female rep organs to high radiation doses Mainly by laparoscopy, one or both ovaries are (temporarily) positioned at least 2 cm above the pelvic brim. After ligating the Fallopian tube and the ovarian ligament, the ovary is attached to the abdominal wall. Both ovaries are marked with titanium metallic clips
  21. Opponents argue that the research is unethical, because deriving the stem cells destroys the blastocyst, an unimplanted human embryo at the sixth to eighth day of development “the taking of innocent human life.” Appliction of stem cells in infertility All cells of body come from stem cells which are undifferentiated cells Under physiologic or experimental conditions, they can be induced to become tissue or organ specific cells with special functions Bone marrow is richest source of stem cells
  22. AUGMENT is an innovative treatment targeted at improving a mother’s egg health by injecting stem cells from the ovarian lining to mature egg cells.  These stem cells enhance necessary energy production from existing mitochondria
  23. Sperms and oocytes An embryo forms when sperm meets egg. But what if we could start with other cells—if a blood sample or skin biopsy could be transformed into “artificial” sperm and eggs? The advances could herald the end of infertility—there’s no need to worry about a lack of healthy eggs or sperm if you can create new ones in the lab Same-sex couples could have genetically related children The technology would allow four parents to make equal genetic contributions to a baby, for example. Or a single person could produce both the sperm and the egg that create an embryo. 
  24. Preimplantation genetic diagnosis and screening is another game changing innovation
  25. 3- person IVF would result in inheritable genetic modification The first three-parent babies were born in the 1990s and early 2000s, the products of a then-novel IVF-based technique known as cytoplasmic transfer.
  26. Today's response is identical to when the world's first IVF baby was announced in 1978. The major news media didn't take it seriously and thought it was evil Many countries even abandoned IVF, but today you see it is a normal practice. And it took almost 40 years [for the researchers] to win a Nobel Prize. I think we need more time to understand how this work was done medically, ethically, and let the scientist have the opportunity to present how it was done and let a scientific journal publish the paper. The procedure was carried out in Mexico in order to bypass U.S. regulations.
  27. Advances in tt of infertility is flourished Almost all advances in art have been performed in Nepal except piezo, OTC, O trans, stem cells, It is a medical hub for IVF for foreigners as cost is relatively cheap.
  28. Altruistic Surrogacy: women agree to hold the baby in their womb for social service Commercial Surrogacy: is done for commercial benefit and it has been banned in most countries. Traditional surrogacy The surrogate provides her own egg, which is inseminated with the parent’s sperm. In this case, the baby is biologically related to the surrogate. Gestational surrogacy In this type of pregnancy, an embryo is transferred into the surrogate’s uterus. The embryo is formed from the egg and sperm of the intended parents or from donors, using IVF Law Relating to Surrogacy in Nepal Supreme Court  gave a directive order to the concerned authority to make an appropriate law to regulate surrogacy in Nepal considering the following fact (December 12, 2016) Completely ban commercial surrogacy since a mother’s womb can never be commercialized. If a Nepali married couple has been certified by a medical board that they are incapable of producing children because of infertility or other health conditions, they should be allowed. Same-sex couples or single men and women shall not be allowed to practice surrogacy Foreigners are not to be allowed to practice surrogacy in Nepal The mutual consent of the intended married couple and surrogate is required Only for altruistic and non-commercial purposes Criteria for surrogate mother Service to be provided by health institutions that fulfill criteria as prescribed by the law upon taking consent of the such authority Both the intended couple or surrogate has to apply to the concerned authority first Determination of legal rights and duties of legal parents Determination of rights and duties of surrogate mother Clarity on registration of birth and other events Provision of institutions for supervision, monitoring, and inspection of whether laws have complied with or not It’s a popular option for male same-sex couples who want to have a family and also can be used by people who are single in other countries. a last resort for A heterosexual couple who have struggled with fertility Intended mothers who are unable to carry a child Intended parents who have a genetic defect or health condition they don’t want to pass onto the child Same-sex parents who want to have a genetic link to the baby -It’s a popular option for male same-sex couples who want to have a family and also can be used by people who are single in other countries.
  29. Surrogacy Services are banned in Nepal since 2015, therefore it cannot be performed in Nepal; however if you are a foreigner and seeking for an IVF treatment in Nepal or Surrogacy option in abroad, we can surely assist you for the legal SURROGACY IN UKRAINE, GEORGIA, AND USA.  National Health Policy 2014 policy no 12 (as per which fertility shall be managed by the surrogacy-related laws ) -Despite the directive order, no efforts have been made in regard to surrogacy. This reflects the reluctance of parliament in this matter.
  30. Nepalese tourism received bad press when, following two earthquakes, Israel evacuated surrogate born children, who were born prematurely. The surrogates themselves were not evacuated, and therefore those children without intended parents in Nepal at the time of the quakes were left to be cared for by other Israeli passengers during the flights. even as the mothers, mostly Indian women, were left behind. The parents of the babies were mostly gay Israeli men, who are not allowed surrogacy under Israeli laws.
  31. Nepal's Supreme Court ruled that the provision in the country's 1963 Civil Code that gave men the right to divorce their wife on grounds of infertility was unconstitutional. A man had right to divorce his wife on grounds of infertility if government recognized medical facility certified that a woman was infertile after ten years of marriage. But a woman could not divorce her husband if he was infertile
  32. , so that it can be accessible and affordable by everyone