General information and international perspective
The birth of Louise Brown (the world’s first IVF baby) in 1978 ushered in a new
revolution in the treatment of infertility.
IVF and its derivatives in preimplantation diagnosis, stem cells and the ethics
of assisted reproduction continue to attract immense attention scientifically and
socially. All these topics were introduced by 1970 but yet hardly a day passes without
some public recognition of events related to IVF, and clinics spread even further
worldwide. Now we must be approaching 2 million IVF births, it is time to celebrate
what has been achieved by so many investigators, clinical, scientific and ethical.
IVF primarily dealt with female related infertility for patients with blocked tubes,
endometriosis, PCOS and unexplained Infertility. Little could be done for sever
male related infertility until the advent of Intra Cytoplasmic Sperm Injection (ICSI),
about 20 years ago wherein scientists could actually inject a single sperm into
the egg of the wife and produce a baby even with the lowest of sperm counts and
worst of sperm motility. It is now possible to extract sperm from the testicles
(TESA) in cases of azoospermia (zero sperm counts) and use these for ICSI and help
the couple have their own biological child (without the need for sperm donors).
Also, for men with blocked vas deferens (the tube that transports sperms from the
testicles to the outside) can avail of Percutaneousepididymal sperm aspiration (PESA)
with ICSI for the same successful outcome as TESA-ICSI.
The third biggest advance since the introduction of IVF & ICSI has been vitrification
(cryo-freezing) of gametes and embryos. Over the past two years there has been a
shift towards performing more frozen embryo transfers with better preparation of
the uterus resulting in higher take home baby rates. Most clinics with a good vitrification
program can now deliver success rates of 50% per IVF cycle as compared to about
35-40% with conventional fresh embryo transfer.
More and more women are opting for higher education and pursuit of their career
ambitions. In the bargain, marriage and child bearing are being deferred to a later
age. Often, after the age of 37 the egg quality is not the best and many of them
have to resort to egg donation, thereby sacrificing their genetic component in the
child. These young and dynamic women now have the option of freezing their eggs
(saving their fertility “in time”) at a young age for use at a later date thereby
making their lives complete both on the career as well as personal front.
A simpler technique called Intrauterine insemination (IUI) has been in existence
for a long time and is beneficial for young couples with minor problems or those
experiencing sexual dysfunction.
Recently, Preimplantation genetic diagnosis (PGD) has further helped to enhance
success rates especially in women over the age of 35 or those with history of miscarriages
or abnormal offspring. In this technique, the embryos are biopsied and evaluated
in a special genetic laboratory to ensure that only genetically normal embryos are
transferred back into the woman.
There is another very important aspect of ART practice and that is third party reproduction
which is extremely successful but governed by religious, ethical and legal issues.
In India, most of the clinics are compliant with the ART guidelines laid down by
the Indian Council of Medical Research for the practice of these techniques. There
is sperm donation for men who have total testicular failure and zero sperm counts
or for those who cannot afford ICSI. There is egg donation for women who are menopausal
or have had multiple IVF failures owing to poor egg quality. And finally, there
is gestational surrogacy for women who have had failed multiple cycles of IVF because
of problems in the uterus.
On the horizon, we have stem cell treatment for augmenting oocyte and endometrial
quality (in women with poor quality eggs or uterus). Also, a fast developing field
of epigenetics (DNA contribution from the mother even if there is a donor egg involved)
offers renewed hope to many patients who have to opt for a donor egg. Three-parent
IVF holds great promise for couples as it would ensure that the genetic component
is the mother’s even if she has to take a donor egg for some help with the pregnancy.
Intra-ovarian PRP activation also seems promising but we need more data for routine
implementation.
The Indian Perspective
In an over populated nation such as ours, the problem of infertility is still a
major health problem. As per WHO statistics in 1982, 1 out of every 16 couples was
reported to be infertile. Today the figure stands at 1 in 4 couples. In fact, in
a recent survey of our major metropolitan cities, the incidence of infertility in
the 30 plus age group was found to be 46% (Alarming!!). Late marriage, delayed child
bearing, increased use of contraceptives and the increasing incidence of medical
disorders such as endometriosis, polycystic ovaries, genital tuberculosis and male
sub fertility have all contributed to this increased incidence. Current data suggests
that male factor infertility is on the rise. In almost 50% of couples, low sperm
count, poor sperm motility and zero sperm count are the prime causes of infertility.
We (Indians) less fertile?
A recent study comparing Spanish and Indian women showed that Indian women have
a lower ovarian (egg) reserve than their caucasian counterparts (lower AMH, higher
FSH and longer duration of infertility). Also, Indian American women showed a significantly
lower Live birth rate with IVF than white American women (24% vs 41%).
Increased maternal and age at marriage, increased number of working women, rising
tobacco and alcohol consumption and rising levels of obesity are all contributory.
Also, Indian women show a higher incidence of polycystic ovaries and genital tuberculosis
as compared to the USA.
Studies have confirmed that South Asian women have a poor egg reserve as compared
to Caucasian women, and are likely to suffer from earlier onset of infertility and
poorer outcomes from infertility treatment.
Preliminary evaluation of the couple involves a clinical history, examination of
the female partner by transvaginal ultrasonography, semen analysis, hormone estimations
(Day 2 serum FSH, LH, Prolactin, and TSH) and a diagnostic laparoscopy and hysteroscopy.
On completion of the investigations, the diagnosis is established as one of.
Hormonal problems : Failure to produce eggs and irregular
menses.
Blocked fallopian tubes : Tuberculosis being a common
cause in our country.
Endometriosis : Menstruation occurs inside the body
in the ovaries or elsewhere causing cysts and infertility.
Male factor : Low sperm counts, poor sperm motility
or zero sperm counts.
Unexplained infertility : Where there is no apparent
cause for the infertility.
Conventional Management by medical or surgical means would help approximately 40%
of couple to conceive. These would include laparoscopic surgery for fibroids, endometriosis,
surgery for opening the fallopian tubes, hysteroscopic surgery for septum, polyps,
submucous fibroids and metroplasty for small or T-shaped uterus. In addition, ovulation
induction (drugs given to stimulate egg production) with clomiphene citrate and
gonadotropins would benefit the women with PCOS or other endocrine anomalies. Correction
of associated endocrinopathies such as high prolactin levels or poor thyroid function
is also important. Sperm anomalies would require evaluation by a urosurgeon / andrologist
and medical or surgical therapy such as varicocele ligation in select cases. For
the remaining 60% Assisted Reproductive Technologies have emerged as a great boon
over the past three decades. Today, it is possible to retrieve a human oocyte from
the ovary, fertilize it outside the body in the laboratory with the husband's sperm
and replace it into the uterus for achieving an offspring.
Intrauterine Insemination (IUI)
This entails deposition of washed and capacitated sperm into the uterus at the time
of spontaneous or induced ovulation. The indications include borderline male factor
infertility such as reduced counts and sperm motility, sexual dysfunction and sperm
deposition problems, poor sperm migration in the female genital tract and women
with hormonal defects. Some amount of controlled ovarian hyper stimulation is required
in the form of clomiphene or gonadotropin injections with hCG being added as the
ovulation trigger. Several techniques are available for sperm washing such as layering,
double spin or density gradients. The success rate with this procedure is in the
range of 10 – 30 % @ indication and 2-3 cycles are generally advocated before proceeding
to higher ART forms.
In-Vitro Fertilization and Embryo Transfer (IVF-ET)
The birth of Louise Brown in 1978 (world's first IVF baby) revolutionized the treatment
of moderate to severe female factor infertility. This was the original test tube
baby procedure wherein the woman is subjected to controlled ovarian hyperstimulation
with gonadotropins for obtaining more than one egg (oocyte). We believe in individualised
ovarian stimulation and judiciously use the short antagonist vs the long agonist
protocol for best outcomes. We do not believe in “one size fits all”. For high responders
and patients with PCOS we strictly use the short antagonist protocol with the GnRH
agonist trigger to ensure patient safety and totally eliminate the chance of ovarian
hyperstimulation syndrome (OHSS). Once the follicles are at the size of 18 mm, hCG
/ the agonist trigger is administered and the oocytes are aspirated at 36 hours
post hCG (before they rupture) and transferred to the IVF laboratory. Here they
are cultured in petri dishes containing culture medium. Subsequently, the oocytes
are fertilized with the husband's sperm after 4 - 6 hours of incubation. After 16
- 20 hours, the oocytes are checked for the 2 pronuclear stage implying successful
fertilization. After another 24 hours of culture, the best 1-2 embryos (4-cell stage)
are transferred back to the uterus or frozen and transferred in the subsequent month.
In the event of one of them implanting, successful pregnancy is established. The
most disappointing event in an IVF cycle is to get a negative pregnancy test and
therefore we have a strict policy of NOT transferring poor quality embryos. Rather
we encourage the couple to undergo another round of stimulation with a different
protocol in order to try and get better quality embryos. Also, in recent times,
AMH levels play a predictive role for IVF success. For example, young patients with
a normal AMH of 2-5 ng/ml can expect a 50-60% chance of pregnancy, whereas with
levels of < 2 ng / ml the success rate would reduce to 20-30% only. Indications
for IVF include tubal block, severe endometriosis and PCOD, unexplained infertility
and infertility due to any cause refractory to conventional medical and surgical
management. Success rates are in the range of 40-50% per cycle and 3 - 5 cycles
are recommended before opting for alternate treatment options.
Intracytoplasmic Sperm injection (ICSI)
This technique has been the greatest boon for male factor infertility which does
not respond to conventional medical or surgical treatment. With this technique,
men with severe oligo or asthenozoospermia can still their own child without taking
resort to a semen bank. As with IVF, the wife's oocytes are aspirated. On a special
microscope with a micromanipulator, a single sperm is picked up in fine microneedle
and injected manually into the oocyte. Embryos are transferred fresh or frozen as
per the IVF doctor’s decision. The couple can expect a 40-50 % chance of conception
per cycle. For azoospermic men with an obstructive pathology (eg: Congenital absence
of vas deferens) sperm can be aspirated directly from the epididymis (PESA) and
used for ICSI. In addition, for azoospermic men with a non-obstructive pathology,
sperm can be retrieved directly from the testis (TESA) and used for ICSI. Almost
miraculously, PESA or TESA with ICSI gives the same results as with ejaculated sperm
(50 % per cycle). We also offer Micro TESA (surgical aspiration of sperm under microscopic
control) with cases of primary testicular failure and azoospermia.
Oocyte Donation
Women who are menopausal or suffering from premature ovarian failure and amenorrhoea
can now hope to become mothers with the application of oocyte donation and IVF.
Here, the uterus is prepared for conception with estrogen / progesterone priming.
Once suitable oocytes are available, IVF is performed with the husband's sperm and
the embryos transfered to the recipient. 60 % pregnancy rates per cycle can be expected
with this technique.This technique is also of immense value to patients with repeated
IVF failures owing to poor ovarian reserve (low AMH or high FSH levels) as well
as poor or suboptimal egg quality leading to multiple IVF failures.
Therapeutic Insemination With Donor Sperm (TID)
Where finance is an issue, patients suffering from severe male factor infertility
who cannot afford ICSI or patients with primary testicular failure who do not have
sperm even with TESA can opt for donor sperm from a semen bank. This remains one
of the oldest ART methods known to mankind. The success rate of IUI using donor
sperm is 35% per cycle.
Embryo Donation
In the event of the wife being menopausal and the husband being azoospermic, the
infertile couple can still hope for a pregnancy with embryo donation. This helps
fulfil the biological desire of a woman to be a mother Vis a Vis adoption. It also
helps certain patients with repeated miscarriages or repeated IVF failures. The
success rate with embryo donation is 70% in the presence of a normal endometrium.
Surrogacy
In cases of end organ failure, such as for example uterine damage owing to genital
tuberculosis, the couple can hope to have their own genetic offspring by IVF with
transfer of the embryos to a surrogate mother who carries the child for nine months
and then hands over the baby to the biological parents. The success rate with own
eggs is 40% and with donor eggs is 70%. As per current government regulations, surrogacy
is only available for couples where both partners are Indian citizens. Currently,
the procedure is not available for OCI or PIO status individuals
Facts, Not Myths
Most cases of PCOD benefit with currently available ovulation inducing agents. IVF
remains a promising option for resistant cases of anovulatory infertility. Cases
of genital tuberculosis with tubal damage and a normal uterus are excellent candidates
for conception with IVF. Stage III and IV endometriosis patients are benefited with
IVF. Most cases of severe oligo or astheno- zoospermia can expect to have their
own biological child with ICSI.Azoospermic men with some sperm production in the
testes can hope to father their own child with PESA or TESA with ICSI Menopausal
women can expect to conceive with success rates on par with younger women with the
technique of oocyte donation and IVF.
Important Counselling After Cycle Failure
Please remember that success rates in the best IVF centers in the world are in the
range of 50% per started cycle. It is important for the patient to remember that
the cumulative success rate after 3 cycles of IVF is in the range of 80 %. This
is an important statistic that highlights the need to do repeated cycles.
Dr Jatin is always available for counselling after a failed cycle. It is important
to have this discussion to understand the gravity of the problem. Often, the first
cycle reveals problems of oocyte (egg quality) or fertilization failure, problems
with embryo development or the endometrial lining which need to be discussed and
solved.