Low Cost IVF Presentation

Dr. Laxmi Shrikhande MD; FICOG; FICMU;FICMCH
• Medical Director-Shrikhande Fertility Clinic, Nagpur
• National Corresponding Editor-The Journal of Obstetrics & Gynecology of India
• Senior Vice President FOGSI 2012
• Chairperson Designate ICOG 2020 , Vice Chairperson ICOG 2019
• National Governing Council member ICOG 2012-2017
• National Governing Council Member ISAR 2014-2019
• National Governing Council Member IAGE for 3 terms
• Patron & President -Vidarbha Chapter ISOPARB
• Chairperson-HIV/AIDS Committee, FOGSI (2007-09)
• Received Best Committee Award of FOGSI
• Received Bharat excellence Award for women’s health
• President Nagpur OB/GY Society 2005-06
• Immediate Past President Menopause Society, Nagpur
• Associate member of RCOG
• Member of European Society of Human Reproduction
• Visited 96 FOGSI Societies as invited faculty
• Delivered 11 orations and 450 guest lectures
• Publications-Twenty National & eleven International
• Received Nagpur Ratan Award at the hands of Union Minister Shri Nitinji Gadkari
• Presented Papers in FIGO, AICOG, SAFOG, AICC-RCOG conferences
• Conducted adolescent health programme for more than 15,000 adolescent girls
• Conducted health awareness programme for more than 10,000 women

Low Cost IVF
DR LAXMI SHRIKHANDE
NAGPUR

Subfertility as a global health issue
Subfertility has been overlooked as a global health issue, despite
affecting one in seven couples.
27.5 million couples in India suffer from infertility

Introduction
Since the first test tube baby was born in the year 1978, IVF treatment has been
developed and improved to benefit millions of people who experience
childlessness.
It is estimated that the number of IVF infants in the world has now surpassed
five million. However, there are still many people who are unable to gain access
to this form of treatment.
Reasons are many but mainly it is financial constraint
Many developed countries has a system in place whereby either The Govt bears
the full cost or partial cost
International Journal of Women’s Health August 2014

ART is self financed
In India ART is self financed.
Cost is a major deterrent to couples seeking infertility
treatment.
This is highlighted by the fact that three quarters of
Indian couples decline IVF treatment after first
consultation
Even in the developed world, individual couples find
it difficult to access ART facilities they have to bear
the cost

Unique problems of
developing countries
Health policy makers in developing countries are
confronted by major health problems such as high
maternal mortality, malnutrition and infectious
diseases & hence they find it difficult to give ART
the attention it deserves
A high population growth rate is often used as an
argument to disregard the problems of infertility
as they have to focus on family planning
programmes.

Affordable ART care
The focus of infertility care in developing countries is mainly on
prevention and provision of basic treatment options.
Although expensive, one cannot deny the fact that advanced
technology is required in many clinical situations and is also perhaps
the most successful.
While a great deal has been written about the need for providing
affordable ART care in developing countries, this has not been
translated into actual deeds

Infertile couples sorrows
In the developing world, marriage is almost universal and often occurs at an
early age with the ultimate goal of having a child .
Couples bearing the burden of infertility are subjected to social stigma,
community isolation and harassment from family members, to the extent of
even being excluded from inheritance rights
Without an established social security system, infertile couples are economically
vulnerable in their old age.
In certain cultures, children play an important role in the rituals related to their
parent’s death.
The awareness that they would be deprived of this privilege adds to the infertile
couple’s sorrows and unease.

Women are at the receiving end
Almost always, women tend to be blamed for the situation and they
live in fear of physical abuse, divorce or the embarrassment of the
husband opting for a second marriage or indulging in an extramarital
affair
Psychological distress is also significantly more common, especially
in women subjected to physical trauma, in comparison to their fertile
counterparts

Men also face the stigma
Although women bear the brunt of the social stigma, men are not
unaffected and live in fear of being labelled sexually impotent, often
resulting in a reluctance to come forward for investigations or treatment
Subjected to scorn and ridicule, men often divert their anger and
frustration onto the spouse.
The need to hide their inadequacy often makes adoption an unacceptable
choice and provided secrecy is maintained, makes them amenable to
donor programmes

Public Health issue
As infertility is not a life threatening issue, policy-makers tend to
push it down the priority list.
However, a couple’s reproductive autonomy needs to be respected
and in terms of quality of life; infertility needs to be considered a
public health problem of high priority and provision of affordable
medical facilities is essential.
 In some societies, inability to fulfil the dreams of having children
together with the social stigma associated with infertility makes life
unbearable for the infertile couple.

WHO 2001
In 2001, the World Health Organization organized a meeting entitled “Medical,
Ethical and Social Aspects of Assisted Reproduction”.
Recommendations stated in the meeting include the following:
1) infertility should be recognized as a public health issue worldwide, including
in developing countries;
2) policy makers and health staff should give attention to infertility and the
needs of infertile patients;
3) infertility management should be integrated into national reproductive
health education programs and services; and
4) assisted reproduction treatment should be complementary to other ethically
acceptable social and cultural solutions to infertility.

Suggested strategies to reduce the cost of
IVF treatment
Simplifying investigative methods
Reducing the cost of ovarian
stimulation
Simplifying procedures and
equipment in the laboratory
Minimizing the complications of
IVF

Simplifying investigative methods

inexpensive baseline investigations, along with an adequate medical
history
Avoid duplicate and unnecessary investigations
The reliability of manual semen analysis has not been surpassed by
the more expensive computer-aided sperm analysis system.
Menkveld R, Wong WY, Lombard CJ, et al. Semen parameters, including WHO and strict criteria morphology, in a fertile
and subfertile population: an effort towards standardization of in-vivo thresholds. Hum Reprod. 2001;16(6):1165–1171.
Gunalp S, Onculoglu C, Gurgan T, Kruger TF, Lombard CJ. A study of semen parameters with emphasis on sperm
morphology in a fertile population: an attempt to develop clinical thresholds. Hum Reprod. 2001;16(1):110–114.

Although assessment of pelvic anatomy and ovarian reserve by
antral follicle count (AFC) requires an ultrasound scan machine with
adequate resolution, advanced digital function or three-dimensional
imaging is not necessary and has not been shown to provide any
advantage.
Jayaprakasan K, Hilwah N, Kendall NR, et al. Does 3D ultrasound offer any advantage in the pretreatment assessment of
ovarian reserve and prediction of outcome after assisted reproduction treatment? Hum Reprod. 2007;22(7):1932–1941.

Hysteroscopy may be necessary to investigate and treat submucosal
fibroids, polyps, septa, and intrauterine adhesions for patients
suspected to have these intrauterine abnormalities.
These procedures are more expensive but are typically performed as
day cases to avoid the expenditure of inpatient hospital stay.
With the invention of office endoscopic instruments and techniques,
some of the procedures can now be performed safely using an
ambulatory approach in “one-stop subfertility clinics”

To keep the cost of fertility investigations down, the levels of either
AMH or AFC alone, but not both, are sufficient for determining the
individualized protocols for ovarian stimulation for most patients.

Reducing the cost of ovarian stimulation

Reducing the cost of ovarian stimulation
The price of medications used for pituitary downregulation and
ovarian stimulation is a major contributing factor to the high cost of
IVF treatment.
The clinical and cost effectiveness of various IVF protocols has been
researched.
Recently, there has been some renewed interest in natural cycle and
mild ovarian stimulation IVF protocols.

Natural cycle IVF
no ovarian stimulatory drugs are administered.
HCG trigger is given when the follicle matures, reaching the size of
15–20 mm, or when serum estradiol level rises.
OPU is done under conscious sedation
With the avoidance of expensive drugs, natural cycle IVF is
considered a cost-effective alternative to conventional IVF
techniques.
Allersma T, Farquhar C, Cantineau AE. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane
Database Syst Rev. 2013;8:CD010550.
Nargund G, Waterstone J, Bland J, Philips Z, Parsons J, Campbell S. Cumulative conception and live birth rates in
natural (unstimulated) IVF cycles. Hum Reprod. 2001;16(2):259–262.

Natural Cycle IVF
The major issue with natural cycle IVF is its high cancellation rates
due to premature luteinizing hormone (LH) rise and ovulation; thus
overall, the current evidence does not favor natural cycle IVF.
Ingerslev HJ, Højgaard A, Hindkjaer J, Kesmodel U. A randomized study comparing IVF in the unstimulated cycle with IVF
following clomiphene citrate. Hum Reprod. 2001;16(4):696–702.
MacDougall MJ, Tan SL, Hall V, Balen A, Mason BA, Jacobs HS. Comparison of natural with clomiphene citrate-stimulated
cycles in in vitro fertilization: a prospective, randomized trial. Fertil Steril. 1994;61(6):1052–1057
Pelinck MJ, Hoek A, Simons AH, Heineman MJ. Efficacy of natural cycle IVF: a review of the literature. Hum Reprod
Update. 2002;8(2):129–139.

Mild ovarian stimulation protocol
a short stimulation period of 2–6 days during the mid-to-late
stimulation phase is introduced using FSH, combined with a GnRH
antagonist at approximately the same time.
 This method allows undisturbed recruitment of a cohort of follicles
during the early follicular phase in the IVF treatment cycle, reducing
the dose of FSH needed for ovarian stimulation.
The treatment also reduces the cancellation rates seen in natural
cycle IVF due to premature LH rises and ovulation.
Verberg MF, Macklon NS, Nargund G, et al. Mild ovarian stimulation for IVF. Hum Reprod Update. 2009;15(1):13–29

Oocyte quality in mild stimulation
It has been suggested that although mild ovarian stimulation results
in a lower oocytes yield, the oocytes retrieved are of a better quality.
In a randomized trial, it was discovered that a significantly higher
proportion of euploid embryos are formed using the mild stimulation
approach as compared with conventional stimulation.
Baart EB, Martini E, Eijkemans MJ, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human
preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22(4):980–988.

CC in IVF
Edwards and Steptoe tried and then largely abandoned but others have continued to
demonstrate that it can be a cost-effective way to achieve full-term IVF pregnancies.
 The advantages include oral administration, low price, and widespread availability
 CC can be used as a sole stimulatory medication in mild ovarian stimulation IVF.
 the clinical pregnancy rate in IVF stimulation by CC is superior to natural cycle IVF.
The major disadvantage of clomiphene is its antiestrogenic effect on the endometrium,
which may adversely affect the receptivity for embryo implantation.
Amita M, Takahashi T, Tsutsumi S, et al. Molecular mechanism of the inhibition of estradiol-induced endometrial epithelial cell
proliferation by clomiphene citrate. Endocrinology. 2010;151(1):394–405.
Siristatidis C, Trivella M, Chrelias C, Sioulas VD, Vrachnis N, Kassanos D. A short narrative review of the feasibility of adopting mild
ovarian stimulation for IVF as the current standard of care. Arch Gynecol Obstet. 2012;286(2):505–510.

CC in IVF
Clomiphene may be combined with exogenous gonadotropins, with or without
GnRH antagonists, to prevent a spontaneous LH surge.
 This practice reduces the total number of ampoules of gonadotropins needed,
thus lowering the cost of treatment.
Lin YH, Hwang JL, Seow KM, Huang LW, Hsieh BC, Tzeng CR. Comparison of outcome of clomiphene citrate/human menopausal
gonadotropin/cetrorelix protocol and buserelin long protocol – a randomized study. Gynecol Endocrinol. 2006;22(6):297–302.
Weigert M, Krischker U, Pöhl M, Poschalko G, Kindermann C, Feichtinger W. Comparison of stimulation with clomiphene citrate in
combination with recombinant follicle-stimulating hormone and recombinant luteinizing hormone to stimulation with a gonadotropin-
releasing hormone agonist protocol: a prospective, randomized study. Fertil Steril. 2002;78(1):34–39.
Gibreel A, Maheshwari A, Bhattacharya S. Clomiphene citrate in combination with gonadotropins for controlled ovarian stimulation in
women undergoing in vitro fertilization. Cochrane Database Syst Rev. 2012;11:CD008528.

CC in IVF
Several studies have reported that this option does not affect the pregnancy
rates of IVF treatment; however, one study indicated that CC and gonadotropin
results in a higher cancellation rate and lowers the ongoing pregnancy rate.
 Although more studies are needed to confirm the clinical and cost effectiveness
of using clomiphene with or without gonadotropins and GnRH antagonists,
overall, these are attractive methods for reducing the cost of IVF treatment.
Lin YH, Hwang JL, Seow KM, Huang LW, Hsieh BC, Tzeng CR. Comparison of outcome of clomiphene citrate/human menopausal
gonadotropin/cetrorelix protocol and buserelin long protocol – a randomized study. Gynecol Endocrinol. 2006;22(6):297–302.
Weigert M, Krischker U, Pöhl M, Poschalko G, Kindermann C, Feichtinger W. Comparison of stimulation with clomiphene citrate in
combination with recombinant follicle-stimulating hormone and recombinant luteinizing hormone to stimulation with a gonadotropin-
releasing hormone agonist protocol: a prospective, randomized study. Fertil Steril. 2002;78(1):34–39.
Gibreel A, Maheshwari A, Bhattacharya S. Clomiphene citrate in combination with gonadotropins for controlled ovarian stimulation in
women undergoing in vitro fertilization. Cochrane Database Syst Rev. 2012;11:CD008528.

CC Stimulation protocol
CC 50 mg daily drom D2 of the cycle and continued till the day of hCG trigger.
Urinary gonadotrophin 150 IU IM was started from Day 5 and given on alternate days.
 Follicular monitoring was initiated on Day 8.
Oocyte retrieval was planned when at least two follicles of greater than 18 mm were seen on
ultrasound and was carried out 35 h after Inj. hCG 5000 IU (Intramuscular) administration.
Oocyte retrieval was performed as a day care procedure under conscious sedation.
Patients were discharged the same day after starting luteal support in the form of micronized
progesterone 400 mg twice a day, administered vaginally.
No biochemical monitoring was performed during controlled ovarian hyperstimulation (COH).
Cycles with single follicle development were either cancelled or converted to an intrauterine
insemination cycle provided tubal patency had been documented earlier.
Human Reproduction, Vol.26, No.12 pp. 3312–3318, 2011

Letrozole in IVF
Aromatase inhibitors can be used for the same purpose as clomiphene.
 have an additional advantage of not causing depletion of estrogen receptors.
There are few reports of trials involving aromatase inhibitors, with most of them
combining letrozole with gonadotropins for ovarian stimulation.
One uncontrolled study favored aromatase inhibitors as effective and
inexpensive treatment alternatives; the study reported an ongoing pregnancy
rate of 27% following treatment using letrozole and a reduced amount of HMG.
Garcia-Velasco JA, Moreno L, Pacheco A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian
androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril. 2005;84(1):82–87.
Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for controlled ovarian stimulation in women
with unexplained infertility. Hum Reprod. 2003;18(8):1588–1597.
Grabia A, Papier S, Pesce R, Mlayes L, Kopelman S, Sueldo C. Preliminary experience with a low-cost stimulation protocol that
includes letrozole and HMG in normal responders for assisted reproductive technologies. Fertil Steril. 2006;86(4):1026–1028.

Letrozole in IVF
Another study reported that the addition of letrozole to recombinant FSH increased the oocytes
yield and resulted in a tendency towards higher clinical pregnancy rates; however, in this study,
the dose of FSH was the same between the groups compared, and thus no cost saving was
made.
In patients with poor prognosis, the addition of aromatase inhibitors does not improve
outcomes.
At present, more information on cumulative clinical effectiveness and cost effectiveness is
needed to confirm the efficacy of this IVF treatment regimen. In summary, it seems
appropriate to use aromatase inhibitors in a limited resource setting if they reduce the cost of
the treatment.
Verpoest WM, Kolibianakis E, Papanikolaou E, Smitz J, Van Steirteghem A, Devroey P. Aromatase inhibitors in ovarian stimulation
for IVF/ICSI: a pilot study. Reprod Biomed Online. 2006;13(2):166–172.
Goswami SK, Das T, Chattopadhyay R, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in
women with poor ovarian response: a preliminary report. Hum Reprod. 2004;19(9):2031–2035.

Simplifying procedures and equipment in
the laboratory

Over the years, the laboratorial procedures in IVF treatment have become
increasingly complex. Additional interventions have been supplemented in IVF
laboratories; not all of them are proven to be beneficial.
ICSI / IMSI
PGS / PGD
Embryoscope
Laser hatching
However, one has to acknowledge that the cost of IVF treatment may be
substantially increased with any additional laboratory intervention

Closed culture system
Recently, there was a breakthrough by researchers in Belgium.
The team developed a closed culture system using an inexpensive, disposable 10 mL
plain glass vacutainer.
With the single-tube method, the researchers could adequately visualize oocytes,
pronuclear eggs, and preimplantation embryos to the hatched blastocyst stage.
 This setup enables stage and performance assessments of sufficient detail to select
single embryos for transfer
The preliminary result indicates that good live birth rates and tremendous cost savings
can be achieved by adapting to this laboratory technique. The system has the
disadvantage that it is currently not suitable for ICSI.
Van Blerkom J, Ombelet W, Klerkx E, et al. First births with a simplified culture system for clinical IVF and embryo transfer.
Reprod Biomed Online. 2014;28(3):310–320.

Invocell
There have been reports of intravaginal
fertilization and incubation of oocytes and
sperms.
 This technique has not been widely
accepted and adopted.
Taymor ML, Ranoux CJ, Gross GL. Natural oocyte retrieval with intravaginal
fertilization: a simplified approach to in vitro fertilization. Obstet Gynecol.
1992;80(5):888–891.

INVO cell
Cost-effective innovations like the INVO cell in
which the gametes and later embryos are placed
in the device and deposited in the maternal
vagina, thus eliminating the need for a complex
ART laboratory, report similar clinical pregnancy
rates of 19% per cycle (Frydman and Ranoux,
2008).
These methods are potentially useful in low
resource settings in developing countries, where
establishing and sustaining a full fledged ART
laboratory would be an expensive proposition.

IVF Lab conditions
The ‘lab air quality’, a vital invisible factor of an IVF set up, should
not be compromised at any stage.
Nevertheless a few cost cutting measures has to be taken like
careful use of disposals, no review on Day 2 and early transfer of
embryos on Day 3.

Minimizing the complications of IVF

In a competitive world, IVF centers are increasingly focused on
staying at the top of the league tables of success rates;
patients often choose the centers with the best success rates
without paying much attention to other factors like the rates of the
two most common complications,
which are OHSS and multiple pregnancies.
Alper MM, Brinsden PR, Fischer R, Wikland M. Is your IVF programme good? Hum Reprod. 2002;17(1):8–10.
Lass A, Brinsden P. How do patients choose private in vitro fertilization treatment? A customer survey in a tertiary
fertility center in the United Kingdom. Fertil Steril. 2001;75(5):893–897.

eSET
The practice of elective single embryo transfer has been shown to
drastically reduce the incidence of IVF multiple pregnancies and the
associated complications.
Ombelet W, Cooke I, Dyer S, Serour G, Devroey P. Infertility and the provision of infertility medical services in developing
countries. Hum Reprod Update. 2008;14(6):605–621.
McLernon DJ, Harrild K, Bergh C, et al. Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of
individual patient data from randomised trials. BMJ. 2010;341:c6945.

Mild vs conventional
recent meta-analyses failed to reveal any differences in cumulative live births,
OHSS, or ongoing pregnancy.
Due to the heterogeneity of the trials involved, the clinical superiority or
inferiority of one approach over the other could not be concluded.
Although in each cycle the amount of drugs administered using the mild
stimulation protocol is considerably less, the patients may need to undergo
more treatment cycles due to the lower pregnancy rate per cycle of treatment.
Allersma T, Farquhar C, Cantineau AE. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database Syst
Rev. 2013;8:CD010550
Groen H, Tonch N, Simons AH, van der Veen F, Hoek A, Land JA. Modified natural cycle versus controlled ovarian hyperstimulation IVF:
a cost-effectiveness evaluation of three simulated treatment scenarios. Hum Reprod. 2013;28(12):3236–3246.

Mild vs conventional
Per IVF cycle in the mild stimulation approach, there are lower pregnancy rates;
due to the fewer number of embryos retrieved, the number available for
cryopreservation is usually small. This method also requires excellent laboratory
performance, as the margin for error and subpar performance is lower.
One recent retrospective study found that the mild stimulation cycle was less
cost effective and had a lower cumulative live birth rate in comparison with
conventional IVF.
In summary, when appropriate clinical expertise and laboratory resources are
available, there may be a place for mild ovarian stimulation IVF for selected
patients.
Allersma T, Farquhar C, Cantineau AE. Natural cycle in vitro fertilisation (IVF) for subfertile couples. Cochrane Database Syst
Rev. 2013;8:CD010550

Summary
High cost involved in establishing and maintaining a good ART
laboratory, the constant need to upgrade and adopt new technology
and the use of stimulation protocols that use expensive drugs, makes
ART treatment expensive.
With most ART centres being in the private sector and with non-
existent insurance cover, IVF as a treatment option becomes
unaffordable for the majority

Summary
The concept of affordable ART was developed in an attempt to make
available these services at a reasonable cost.
Low cost should not in any way imply a compromise on quality.
Use of minimal stimulation protocols, an emphasis on clinical
judgment, eliminating superfluous investigations and use of well
thought-out laboratory protocols would help in limiting costs,
without compromising quality.
An optimally functioning laboratory is a prerequisite to ensure good
results.
Human Reproduction, Vol.26, No.12 pp. 3312–3318, 2011

Conclusion
A government sponsored insurance programme for low cost
infertility treatment involving selected private institutions would be
the ideal answer to making available ART facilities all over the
country.
This public-private sector partnership would eliminate the cost of
setting up and maintaining an ART laboratory and limit the public
funding required for actual costs of treatment.
However considerable political will and determination will be
required to make this feasible

Dr. Laxmi Shrikhande
Shrikhande Fertility Clinic
Ph-8805577600 /8805677600
shrikhandedrlaxmi@gmail.com

The Art of Living
Anything that
helps you to
become
unconditionally
happy and loving
is what is called
spirituality.
H. H. Sri Sri Ravishakar

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