Jaideep Malhtora1 and Diksha Goswami Sharma2
IVF and Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Global Rainbow Healthcare, Rainbow Hospitals, Rainbow IVF, NH-2 84, Mahatma Gandhi Road, Agra, Uttar Pradesh, 208010, India
IVF and Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Rainbow IVF, Global Rainbow Healthcare, Agra, Uttar Pradesh, India
It is important to consider the economics of ovarian stimulation in order to limit the cost of each ART cycle, which translates into reduced dropout rates and maximum cumulative pregnancy rates for the couple. Major cost of IVF cycle is attributable to the drugs for ovarian stimulation.
Various options to optimize the cost include intensive weight loss prior to stimulation, use of GnRH antagonist protocols, natural IVF and mild stimulation regimes. Use of urinary gonadotropins or human menopausal gonadotropins instead of recombinant products, lower starting dose of gonadotropins and correct choice of ovulation trigger will also cut down the cost of ovarian stimulation. A good understanding of the physiology of ovarian stimulation and finer aspects of the drugs used is imperative to make IVF more cost effective.
Direct and indirect costs of IVF cycleIndividualizing stimulationOptimizing costsRight protocolMild regimesGonadotropin preparationStarting dose gonadotropinsOvulation trigger
Approximately 15–20 % of married couples in the fertile age-group suffer from infertility, which is on the rise because of various reasons like urbanization, pollution, chemical exposure, stress, competitive work environment, fast-paced lifestyle, more women opting to work and increased incidence of diabetes and pelvic inflammatory disease (PID), etc. Today, an array of treatment options are readily available to treat infertility, and these include medications for ovulation induction, endoscopic surgery to correct anatomical problems and the assisted reproductive technologies (ARTs) including IUI, IVF and ICSI.
Despite the increasing demand for ART treatment, many patients withdraw from IVF treatment mainly for two reasons: poor prognosis and the inability to afford further treatment . Many patients withdraw from treatment or choose not to pursue treatment because of cost, especially in developing countries, where there is no insurance covering infertility treatment and they have to pay for their own treatment. It is therefore of growing importance to limit the cost of each treatment cycle and to maximize the chances of pregnancy for patients, as it is well known that the cumulative pregnancy rates in ART are much better.
The maximum cost in an ART cycle is attributable to the drugs for ovarian stimulation, which contribute approximately 60 % to overall cost. The conventional protocols aim at quantitative and qualitative factors in oocyte production and have a positive influence on the IVF outcome. Today when we are looking at the economics of ART, we aim at not only making ART affordable but at the same time not compromising with the quantity or quality of oocytes. As we do understand that the conventional ovarian stimulation protocols are expensive and also have been shown to have detrimental effects on the luteal phase, so there lies merit in looking at protocols that are easy on the pocket without affecting the outcome of pregnancy.
Costs associated with ART treatment can be characterized as indirect cost, those occurring as a consequence of ART treatment, and as direct cost, attributed to providing ART treatment itself,
18.2.1 Indirect Costs
Multiple-birth infants and the possibility of ovarian hyperstimulation syndrome (OHSS) resulting from ART need to be considered, as the patient's and the family's happiness or stress is directly related to the costs involved, especially in countries like India where there is no medical coverage for these expenses.
18.2.2 Direct Costs
The direct cost of ART mostly includes the cost of pre-investigations, the pre-preparation (downregulation) followed by the cost of drugs for ovarian stimulation (gonadotropins) or luteal support (progesterone), etc. all of which can lead to a high degree of expenditure to get the desired one live birth. Additional costs include that of medical consultation, laboratory and embryology services, ultrasound scanning, medical procedure such as oocyte retrieval and embryo transfer, hospital charges, nursing and counselling services and administrative and overhead charges.
Along with this, there could be additional cost of cryopreservation, laser-assisted hatching, IMSI, etc. According to the available evidence, there is a difference between cost and cost-effectiveness. And what one should be looking at is cost-effectiveness, which can depend on the following factors:
So calculating the cost-effectiveness may not be as simple as it appears because of the variation of the different components. However, to keep the discussion simple in this chapter, we will consider only the various ways of optimizing the cost of ovarian stimulation in ART.
A detailed analysis of different cost components per treatment cycle demonstrates that the hormonal stimulation stage is the most expensive part. This percentage could be higher if we consider older women who have increased cost per cycle than younger women, because of higher mean dosage of FSH needed during hormonal stimulation. Aim is to make IVF affordable by changing the stimulation protocol without affecting the pregnancy rates or affecting the luteal phase. Nowadays, individualizing the ovarian stimulation protocol is a more feasible approach, and individualizing in each group of women will help make it more affordable while reducing the complications and not compromising with the cryopreservation programme. Though such a situation is a win-win for all, it is difficult to achieve and will need a thorough understanding of the patient profile, type of treatment required, understanding the drugs being used for ovarian stimulation and adequate monitoring of the response of stimulation.
So the question is: How and what can be done to modulate the ovarian stimulation? To economize it when we know that in ART the ultimate justification is by live birth rate. We can consider using one protocol over the other, keeping in mind that a larger number of mature oocytes retrieved and high fertilization rates translate into more embryos for cryopreservation with ultimately increased cumulative pregnancy rate.
The options available too are many, but the trick lies in fitting the glove to the therapy. Let’s look at what can be done to optimize the costs.
18.3 Optimizing the Costs
18.3.1 Weight Loss
High BMI is associated with a higher FSH requirement during ovarian stimulation, fewer normally fertilized oocytes, lower oestradiol levels, frequent cycle cancellation and lower pregnancy and live birth rates. Infertile women requiring IVF should be encouraged to maintain a normal weight during treatment . Maintaining a certain amount of physical activity irrespective of weight loss should be highly recommended and it helps not only in improving the pregnancy outcome by threefold  but also cuts down the cost of stimulation.
18.3.2 Choosing the Right Protocol
18.104.22.168 Antagonist Protocol
Antagonist regime provides a more patient-friendly alternative with shorter and more cost-effective ovarian stimulation protocol compared to agonist . It has also been seen that the dropout rates have been much lesser with antagonist cycles than agonist.
GnRH antagonist protocol when compared with long agonist protocol is shorter, rapidly reversible and requires fewer injections and lesser amount of gonadotropins, which definitely makes it more patient friendly and that too at a lower cost. Despite initial studies about the pregnancy outcome being inferior to agonist protocol, more recent studies have indicated that there is not much difference as far as pregnancy rates are concerned and GnRH-antagonist regimen is as effective in preventing a premature rise of LH. Now the flexible dosing regimen is definitely showing promise amongst PCOS .
Also GnRH-antagonist protocol becomes a preferred protocol in cases at high risk of developing OHSS and is the protocol of choice for oocyte donation programme because it allows use of agonist trigger for the final maturation, further enabling reduction in OHSS without compromising on the oocyte quality.
22.214.171.124 Natural Cycle IVF
Natural cycle IVF is carried out without use of any drugs for ovarian stimulation. The first test tube baby Louise Brown was conceived with natural cycle. But the success rates of IVF dramatically increased only with the use of gonadotropins. Though it provides a cheaper alternative to patients who are ovulating spontaneously and may be indicated in patients with hormone-dependent tumours , they need to be counselled regarding the possibility of cancelled oocyte retrieval, fertilization failure and failure to reach embryo transfer . According to HFEA data, only 1/26 cycle in women less than 35 years opting for natural cycle IVF resulted in a live birth in the year 2008.
126.96.36.199 Minimal or Mild Stimulation Regimes
Minimal or mild stimulation regimes are designed to recruit a fewer number of eggs, thus avoiding the risks of hyperstimulation and reducing the number of injections also dramatically reduce the cost of medications . Frequently low-dose gonadotropins 75–100 IU are used or combined with oral agents like clomiphene with or without use of GnRH antagonist . Sample regime: low dose of clomiphene 50 mg is given without discontinuing the clomiphene after 5 days as is usually the custom but to continue the clomiphene until ultrasound monitoring shows the follicle size ready for ovulation and gonadotropins (150 IU of uFSH) are added on days 8, 10 and 12. Clomiphene not only stimulates the pituitary to release FSH but also blocks the oestrogen-stimulated release of LH so prolonged downregulation with lupride is not required. With this ‘mini- IVF’, though lesser number of oocytes are obtained, less oocyte and embryo aneuploidy is reported and the pregnancy rates are acceptable and similar to conventional protocols.
Mild treatment strategy for in vitro fertilization was shown in a randomized non-inferiority trial by Heijnen et al. to have much lower dropout rates: Mild cycle 5–11 % vs standard cycle 9–19 % and similar cumulative pregnancy with live birth at 1 year: mild: 43 % vs standard: 44 %. In this study, mean total cost of mild IVF was €8,333 while that of a standard IVF protocol was €10,745. Also these regimes drastically lower the multiple pregnancy rates and the associated indirect costs.
Milder stimulation protocols can be used for patients who are presumed high responders, normal responders as well as those with poor ovarian reserve  as an option to reduce the cost of stimulation.
In both natural or minimal stimulation protocol, cost is reduced because of
· Fewer office visits
· Less need for monitoring
· Decreased risk of multiple birth
· Possible avoidance of anaesthesia during oocyte retrieval
18.3.3 Type of Gonadotropin Preparation
188.8.131.52 Urinary Gonadotropins
Recombinant FSHs have a higher cost compared with urinary gonadotropins. Initially, a lot of studies were carried out to also prove the superiority in safety, purity and effectiveness of recombinant products when compared with urinary gonadotropins . None of these studies focussed on the cost which is an equally important issue especially in the developing countries. Currently there is no clear evidence of the superiority of r-FSH over urinary gonadotropins in effectiveness . There are number of meta-analyses which suggest that recombinant products may be more costly without much difference in the pregnancy rates, live birth rates and complication rates. Baker et al. compared the efficacy of highly purified hFSH (HP-hFSH) versus rFSH in volunteers undergoing controlled ovarian stimulation for IVF , and in this report the authors concluded that there were no statistically significant differences in live birth rate between HP-hFSH and rFSH treatment groups (38.2 % in each group) but there is a lot of difference in the cost.
184.108.40.206 Human Menopausal Gonadotropins
Use of human menopausal gonadotropins (HMGs) instead of recombinant gonadotropins has never gone out of the prescription of ART practitioners for the simple reason that there are certain groups of patients who would actually do well with the HMG due to the addition of LH. Even for other patients also currently, there is no clear evidence of the superiority of rFSH over HMG in effectiveness. In terms of clinical efficacy, there are a number of meta-analyses demonstrating no significant difference in clinical/ongoing pregnancy/live birth rate, miscarriage rate, multiple pregnancy rate and incidence of ovarian hyperstimulation syndrome between rFSH and hMG  and between rFSH and hFSH . A study by Wes-Wechowski et al. published in 2010  analyzing the economic implications of choice of gonadotropin on IVF cycles including fresh and up to two fresh or frozen cycles, conditional on the availability of cryopreserved embryos, demonstrated not only a superior cumulative live birth rate for HP-HMG compared with rFSH but also showed that the mean costs per IVF treatment were significantly less for HP-HMG. When maternal and neonatal costs were applied, the median cost per IVF baby delivered was still significantly less with HP-HMG. This cost saving from using HP-HMG depicted in this model would allow an additional treatment cycle for every seven patients treated .
18.3.4 Starting Dose of Gonadotropins
The optimal starting dose of FSH for controlled ovarian stimulation is an important issue in IVF cycles since drugs contribute a major part to the cost involved. Already having discussed the type of gonadotropins, the dosage used can also have major implications for the economics.
For a conventional IVF cycle, the starting dose can vary from 100 IU to 450 IU depending on the assessment of expected response. The decision of what dose to start with is also influenced by whether minimal or large number of oocytes are considered a success. With the legal restriction in some European countries on number of oocytes that can be inseminated, a balance has to be drawn between the number of oocytes and the cost of drugs with minimal wastage of both, hereas Oliviennes et al. in the CONSORT study  have suggested an FSH dosage normogram based on age, basal FSH levels, BMI and antral follicle count where dose adaptations, ranged from 75 up to 225 IU/day, revealed that in 30 % of patients, a dose of 100 IU/day or less is sufficient to obtain moderate oocyte numbers with high pregnancy rates.
There is still no universal consensus regarding the optimal starting dose of FSH in presumed normal responders. A recent meta-analysis of ten studies by Sterrenburg et al.  has suggested that the optimal starting dose of rFSH for IVF/ICSI is 150 IU daily in young normal responders. This dose was associated with a more modest oocyte yield but an equal pregnancy rate compared with higher doses.
This study demonstrates that though the average number of oocytes retrieved per pickup is increased when FSH doses over 100 IU/day are given, there is no difference in the pregnancy rates. Moreover, the number of frozen embryos and cumulative pregnancy rates does not improve with dosages exceeding 150 IU/day. The use of a standard lower dose of 150 IU/day, instead of 225 IU/day, would reduce per-cycle costs of gonadotropin medication by 30 % with added decline in the risk for OHSS and reducing the need for intense monitoring of ovarian response. At the other end of the spectrum, no difference was seen in the number of oocytes obtained or pregnancy rate in poor responders on doubling the starting dose of rec FSH from 150 to 300 IU .
18.3.5 Trigger for Ovulation: hCG or GnRH Agonist?
Controversy regarding trigger for final oocyte maturation has been going on; however, one must realize that the trigger for final oocyte maturation can vary from urinary HCG to recombinant HCG and to agonist trigger. This individualization should come after analyzing the stimulation. Urinary HCG has a longer half-life and may not be suitable for hyperstimulated ovaries. Reducing the dose can affect the number of oocytes retrieved and still may not reduce the incidence of delayed ovarian hyperstimulation. Triggering with recombinant HCG as compared to urinary HCG is costly.
Triggering of final oocyte maturation with a single bolus of low-cost GnRH agonist (GnRHa) Lupride 1 mg or Decapeptyl 0.1 mg as an alternative to hCG is a viable option with the introduction of GnRH antagonist protocols. However, GnRH agonist-induced LH surge lasts for shorter duration of 24–36 h. And first reports from prospective RCTs subsequently showed a very poor clinical outcome when GnRH agonist was used to trigger final oocyte maturation, due to a deficient luteal phase [19–21].
But in oocyte donation programmes, GnRHa triggering has been successfully applied with pregnancy rates similar to hCG triggering in recipients and additional advantage of no OHSS in the donors . The largest study of 2,077 stimulated donor cycles in 1,171 egg donors reported an incidence of 1.26 % of moderate or severe OHSS in the rhCG group compared with no cases in the GnRHa group .
In case of high reponders, hCG triggering had a 3.79 times greater risk of developing any form of OHSS and a 1.35 times greater risk of developing moderate to severe OHSS when compared to GnRH agonist . Still, controversy exists in literature regarding the pregnancy outcome in GnRH agonist-triggered cycles and the best luteal phase support. Good live birth rates are reported in frozen thawed embryo replacement cycles in which embryos were derived from GnRHa-triggered cycles . Also more mature oocytes (4 %) in the GnRHa-triggered group supported previous clinical findings of a possible beneficial effect of the midcycle FSH surge .
Triggering with urinary hCG 5,000 IU as compared to standard dose of 10,000 IU reduces the risk of OHSS without impairing the clinical outcome in terms of oocyte retrieval rate, egg quality and fertilization rate [26, 27]. Thus the indirect cost because of OHSS and related hospitalization and procedures is reduced. Cornell low-dose protocol has been suggested which determines hCG dosage according to serum E2 levels on the day of hCG administration using sliding scale between 5,000 and 3,300 IU of hCG administered to women with E2 levels of 2,000–3,000 pg/mL . Significant reductions in early OHSS (occurring before ET; P < .001) and severe OHSS (post-ET, requiring hospitalization; P < .05) have been reported with this low-dose hCG protocol .
In patients undergoing IVF, urinary hCG still remains a feasible and cost-effective outcome compared to recombinant hCG as supported by the Cochrane database. Cochrane review by Mohamed AFM Youssef et al. concludes that there is no evidence of difference between rhCG or rhLH and uhCG in achieving final follicular maturation in IVF, with equivalent pregnancy rates and OHSS incidence . According to these findings, uhCG is still the best choice for final oocyte maturation triggering in IVF and treatment cycles.
To conclude, considering the pharmacoeconomics of ovarian stimulation protocol in ART cycles can have long-term economic implications and also can have impact on the number of cycles the patient tries to achieve a live birth. However, due understanding of the patient profile and the drugs available along with type of infertility treatment required will play a major role in this decision-making, and we strongly feel that this should be encouraged.
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