This report explores the current role of in vitro fertilization (IVF) in the management of infertility. The inquiry on IVF was initiated by the Infertility Awareness Association of Canada, which requested a reconsideration of the present funding policy for IVF. According to this association, broader coverage of IVF with a restricted number of embryos transferred in IVF cycles would bring substantial overall cost savings owing to avoidance of multiple pregnancies. The request for reconsideration from this association was approved for further investigation by the Provider Services Branch, Ministry of Health and Long-Term Care, and the Ontario Health Technology Advisory Committee. Specifically, the Medical Advisory Secretariat was asked to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.

Typically defined as a failure to conceive after one year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Main causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). Assisted reproductive technologies include IVF and IVF-related procedures such as intracytoplasmic sperm injection (ICSI) and, according to some definitions, intrauterine insemination (IUI).

Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART than after natural conception. Multiple pregnancies are associated with negative consequences for mother and fetus. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios (an excess of amniotic fluid), gestational diabetes, fetal malpresentation requiring Caesarian section, postpartum hemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of dying early, being born prematurely, and having low birth weight, as well as having mental and physical disabilities related to prematurity. Increased maternal and fetal morbidities lead to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.

In vitro fertilization was first developed as a method to overcome bilateral fallopian tube obstruction. The procedure includes several steps:

• The woman’s egg is retrieved from the ovaries.
• The egg is exposed to sperm outside the body and is fertilized.
• The embryo is cultured for 3 to 5 days.
• The fertilized egg is transferred back to the uterus.

In vitro fertilization is considered to be one of the most effective treatments for infertility. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after an IVF cycle in Canada is around 30%, but there is considerable variation by woman’s age, primary diagnosis, and individual clinical centre.

An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer (eSET) in IVF cycles adopted in many European countries was shown to reduce significantly the risk of multiple pregnancies while maintaining acceptable birth rates. However, when the number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF cycles is often a result of pressure to increase success rates because the cost of the procedure is high. The average rate of multiple pregnancies resulting from IVF in Canada is around 30%. 

An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%), IUI is generally attempted before IVF because of its lower invasiveness and cost. Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it allows little control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.

Diffusion of Technology

According to Canadian Assisted Reproductive Technology Registry data, in 2004, 25 infertility clinics across Canada offered IVF, and 7,619 IVF cycles were performed. In Ontario in 2004, there were 13 infertility clinics with about 4,300 IVF cycles performed annually.

In Ontario, the Ontario Health Insurance Plan (OHIP) covers the cost of IVF only for women with bilaterally blocked fallopian tubes, in which case IVF is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered, except for costs pertaining to preparation of the sperm and drugs used for COS.

The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario. Prior to 1994, IVF was fully funded. Recommendations of the commission to withdraw IVF funding were largely based on findings of a systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF was effective only in cases of bilateral tubal obstruction. Insufficient evidence existed to establish whether or not IVF was effective for nontubal causes of infertility.

Because the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include increased success rates of IVF, introduction of ICSI in the early 1990s as a treatment for male factor infertility, and improved embryo implantation rates that allow transfer of a single embryo to avoid multiple pregnancy after IVF. Therefore, the Medical Advisory Secretariat searched for articles published since the release of this report, the findings from which form the basis of this health technology policy assessment.

The Medical Advisory Secretariat searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library, the International Agency for Health Technology Assessment database, and Web sites of other health technology assessment agencies using specific subject headings and keywords to identify relevant studies.

Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.

• Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, in which the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility
• Cost-effectiveness  of IVF: All relevant economic studies comparing IVF to alternative methods of treatment
• Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos

Overall, there is a lack of good RCTs in this area. Moreover, there is a considerable diversity in definition and measurement of outcomes between existing trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (for example, rates were calculated per cycle started, per cycle completed, per couple, etc.).

Nevertheless, a few studies of sufficient quality were identified that were categorized by the cause of infertility and included existing alternatives to IVF. Following are the key findings from these studies:

• A 2005 meta-analysis showed that in patients with idiopathic infertility IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, or between IVF and gamete intrafallopian transfer.
• For patients with moderate male factor infertility, standard IVF was compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI. The pooled risk ratio for oocyte fertilization was 1.9 (95% confidence interval, 1.4–2.5) in favour of ICSI. Two other RCTs concerning moderate male factor infertility published after the 2002 meta-analysis had similar results to the 2002 meta-analysis and further confirmed these findings. No RCTs compared IVF with ICSI in patients with severe male factor infertility; this is because, based on mainly expert opinion, ICSI might be the only effective treatment for severe male factor infertility.
• A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.

Five economic evaluations of IVF were found, including a comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, and varicocelectomy (the surgical removal or ligation of varicose veins in the scrotum). The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that, due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in most cases. The only exceptions were bilateral tubal obstruction and severe male factor infertility, for which an immediate offer of IVF/ICSI might the most cost-effective option.

Since SET strategy is more widely adopted in Europe, all RCTs on outcomes of SET were conducted in European countries. The major study in this area was a large meta-analysis done in 2005.  Two other RCTs were published later.  

All of these studies reached similar conclusions:

• Although a single cycle of SET (single SET cycle) results in lower birth rates than a single cycle of double embryo transfer (single DET cycle), the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (about 40%). 
• SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1%, respectively, in the largest RCT).

Most trials on SET included women aged younger than 36 years with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to women aged older than 36 years.

Based on results of the literature review and consultations with experts, 4 categories of infertile patients who may benefit from additional IVF/ICSI coverage were identified. They include the following:

• patients with severe male factor infertility, for whom IVF should be offered in conjunction with ICSI;
• infertile females with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET; 
• infertile patients who want to avoid the risk of multiple pregnancy and therefore choose IVF-SET; and
• patients who failed treatment with IUI and wish to try IVF.

However, since the last indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered.

Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent across studies. Some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies. Other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.

An Ontario-based economic analysis compared cost per birth using 3 treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed 3 cycles for each treatment option. Two IVF scenarios were considered: all 3 cycles with fresh embryos; and a combination of fresh and frozen embryos throughout cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancy (only short-term complications), IVF-SET was associated with the highest cost per birth. The approximate budget impact to cover the first 3 indications listed above for IVF (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of a multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of ICSI in patients with severe male factor infertility and for infertile females with serious medical contraindications to multiple pregnancy is a combined estimate of $3.8 to $5.5 million (Cdn).

• International data shows that both IVF utilization and average number of embryos transferred in IVF cycle are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by the government.
• Surveys of patients with infertility demonstrated that a significant proportion (about 40%) do not mind having multiple babies and consider twins to be an ideal outcome of infertility treatment.
• A woman’s age may impose some restrictions on the implementation of a SET strategy.

• A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
• However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancy after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
• In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.