Access to IVF with Reduced Multiple Birth Risks

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A Public Health Strategy for Assisted Reproduction in Canada

Beverly Hanck
Executive Director

Katharina Böcker
Executive Assistant

Infertility Awareness Association of Canada
Association canadienne de sensibilisation à l’infertilité 

Montreal, Quebec
August 30, 2005

SUMMARY

Canada has experienced a steady decline in the national birth rate for many years. At the same time, infertility has risen and now affects 10% to 20% of the population. Today increasing numbers of Canadians are seeking infertility evaluation and treatment. 

This paper sets out the rationale for government funding of in vitro fertilization (IVF) and other assisted reproductive technologies (ART) in Canada and includes an economic analysis to support the authors’ recommendation that Canada’s public health care system should provide safe and effective infertility treatment for all Canadians who need it.

IVF is the most effective infertility treatment available today. The cost of IVF is covered by the state in many Western European countries and Australia. In the United States, several states mandate insurance companies to cover this treatment. 

In Canada, the need for IVF far exceeds its accessibility, and the treatment remains financially out of reach for many infertile Canadian couples. Because there is virtually no funding, infertile Canadian couples resort to cheaper but less effective alternatives such as ovarian stimulation by fertility pills and/or hormone injections (with or without artificial insemination). These regimens have a major downside in that they entail a significant risk of multiple pregnancy. With ovarian stimulation, poor control over the number of mature eggs produced may result in the birth of triplets, quadruplets and even higher-order multiples. Statistics show multiple-pregnancy rates of 30% through ovarian stimulation.

In the last ten years, Canada’s birthrate has dropped 25%, while during the same period the number of multiple births has increased by 25%. Available data from Europe and North America suggest that infertility treatment accounts for 30% to 50% of all twin births and for up to 80% of all higher-order multiple births. Of these higher-order multiple births about 50% are attributable to fertility pills and hormone injections.

Multiple pregnancies have very broad repercussions: they severely affect the families involved psychologically, medically and financially, and ultimately cost the provinces much more than singleton pregnancies, due to increased needs for medical and social support. Multiple pregnancies also lead to elevated health risks for mothers and infants, increased perinatal and neonatal costs and, in extreme cases, lifelong costs because of the disabilities that occur more frequently in multiples and multiple related pre-term births.

Accordingly the authors recommend the following strategies: (1) education of the medical and allied professions, as well as prospective parents; (2) monitoring of women during ovarian stimulation treatments, with the option to switch to IVF; (3) reduction of the number of embryos transferred in IVF treatment and encouragement of elective single embryo transfer (eSET), with couples seeking treatment at younger ages; (4) optimal availability of IVF treatment, based on a 100% refundable tax credit, the cost of which would be easily offset by significant savings associated with reduced incidence of multiple pregnancies.

These strategies should result in a 50% decrease in the rate of multiple births in every province that adopts funded IVF. 

ACKNOWLEDGEMENT

The authors wish to thank William Buckett, MB, ChB, MD, MRCOG, Assistant Professor, Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada, who contributed comments on ovarian stimulation and strategies to reduce multiple pregnancies, and made other valuable suggestions which have been incorporated into this paper.

INTRODUCTION

Canada’s crude birth rate fell to its all-time low in 2002 and dropped to 10.5 live births for every 1,000 population, the lowest rate since vital statistics began to be produced nationally in 1921. From 1993 to 2002 the rate has dropped 25.4%. The fertility rate, which estimates the average number of children women aged 15 to 49 will have in their lifetime, fell to 1.50 per woman in 2002. 

Conversely, infertility has been on the rise and now affects from 10% to 20% of the population of Western Europe and North America.  A growing number of Canadians are seeking infertility investigation and treatment. 

The consequences of infertility, though wide-ranging, are not always obvious. A literature review and interviews with medical, scientific and psychological experts conducted by the British Royal College of Obstetricians and Gynaecologists found that infertility costs the nation in absenteeism, poor productivity and wasted resources. 

The most effective treatment today is in vitro fertilization (IVF). In IVF, hormonal medications are administered to the woman to cause her ovaries to produce an increased number of mature eggs that are suitable for fertilization. These mature eggs are then collected from the ovaries and cultured with her partner’s sperm to achieve fertilization; the resulting embryos are then transferred to the uterus for implantation.

In 2002, Collins  estimated that 1,500 IVF cycles (with appropriate investigation and treatment) per million population are needed each year. In Canada, the need for IVF far exceeds its accessibility. In 2003, the population of Canada was listed by Statistics Canada as 31.5 million.  According to the above estimate, we would expect approximately 47,000 IVF treatment cycles to be performed annually, when in fact fewer than 8500 cycles were undertaken. 

Couples with unexplained or male-factor infertility, particularly those who cannot afford IVF, are often treated by ovarian stimulation with injectable hormones (gonadotropins), often followed by intra-uterine insemination (IUI). The principle of this treatment is to induce several mature eggs to develop and then to inject sperm directly into the uterus so as to increase the chance of conception. This is a less expensive procedure, but it is also less effective; further, it has proven to result in much higher rates of multiple pregnancy.  

Unlike IVF, which is a controlled procedure because a limited number of embryos are implanted, ovarian stimulation/IUI is uncontrolled. If a woman produces eight to ten follicles, she could, in theory, release up to eight or ten mature eggs and potentially have a very high-order multiple pregnancy. Ideally, a woman would produce only two to four follicles, which would increase her chances of pregnancy without running an inordinately high risk of high-order multiple pregnancy. Unfortunately, because different women respond differently to the same dose of gonadotropins and the same woman can respond differently in repeated treatment cycles of ovarian stimulation with the same dose of medications, the treatment is very difficult to control.

Any increase in the availability of infertility treatments must be accompanied by appropriate measures to ensure that effective methods are used to minimize any associated risks. Multiple pregnancy has been identified as a major complication of infertility treatment. The challenge, therefore, for Canadian patients, health care providers and governments is to reduce the risk of twin, triplet and higher-order multiple births while maintaining good success rates of fertility treatment. 

MULTIPLE PREGNANCY: RISKS AND COSTS

In the last ten years, Canada’s birthrate has dropped 25%.1 In the same period the number of multiple births has increased by 25%.  Multiple pregnancy has been called “the most important adverse outcome in current methods of infertility treatment,”   entailing greater risks of neonatal complications, higher costs for perinatal and neonatal care, and, in extreme cases, lifelong costs because of the physical and mental disabilities associated with multiple births. 

Risks to the mother 

Maternal complications associated with multiple pregnancies9,  include increased risk of: 

 gestational diabetes 

 iron and folate deficiency anemia (due to higher fetal demand)

 gestational hypertension and pre-eclampsia (high blood pressure) 

 fetal malpresentation requiring Caesarean section

 postpartum hemorrhage

 postnatal psychological and social problems 

Risks to infants

Although they account for 1 in 40 births overall, multiple births10 represent:

 1 in 5 low birth weight (LBW) births (under 2,500 g)

 1 in 4 very low births weight (VLBW births (under 1,500 g)

 1 in 6 pre-term births

Fifty-five percent of all multiple-birth babies are LBW, VLBW or ELBW (extremely low birth weight, under1000g). Multiples represent about 20% of all low birth weight infants and 25% of the very low birth weight infant population. LBW and VLBW occur about 9 times more frequently among multiple than singleton births.9 

The duration of a full-term pregnancy is 40 weeks; the average length of pregnancy for twins is 36 weeks, for triplets 33 weeks and for quadruplets 31 weeks. Most multiple births end prematurely and about half are born pre-term. They thus account for the fastest growing segment of the pre-term birth infant population.9,10 Pre-term births also account for a high proportion of childhood disabilities such as blindness, cerebral palsy, dysfunction of one or more organs, or learning disabilities. 

Infant death is four to five times more likely among multiples.10 LBW and pre-term delivery are the leading factors in the excess perinatal mortality and morbidity in multiple pregnancies. 9 The perinatal mortality rate for twins is five times higher than for singletons; it is 12 times higher for triplets and 21 times higher for quadruplets.10 

Neonatal and long-term costs

Few studies are able to establish the costs of multiple pregnancies, but some data are available nonetheless. 

In patients pregnant with twins, the incidence of hospital antenatal care, complicated vaginal deliveries and Caesarean sections is higher and is associated with more frequent and longer maternal and neonatal hospital admissions. In the Netherlands, the medical cost per twin pregnancy was found to be more than five times higher than per singleton pregnancy.  (Singleton pregnancy care in the Netherlands, however, is primarily community-based, with home deliveries; caution therefore should be exercised when extrapolating these data to Canada.) 

A British long-term study has shown that for children who weigh less than 2000 g at birth the cost of neonatal care up to age 8 was 13 times greater than for children with normal birth weights. For the children who weighed less than 1000 g at birth, the costs were 55 times greater than for the control group. , 

Social Costs

A major study of infertility treatment in Belgium9 noted significant psychological impacts at all family levels associated with failed multiple pregnancies: personal loss, guilt and negativity in bereaved parents; behavioural problems in affected siblings; marital problems, emotional stress and financial strain – often requiring professional psychological support, home care and other costly social interventions.

STRATEGIES TO REDUCE MULTIPLE PREGNANCIES

In a 2005 review, Fauser, Devroey and Macklon concluded that up to 80% of all higher-order multiple births and up to 50% of all twins are attributable to Assisted Reproductive Technology (ART).7 On a breakdown by different treatments, they found that ovarian stimulation alone accounts for 30% of all multiple births and ovarian stimulation and ovulation induction, together, contribute to almost 50% of all higher-order multiple births. 

In 2002, 30% of pregnancies resulting from IVF in Canada were multiple. To reduce the number of multiples due to IVF treatment, numerous studies have shown that limiting the number of embryos transferred will reduce the number of multiple births while maintaining a comparable live birth rate. Consequently in some countries, there has been a trend towards elective single embryo transfer (eSET) for selected couples.7,9, , 

SPECIFIC STRATEGIES

1. Education

Any strategy to reduce multiple pregnancy must include extensive education of both the medical and allied professions as well as the general public of the risks associated with multiple birth. Once aware of the dangers involved, patients would be less willing to accept the higher risks in return for higher pregnancy rates, and medical and allied staff would be less reluctant to cancel or modify treatments when necessary.

Furthermore, women must be educated about the problems associated with delayed childbearing, particularly the rapid decline of fertility after the age of 35 (and in the quality of the embryos a woman’s body produces), as well as elevated risks of spontaneous multiple pregnancy, miscarriage and congenital abnormalities.3,  

2. Close monitoring of ovarian stimulation

All patients undergoing ovarian stimulation should be monitored with serial ultrasound scans during treatment. When more than three large follicles develop which can occur in up to 40% of treatment cycles, the cycle should either be cancelled, and the medication adjusted for the subsequent cycle; or the cycle should be converted to IVF and a limited number of embryos transferred after fertilization.7 

3. Reducing the number of embryos transferred in women undergoing IVF

Recent studies strongly suggest that the inherent risks of multiple pregnancy to mothers and babies and the resulting health care and social costs could be greatly reduced by introducing elective single embryo transfer (eSET) for selected patients under the age of 35. 

Several studies have shown that eSET in the first IVF cycles reduces the incidence of multiple pregnancy from about 30% to single digits, while maintaining pregnancy rates of 20% to 25%.9,15,16, ,  For example, Tiitinen et al. reported that the pregnancy rate per cycle of IVF was 22.9% in 1994, when an average of 2.2 embryos were transferred, compared to a pregnancy rate of 25.3% per cycle in 2002, when an average of 1.6 embryos were transferred. Over the same ten-year period the rate of multiple births decreased from 21.6% in 1994 to 13.9% in 2002.19 Likewise Ombelet et al. reported that the ongoing pregnancy rate fluctuated by approximately 20% in the ten-year period covered by their study, and remained at 22% in 2001. eSET resulted in a pregnancy rate of 19%, compared to 26% for elective double embryo transfer and 23% for triple embryo transfer.9

It should be noted, however, that European success rates are lower than those attained in North America (live births of 17% in Europe vs. 27% in the US), as are resultant rates of multiple births (27% vs. 36%).7 Moreover the age of the participating women in the European studies was lower than the average age of IVF patients in Canada. 

It is our recommendation that the number of embryos transferred in funded IVF cycles in Canada should be:

Figure 1. IVF Embryo Transfer Strategy

These recommendations would need to be modified in cases where the implantation rates are lower, such as severe endometriosis or non-obstructive azoospermia (in which sperm is recovered from testicular biopsy) or certain new treatment modalities (such as in vitro maturation of eggs or frozen oocytes or embryos). , ,  

Progressively higher numbers of embryos would be transferred in older women because (1) fertility declines rapidly with increasing age and (2) the majority of embryos in older women are genetically abnormal and will not implant.  

4. Optimal availability of IVF treatment

Funding IVF would reduce multiple-pregnancy rates in three ways:

i) Access to previously unaffordable IVF would significantly limit the use of gonadotropin stimulation, since patients would have no economic reason to undertake a less successful treatment. This measure alone would reduce the incidence of multiple pregnancy. In addition, free IVF would eliminate the need for the increasingly aggressive series of treatment cycles in the ovarian stimulation procedure, which tends as a result to produce much higher rates of multiple pregnancy.  

ii) Women could afford to obtain treatment at an earlier age, when they are likelier to produce better quality embryos and embryo implantation has a greater chance of success. This alone would reduce the number of embryos that need to be transferred. Further, at earlier ages a higher proportion of couples would be eligible for elective single embryo transfer (eSET).7

iii) Funded IVF reduces pressure from couples on the treating clinic to transfer more embryos to improve their chances of becoming pregnant. There is substantial evidence that the total number of embryos transferred is lower when IVF costs are covered.7,18,24

ECONOMIC CONSIDERATIONS

It is a reflection of the difficulties facing infertility patients in Canada that fewer than 8500 IVF cycles are performed each year, compared with over 30,000 in the UK and almost 50,000 in France. This difference is not proportional to differences in population (both countries’ populations are roughly twice that of Canada).

In 2002, based on the number of prescriptions dispensed by Canadian retail pharmacies, there were 83,844 cycles with oral treatments (clomiphene) (see Appendix A). With a pregnancy rate of at least 10% per cycle7, this would have resulted in at least 8400 pregnancies. A multiple pregnancy rate of 10%7 would therefore have resulted in approximately 840 multiple pregnancies.

In the same year, based on the number of prescriptions dispensed by Canadian retail pharmacies, there were 24,606 treatment cycles using injected hormonal treatments, including Puregon, Gonal-f, Pergonal, Humegon and Repronex (see Appendix A). Given a pregnancy rate of more than10%7 per cycle this would have lead to about 2500 pregnancies. A multiple pregnancy rate of 30%7 with injected gonadotropins would therefore have resulted in a further 750 multiple pregnancies. 

In 2002 there were 9712 multiple births in Canada,6 and it can be estimated that at least 1600 or 15% of them were caused by ovarian stimulation and ovulation induction. This figure represents a conservative estimate as some literature cites ovarian stimulation as being responsible for as much as 30% of all multiples.7

In the same year less than 8500 IVF cycles were performed, with an overall live birth rate of 24% or approximately 2000 births. Of these, 35% were multiple; thus IVF treatment generated roughly 715 multiple births.6 

To meet the requirements of infertility patients in Canada, we forecast that 17,000 IVF cycles would be undertaken in years 1 to 5, with the number of cycles increasing to 34,000 beyond year five. This would result in a maximum of 4080 and 9,160 pregnancies, respectively, assuming an overall live birth rate of 24% per cycle.6

This, in turn, will produce 612 and 1024 multiple births, respectively.

Concerning the funding of this treatment, we cite here the Quebec model for all of Canada. In 2002 Quebec established a 30% refundable tax credit for IVF treatment. The Revenue Quebec form TP1029.8.66.2, “Tax Credit Respecting the Treatment of Infertility,” sets forth the details of this model with respect to user eligibility, benefits and required information accordingly is to be read (see Appendix B) as forming part of this proposal.

For Canada, we recommend a 100% refundable tax credit for IVF (with an annual ceiling of $30,000). At approximately $10,000 per cycle (treatment, drugs and related costs inclusively) the total cost of IVF for the country would be $170 million annually at the outset, increasing to $340 million annually beyond year five. 

Because IVF is a controlled treatment, the multiple-birth rate resulting from procedures employing the embryo transfer strategy recommended in this essay (see Figure 1) would drop to 15% from 35%.7,9 

A 50% decrease in multiple births should be realized in each and every province where funded IVF treatment following this recommended embryo transfer strategy is implemented; this anticipated decline will be further enhanced by a significant decrease in the practice of aggressive ovulation induction treatments. Removal of financial constraints would encourage patients to seek treatment at a younger age, when success rates are higher and patients are more frequently able to undergo single rather than multiple embryo transfers. The savings to government realized from this decrease in multiple pregnancies in terms of reduced demands on the medical and social services systems thus would far outweigh the costs of funding IVF.

CONCLUSION

In this era of health cost awareness, governments feel strongly the responsibility to manage and distribute health care and social service resources justly and equitably for the good of the whole community. Government must therefore take into account the cost of infertility as a medical and social disability, the effective and responsible management of which is worthy of inclusion in Canada’s national health plan. Close monitoring of ovarian stimulation cycles and reducing the number of continuing and increasingly aggressive infertility treatment cycles would lead to a major reduction in multiple pregnancies. There is also increasingly strong evidence that reducing the number of embryos transferred, including the use of eSET in selected patients, substantially lowers the chance of multiple pregnancy. Governments in other countries have started responding to these findings.

In Canada, a strategy to substantially reduce the numbers of multiple pregnancies by funding IVF and controlling the number of embryos transferred in funded cycles therefore seems highly desirable – both as a means of supplying an effective standard of infertility treatment leading to successful outcomes and as a means of reducing short- and long-term medical and social costs. 

A 50% decrease in multiple births should be realized in each and every Canadian province where funded IVF treatment using the embryo transfer strategy recommended in this paper is implemented. The savings realized from this decrease, in terms of reduced demands on the health care and social services systems, would far outweigh the costs of funding IVF. 

REFERENCES

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