We wish to comment on the article by Kamphuis et al [1] which poses several questions, including “Does applying IVF to wider forms of infertility result in overtreatment of couples who had a reasonable chance of conceiving naturally?”
This presumption of overtreatment is based, in part, on the authors’ portrayal of IVF indications as having recently “expanded to include the effect of ageing on ovarian function”. This critique is incorrect. Patients with borderline or declining ovarian reserve have long been considered suitable candidates for IVF, often selecting this route on a difficult journey culminating with IVF and donor gametes [2].
The reasons for the increase in IVF use are indeed complex. Population ageing and overall growth must not be overlooked, as they lift utilization rates for many elements in the healthcare sector over time [3]. Developed regions still have fertility levels well below replacement rate, and average maternal age at first birth has been climbing for years [4]. These processes interlock with the authors’ statement about women who “plan to have their children later”, because the most important factor influencing reproductive outcome is the age of the female [5]. Accordingly, this topic must occupy the starting ground for any serious policy discussion concerning IVF utilization.
Changing attitudes toward IVF also merit consideration. In Australia, general public opinion of IVF treatment warmed, increasing from 77% in 1981 to >90% in 2011 [6]. Similarly in Ireland, more than half the general public regarded IVF favorably, and, remarkably, this support extended to senior citizens who would never even use the treatment themselves [7]. It is fair to say that IVF is now well established in the social consciousness as well as in the mainstream of medical therapy.
While Kamphuis et al concede that IVF is appropriate for tubal factor and severe male factor infertility, and admit that “evidence has…undermined alternatives to IVF such as clomiphene citrate”, the clinical significance of these statements seems lost in the analysis. For patients with unexplained infertility, it is precisely this dearth of effective medical alternatives which has helped make IVF all the more compelling, thus contributing to the “overuse” they find so perplexing.
For example, a 34-year old infertility patient with bilateral tubal patency can request intrauterine insemination at most any clinic for a pregnancy rate of 20% per cycle. That same woman can instead undergo one IVF treatment and might reasonably expect a nearly three-fold higher success rate. Recalling the relatively higher risk of multiple gestation following treatment with fertility medications and artificial insemination [8], it is easy to understand the appeal of IVF.
Data from multiple, large comparative studies show IVF to be generally safe for both mothers and babies. We believe this to be the case. The latest multi-centre investigation assessing >15,000 IVF offspring found the congenital anomaly rate among infants born after IVF (with or without ICSI) similar to that observed in the background population [9]. While others may reach different conclusions, evidence of adverse consequences following IVF seems at best controversial [10,11]. The authors’ premise that assisted fertility services are somehow safer under the watch of regulatory bodies remains unproven—if anything, this only increases cost [12,13].
The authors rightly draw attention to some concerns with IVF as currently practiced. In California, IVF strongly skews the multiple gestation/preterm birth rate upward to approximately 50% of deliveries in this subset, whereas this happens in only about 3% of unassisted conceptions. Especially during the first year of life, these IVF babies often become “super utilizers”, consuming a disproportionate share of healthcare resources. In absolute terms, the contribution made by conventional IVF to these adverse outcomes is numerically low. However, substantial costs could be recovered by redirecting expenditures away from high-risk IVF deliveries if the unacceptable multiple gestation/preterm birth rate from standard IVF were corrected. But how might this be achieved?
First, expectations must be set realistically. Last year, an initiative studied causes of all preterm births in countries with a very high human development index, yet no contributing factors could be found in about half of cases [14]. That study did, however, ascribe partial blame to the assisted reproductive technologies. So, for IVF practitioners, an ideal response would be single embryo transfer (although many fertility patients object to this approach given its relatively low pregnancy rates) [15]. Fortunately, methods now exist to select a single euploid embryo for transfer to offer an overall pregnancy rate of 70% per cycle [16].
As molecular techniques are refined and become available at lower cost, we hope it will soon be routine for just one embryo to be transferred after first determining its chromosomal competency [17].
Another way to look at IVF utilization patterns could be to focus on the fresh embryo transfer component. Obstetric and perinatal outcomes may be better in pregnancies resulting from frozen embryo transfer cycles, compared to traditional IVF where embryo transfer is near the time of oocyte retrieval [18,19]. Is it time to avoid fresh embryo transfers in IVF, cryopreserve all available embryos, and replace them in subsequent cycles? The plausibility of this concept is being studied to see how this might be deployed in routine clinical practice [20].
We agree that patients do face a choice. Timely IVF should be regarded as an elective, low-risk medical procedure with years of evidence-based outcomes data to underpin its success rates and safety. We join Kamphuis et al in the laudable work of IVF outcomes surveillance, although we disagree with the call for alarm in the meantime. Fertility patients who share their concerns should not do IVF; they may take a different path to parenthood, possibly including adoption. These patients deserve appropriate support, when requested, from medical professionals. Regrettably, the biggest problem confronting infertility patients today is not the overuse of IVF, but rather limited access to care and the cost of treatment.
E. Scott Sills, M.D., Ph.D.1,2 *
Gary S. Collins, Ph.D.3
1HRC Fertility; Newport Beach, California USA
2Applied Biotechnology Division, School of Life Sciences, University of Westminster; London UK
3Centre for Statistics in Medicine, Botnar Research Centre, University of Oxford; Oxford UK
*500 Superior Avenue, Suite 210, Newport Beach, CA 92663 USA
Telephone: +1 949-287-5600 Fax +1 949 642-2750 Email: sillsivf@havingbabies.com
References
1. Kamphuis EI, Bhattachara S, van der Veen F, Mol BWJ, Templeton A. Are we overusing IVF? BMJ 2014;348:g252.
2. Sills ES, Mykhaylyshyn LO, Dorofeyeva US et al. The long path to pregnancy: early experience with dual anonymous gamete donation in a European in vitro fertilisation referral centre. Reprod Health 2010;7:20.
3. Zhong W, Maradit-Kremers H, St Sauver JL et al. Age and sex patterns of drug prescribing in a defined American population. Mayo Clin Proc 2013;88:697-707.
4. Myrskylä M, Kohler HP, Billari FC. Advances in development reverse fertility declines. Nature 2009;460(7256):741-3.
5. Sills ES, Alper MM, Walsh AP. Ovarian reserve screening in infertility: practical applications and theoretical directions for research. Eur J Obstet Gynecol Reprod Biol 2009;146:30-6.
6. Kovacs GT, Morgan G, Levine M, McCrann J. The Australian community overwhelmingly approves IVF to treat subfertility, with increasing support over three decades. Aust N Z J Obstet Gynaecol 2012;52:302-4.
7. Walsh DJ, Sills ES, Collins GS, Hawrylyshyn CA, Sokol P, Walsh APH. Irish public opinion on assisted human reproduction services: Contemporary assessments from a national sample. Clin Exp Reprod Med 2013;40:169-73.
8. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande V. Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000;343:2-7.
9. Yan J, Huang G, Sun Y et al. Birth defects after assisted reproductive technologies in China: analysis of 15,405 offspring in seven centers (2004 to 2008). Fertil Steril 2011;95:458-60.
10. Caperton L, Murphey P, Yamazaki Y et al. Assisted reproductive technologies do not alter mutation frequency or spectrum. Proc Natl Acad Sci USA 2007;104:5085-90.
11. Feuer S, Rinaudo P. Preimplantation stress and development. Birth Defects Res C Embryo Today 2012;96:299-314.
12. Wingfield M, Cottell E. Viral screening of couples undergoing partner donation in assisted reproduction with regard to EU Directives 2004/23/EC, 2006/17/EC and 2006/86/EC: what is the evidence for repeated screening? Hum Reprod 2010;25:3058-65.
13. Murdoch A. The legacy of the HFEA. Reprod Biomed Online 2013;26(4):307-9.
14. Chang HH, Larson J, Blencowe H et al. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet 2013;381(9862):223-34.
15. van Peperstraten AM, Nelen WL, Hermens RP et al. Why don't we perform elective single embryo transfer? A qualitative study among IVF patients and professionals. Hum Reprod 2008;23:2036-42.
16. Sills ES, Yang Z, Walsh DJ, Salem SA. Comprehensive genetic assessment of the human embryo: can empiric application of microarray comparative genomic hybridization reduce multiple gestation rate by single fresh blastocyst transfer? Arch Gynecol Obstet 2012;286:755-61.
17. Sills ES. An evidence-based policy for the provision of subsidised fertility treatment in California: integration of array comparative genomic hybridisation with IVF and mandatory single embryo transfer to lower multiple gestation and preterm birth rates (PhD thesis). British Library EThOS: uk.bl.ethos.576982 [Univ Westminster, 2013].
18. Aflatoonian A, Oskouian H, Ahmadi S, Oskouian L. Can fresh embryo transfers be replaced by cryopreserved-thawed embryo transfers in assisted reproductive cycles? A randomized controlled trial. J Assist Reprod Genet 2010;27:357-63.
19. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril 2011;96:344-8.
20. Maheshwari A, Bhattacharya S. Elective frozen replacement cycles for all: ready for prime time? Hum Reprod 2013;28:6-9.
Competing interests:
No competing interests
08 February 2014
E. Scott Sills
Reproductive Endocrinologist
Gary S. Collins, Ph.D.
HRC Fertility
500 Superior Avenue, Suite 210, Newport Beach CA 92663 USA
Rapid Response:
Re: Are we overusing IVF?
We wish to comment on the article by Kamphuis et al [1] which poses several questions, including “Does applying IVF to wider forms of infertility result in overtreatment of couples who had a reasonable chance of conceiving naturally?”
This presumption of overtreatment is based, in part, on the authors’ portrayal of IVF indications as having recently “expanded to include the effect of ageing on ovarian function”. This critique is incorrect. Patients with borderline or declining ovarian reserve have long been considered suitable candidates for IVF, often selecting this route on a difficult journey culminating with IVF and donor gametes [2].
The reasons for the increase in IVF use are indeed complex. Population ageing and overall growth must not be overlooked, as they lift utilization rates for many elements in the healthcare sector over time [3]. Developed regions still have fertility levels well below replacement rate, and average maternal age at first birth has been climbing for years [4]. These processes interlock with the authors’ statement about women who “plan to have their children later”, because the most important factor influencing reproductive outcome is the age of the female [5]. Accordingly, this topic must occupy the starting ground for any serious policy discussion concerning IVF utilization.
Changing attitudes toward IVF also merit consideration. In Australia, general public opinion of IVF treatment warmed, increasing from 77% in 1981 to >90% in 2011 [6]. Similarly in Ireland, more than half the general public regarded IVF favorably, and, remarkably, this support extended to senior citizens who would never even use the treatment themselves [7]. It is fair to say that IVF is now well established in the social consciousness as well as in the mainstream of medical therapy.
While Kamphuis et al concede that IVF is appropriate for tubal factor and severe male factor infertility, and admit that “evidence has…undermined alternatives to IVF such as clomiphene citrate”, the clinical significance of these statements seems lost in the analysis. For patients with unexplained infertility, it is precisely this dearth of effective medical alternatives which has helped make IVF all the more compelling, thus contributing to the “overuse” they find so perplexing.
For example, a 34-year old infertility patient with bilateral tubal patency can request intrauterine insemination at most any clinic for a pregnancy rate of 20% per cycle. That same woman can instead undergo one IVF treatment and might reasonably expect a nearly three-fold higher success rate. Recalling the relatively higher risk of multiple gestation following treatment with fertility medications and artificial insemination [8], it is easy to understand the appeal of IVF.
Data from multiple, large comparative studies show IVF to be generally safe for both mothers and babies. We believe this to be the case. The latest multi-centre investigation assessing >15,000 IVF offspring found the congenital anomaly rate among infants born after IVF (with or without ICSI) similar to that observed in the background population [9]. While others may reach different conclusions, evidence of adverse consequences following IVF seems at best controversial [10,11]. The authors’ premise that assisted fertility services are somehow safer under the watch of regulatory bodies remains unproven—if anything, this only increases cost [12,13].
The authors rightly draw attention to some concerns with IVF as currently practiced. In California, IVF strongly skews the multiple gestation/preterm birth rate upward to approximately 50% of deliveries in this subset, whereas this happens in only about 3% of unassisted conceptions. Especially during the first year of life, these IVF babies often become “super utilizers”, consuming a disproportionate share of healthcare resources. In absolute terms, the contribution made by conventional IVF to these adverse outcomes is numerically low. However, substantial costs could be recovered by redirecting expenditures away from high-risk IVF deliveries if the unacceptable multiple gestation/preterm birth rate from standard IVF were corrected. But how might this be achieved?
First, expectations must be set realistically. Last year, an initiative studied causes of all preterm births in countries with a very high human development index, yet no contributing factors could be found in about half of cases [14]. That study did, however, ascribe partial blame to the assisted reproductive technologies. So, for IVF practitioners, an ideal response would be single embryo transfer (although many fertility patients object to this approach given its relatively low pregnancy rates) [15]. Fortunately, methods now exist to select a single euploid embryo for transfer to offer an overall pregnancy rate of 70% per cycle [16].
As molecular techniques are refined and become available at lower cost, we hope it will soon be routine for just one embryo to be transferred after first determining its chromosomal competency [17].
Another way to look at IVF utilization patterns could be to focus on the fresh embryo transfer component. Obstetric and perinatal outcomes may be better in pregnancies resulting from frozen embryo transfer cycles, compared to traditional IVF where embryo transfer is near the time of oocyte retrieval [18,19]. Is it time to avoid fresh embryo transfers in IVF, cryopreserve all available embryos, and replace them in subsequent cycles? The plausibility of this concept is being studied to see how this might be deployed in routine clinical practice [20].
We agree that patients do face a choice. Timely IVF should be regarded as an elective, low-risk medical procedure with years of evidence-based outcomes data to underpin its success rates and safety. We join Kamphuis et al in the laudable work of IVF outcomes surveillance, although we disagree with the call for alarm in the meantime. Fertility patients who share their concerns should not do IVF; they may take a different path to parenthood, possibly including adoption. These patients deserve appropriate support, when requested, from medical professionals. Regrettably, the biggest problem confronting infertility patients today is not the overuse of IVF, but rather limited access to care and the cost of treatment.
E. Scott Sills, M.D., Ph.D.1,2 *
Gary S. Collins, Ph.D.3
1HRC Fertility; Newport Beach, California USA
2Applied Biotechnology Division, School of Life Sciences, University of Westminster; London UK
3Centre for Statistics in Medicine, Botnar Research Centre, University of Oxford; Oxford UK
*500 Superior Avenue, Suite 210, Newport Beach, CA 92663 USA
Telephone: +1 949-287-5600 Fax +1 949 642-2750 Email: sillsivf@havingbabies.com
References
1. Kamphuis EI, Bhattachara S, van der Veen F, Mol BWJ, Templeton A. Are we overusing IVF? BMJ 2014;348:g252.
2. Sills ES, Mykhaylyshyn LO, Dorofeyeva US et al. The long path to pregnancy: early experience with dual anonymous gamete donation in a European in vitro fertilisation referral centre. Reprod Health 2010;7:20.
3. Zhong W, Maradit-Kremers H, St Sauver JL et al. Age and sex patterns of drug prescribing in a defined American population. Mayo Clin Proc 2013;88:697-707.
4. Myrskylä M, Kohler HP, Billari FC. Advances in development reverse fertility declines. Nature 2009;460(7256):741-3.
5. Sills ES, Alper MM, Walsh AP. Ovarian reserve screening in infertility: practical applications and theoretical directions for research. Eur J Obstet Gynecol Reprod Biol 2009;146:30-6.
6. Kovacs GT, Morgan G, Levine M, McCrann J. The Australian community overwhelmingly approves IVF to treat subfertility, with increasing support over three decades. Aust N Z J Obstet Gynaecol 2012;52:302-4.
7. Walsh DJ, Sills ES, Collins GS, Hawrylyshyn CA, Sokol P, Walsh APH. Irish public opinion on assisted human reproduction services: Contemporary assessments from a national sample. Clin Exp Reprod Med 2013;40:169-73.
8. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande V. Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000;343:2-7.
9. Yan J, Huang G, Sun Y et al. Birth defects after assisted reproductive technologies in China: analysis of 15,405 offspring in seven centers (2004 to 2008). Fertil Steril 2011;95:458-60.
10. Caperton L, Murphey P, Yamazaki Y et al. Assisted reproductive technologies do not alter mutation frequency or spectrum. Proc Natl Acad Sci USA 2007;104:5085-90.
11. Feuer S, Rinaudo P. Preimplantation stress and development. Birth Defects Res C Embryo Today 2012;96:299-314.
12. Wingfield M, Cottell E. Viral screening of couples undergoing partner donation in assisted reproduction with regard to EU Directives 2004/23/EC, 2006/17/EC and 2006/86/EC: what is the evidence for repeated screening? Hum Reprod 2010;25:3058-65.
13. Murdoch A. The legacy of the HFEA. Reprod Biomed Online 2013;26(4):307-9.
14. Chang HH, Larson J, Blencowe H et al. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet 2013;381(9862):223-34.
15. van Peperstraten AM, Nelen WL, Hermens RP et al. Why don't we perform elective single embryo transfer? A qualitative study among IVF patients and professionals. Hum Reprod 2008;23:2036-42.
16. Sills ES, Yang Z, Walsh DJ, Salem SA. Comprehensive genetic assessment of the human embryo: can empiric application of microarray comparative genomic hybridization reduce multiple gestation rate by single fresh blastocyst transfer? Arch Gynecol Obstet 2012;286:755-61.
17. Sills ES. An evidence-based policy for the provision of subsidised fertility treatment in California: integration of array comparative genomic hybridisation with IVF and mandatory single embryo transfer to lower multiple gestation and preterm birth rates (PhD thesis). British Library EThOS: uk.bl.ethos.576982 [Univ Westminster, 2013].
18. Aflatoonian A, Oskouian H, Ahmadi S, Oskouian L. Can fresh embryo transfers be replaced by cryopreserved-thawed embryo transfers in assisted reproductive cycles? A randomized controlled trial. J Assist Reprod Genet 2010;27:357-63.
19. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril 2011;96:344-8.
20. Maheshwari A, Bhattacharya S. Elective frozen replacement cycles for all: ready for prime time? Hum Reprod 2013;28:6-9.
Competing interests: No competing interests