Are we overusing IVF?BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g252 (Published 28 January 2014) Cite this as: BMJ 2014;348:g252
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The paper by Kamphuis and colleagues requests that we reopen the debate on the indications and provision of IVF1. Given the risk of iatrogenic complications and potentially limited cost-effectiveness, the authors suggest that conservative treatment should be reconsidered as a viable alternative for couples with a good prognosis1. This position is based on the premise that the primary motivation to seek IVF treatment is to achieve a pregnancy which would otherwise be unlikely to occur at all. In such a case, it may indeed be reasonable to expect couples to wait in excess of three years before embarking on treatment2,3,4. However, national census data indicates that for many this potentially reflects the ideal time frame for completion of their entire family5. ‘Family planning’ is therefore increasingly focused on achieving the family wished for in a desired time. Social demographic trends increasingly require women to conceive their families in a shorter window. The potentially detrimental psychological impact of trying to conceive over a relatively prolonged time may further alter any individual couples analysis of cost-effectiveness6. While we agree that continued development of novel strategies to reduce adverse maternal and perinatal complications are required, at present stratification of ovarian stimulation7, milder stimulation regimens8, use of GnRH agonist triggers and segmentation of the IVF cycle9 are serving to reduce the risk of complications such as ovarian hyperstimulation syndrome while improving success rates. Limiting the number of embryos transferred has also been associated with improved short and long-term maternal, perinatal and offspring outcomes10,11. While we commend the authors on questioning the efficacy of IVF intervention versus time to treat subfertility, we suggest that the premise of this debate is no longer the key issue. Patients now appreciate that IVF can be utilised for family planning in the context of their lifecourse and for many is an effective and efficient strategy for reducing their time to completion of family.
Scott M Nelson1
Nicholas S Macklon4
1. School of Medicine, University of Glasgow, G12 8QQ Glasgow, UK.
2 Center for Reproductive Medicine, Dutch-speaking Free University Brussels, Brussels and AZ Jan Palfijn Hospital, Gent, Belgium.
3. IVI Valencia, Valencia, Spain.
4. Academic Unit of Human Development and Health, University of Southampton, Southampton SO16 5YA UK.
1. Kamphuis EI, Bhattacharya S, van der Veen F, Mol BW, Templeton A; Evidence
Based IVF Group. Are we overusing IVF? BMJ. 2014 Jan 28;348:g252. doi:
10.1136/bmj.g252. PubMed PMID: 24472708.
2. Brandes M, Hamilton CJ, van der Steen JO, de Bruin JP, Bots RS, Nelen WL, et al. Unexplained infertility: overall ongoing pregnancy rate and mode of conception. Hum Reprod 2011;26:360-8.
3.Troude P, Bailly E, Guibert J, Bouyer J, de la Rochebrochard E, DAIFI Group. Spontaneous pregnancies among couples previously treated by in vitro fertilization. Fertil Steril 2012;98:63-8.
4. Steures P, van der Steeg JW, Hompes PG, Habbema JD, Eijkemans MJ, Broekmans FJ, et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368:216-21.
6. Schmidt L. Psychological burden of infertility and assisted reproduction. Lancet 2006;367:379-380
7. Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of
ovarian stimulation for in vitro fertilization. Endocr Rev. 2006 Apr;27(2):170-207.
8. La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in
IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update.
9. Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF
treatment. Hum Reprod. 2011 Oct;26(10):2593-7.
10. Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian
stimulation for subfertility treatment. Lancet. 2005 May 21-27;365(9473):1807-16.
11. Lawlor DA, Nelson SM. Effect of age on decisions about the numbers of embryos to transfer in assisted conception: a prospective study. Lancet. 2012 Feb 11;379(9815):521-7.
Competing interests: No competing interests
We wish to comment on the article by Kamphuis et al  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 .
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 . Developed regions still have fertility levels well below replacement rate, and average maternal age at first birth has been climbing for years . 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 . 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 . 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 . 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 , 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 . 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 . 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) . Fortunately, methods now exist to select a single euploid embryo for transfer to offer an overall pregnancy rate of 70% per cycle .
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 .
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 .
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: email@example.com
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
Kamphuis and colleagues analysed the overuse of IVF treatment focusing on the newer indications such as unexplained subfertility where evidence is sparse.1There is no doubt of an increase in the incidence of unexplained subfertility as an indication for IVF, but it would be pertinent to ask the question “why is this so”? With the cited incidences being especially based on registries from Western countries, one of the most likely reason for the increase in unexplained causes is the increase in female childbearing age2&3 and ovarian senescence in these older women presenting as unexplained subfertility.4
Since the beginning of IVF registries there has been a gradual increase in the mean age of women seeking IVF treatment.5&6 There has been a parallel increase in the proportion of older women seeking IVF treatment5&6 and in the proportion of IVF cycles being offered for unexplained subfertility as correctly pointed out by the authors.1
Human biology dictates conception which has a negative correlation with advancing female age. Epidemiological studies have shown natural conception rates in women aged 40 years or over to be 13.9 conceptions per thousand women.7 Although the success with IVF has seen major increases over the years, IVF success in women aged ≥ 40 years has not much changed despite advances in the technology, with live birth rates being less than 14%.5 However, many women and couples view IVF as a "fix all" for their voluntary postponement of childbearing.8
Is IVF a cure for ovarian senescence which is very often diagnosed as unexplained infertility in older women? What is the management pathway for fertility in these women? The studies cited by Kamphius and colleagues on natural conception rates among women with unexplained infertility involve younger women 9,10 and would be incorrect to extrapolate this evidence to older women. Paucity of evidence to guide management of the ever increasing “older woman” seeking fertility is perhaps leading to IVF being overused. As the authors have rightly pointed out randomised controlled trials of effectiveness on new indications for IVF are needed to inform both clinicians and couples. IVF should not be viewed as a blanket treatment for various causes of subfertility unless substantiated by strong evidence.
We would like to conclude this correspondence by posing a key question on primary prevention. Could the epidemic of ovarian ageing and subfertility be tackled by promoting fertility awareness among women and society? Education would certainly go a long way in health economics and perhaps a remedy for “too much medicine”.
1. Kamphuis E, Bhattacharya S, der Veen Fvan, Mol BWJ, Templeton A, BMJ 2014;348:g252.
2. Bushnick T, Garner R. The children of older first-time mothers in Canada: their health and development. Ottawa (ON): Statistics Canada. Sept 2008. Available at: http://www.statcan.gc.ca/pub/89–599-m/ 89–599-m2008005-eng.htm.
3. Royal College of Obstetricians and Gynaecologists. RCOG statement on later maternal age. Available at: http://www.rcog.org.uk/what-we-do/ campaigning-and-opinions
4. Maheshwari A, Hamilton M, Bhattacharya A. Effect of female age on the diagnostic categories of infertility. Hum Reprod 2008; 23: 538-542.
7. http://www.ons.gov.uk/ons/dcp171778_301080.pdf (Office for national statistics)
8. Maheshwari A, Bhattacharya S, Johnson NP. Predicting fertility. Hum Fertil 2008; 11(2):109-17.
9. Brandes M, Hamilton CJ, van der Steen JO, de Bruin JP, Bots RS, Nelen WL, et al. Unexplained infertility: overall ongoing pregnancy rate and mode of conception. Hum Reprod 2011; 26: 360-8.
10. Steures P, van der Steeg JW, Hompes PG, Habbema JD, Eijkemans MJ, Broekmans FJ, et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368:216-21.
11. Reindollar RH, Regan MM, Neumann PJ, Levine BS, Thornton KL, Alper MM, et al. A randomised clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril 2010; 94:888-99.
Competing interests: No competing interests
Esme Kamphuis and colleagues are concerned that the risks of IVF could outweigh the benefits as world IVF births increased from 2 million in 2005 to 5 million in 2013.1 At the same time the indication of “unexplained” subfertility increased 3-fold in the UK the UK and the Netherlands.
This is failure to use real “Evidence Based Medicine”. All doctors surely have a duty to investigate patients using the best tests available. Since the 1970s it has been possible to investigate couples with “unexplained” infertility or recurrent miscarriages and find numerous nutritional deficiencies and hidden infections.
Commonly zinc, magnesium, selenium, chromium, and copper with poor superoxide dismutase function, and B vitamins are deficient. Toxic metals like cadmium from smoking, nickel from stainless steel and dental braces, and aluminium from cans are often increased. Endocervical infections or prostatitis often need to be treated.2-4
It is wrong that the NICE Fertility (update) guidance summary does not mention the importance and value of preconception care. It is obvious that the nutritional and toxic metal status of both parents should be assessed biochemically and deficiencies supplemented before conception and during pregnancy for the health of the child.
It is unrealistic to believe that giving teenagers and women progestogens for years, especially progestogen containing IUDs, will not increase fertility problems - including blocking tubes, increasing endometriosis and causing biochemical perturbations.
1 Kamphuis EI, Bhattacharya S , van der Veen F, Mol BW, Templeton A, for the Evidence Based IVF Group. Are we overusing IVF? BMJ 2014;348:g252.
2 Barnes B, Grant ECG et al. Nutrition and preconception care.Lancet1985;2:1297.
3 Grant ECG. The declining health of the pill generations. J Nutr Med 1994;4:283-86.
4 Ward N. Preconceptional care and pregnancy outcome. J Nutr Med 1995;5:205-6.
Competing interests: No competing interests
A child for a childless couple is a boon of life. In many societies the pressure to have a baby after a marriage is a psychological burden on the wife. This burden is aggravated by the in laws of the wife, which in turn becomes an expectation to have physiological amenorrhea. Every failed attempt to conceive soon becomes a social stigma and pushes the couples to go for infertility treatment to any clinic that offers them a hope to have a baby soon. Availability of artificial methods of reproduction, its exploitation and the pressure from the family pushes them to go for in vitro fertiliztion (IVF). The IVF clinics become the last resort for such couples and IVF centers become many a time savior of marriages from divorce. A divorce becomes a social stigma more to the woman than to a man.
Therefore, we cannot use the term over-use or under-use for a procedure that is available to give a chance for the patient to take a risk to have a baby like IVF. It is the same as an instrument in the hands of a person being used for good or bad outcomes. The only way we could fulfill the expectations of couples wanting IVF as a procedure is to improve its success rate, minimize psychological stress of the procedure and reduce invasive procedure to the minimum. That will ensure IVF being used optimally as a suitable procedure for couples who are hard pressed to have a baby.
Competing interests: No competing interests
In many Countries where IVF cycles are totally reimbursed by medical insurance schemes, there exists a tendency to overuse them, even in women over 43. 
Without any official guidelines implemented and strictly observed, clinics are pretty much free to judge most of the women visiting as eligible for IVFs. 
Even medical tourism for IVFs is booming!
Competing interests: No competing interests
In the last 12 months my husband and I found ourselves requiring investigation for sub-fertility and for me I personally felt IVF was often offered to easily and too soon.
Couples suffering with sub-fertility are often in significant emotional distress with their situation. We live in a culture where pregnancy is something we can avoid, we are taught in school that even one act of unprotected indiscretion can lead to pregnancy but we are not made aware that when we do decide we want a child we may not fall pregnant immediately. This expectation from the couple, their family and friends adds a huge amount of pressure to the process of trying to conceive. When we fail to conceive within our, or the medical professions, expected timeframe we turn to fertility investigations.
My personal experience of investigation for sub-fertility was far from what I expected. I was shocked when after a pelvic ultrasound, swabs and a few blood tests I was offered IVF as first line. We had been trying for over 2 years, but all our investigations had been normal. I personally felt a procedure as invasive as IVF should be a ‘last resort’. I was told I would need to start the procedure within the next 2-3 months or risk losing funding. I was left with a very difficult decision – to postpone intervention and risk losing my ‘last resort’ treatment, or go ahead with a risky procedure despite my reservations. The clinic did nothing but encourage me to go ahead, especially considering the excellent success rates (over 50%) with women under 30 with unexplained infertility. After careful consideration my husband and I decided not to proceed with IVF despite our very real fear of never being able to have a child.
My husband and I were lucky to find ourselves pregnant 6 months later, with no help to conceive. For many couples it is too much of a gamble to wait and see. Trying to conceive becomes the focus of life, altering plans for holidays, for travel, for change of employment. Along with ensuring the safety and efficacy of IVF we should consider the need for education for couples preparing to conceive, and for the wider population, to reduce the emotional burden and social stigma for those who do go on to have sub-fertility and ensure balanced information is given in fertility clinics to these couples.
Competing interests: No competing interests