ANALYSIS MEHAU KULYK/SPL MEHAU Are we overusing IVF? The indications for IVF have expanded from tubal disorders to many causes of subfertility, including “unexplained.” But with limited evidence underpinning its extended remit Esme Kamphuis and colleagues explain how the risks could outweigh the benefits ince the birth of the first baby by in Ж Read about the BMJ’s alternatives to IVF such as clomifene citrate.8 vitro fertilisation (IVF) in 1978, the Too Much Medicine campaign Another factor is that procedures are increas- technique has earned its reputation at bmj.com/too-much-medicine ingly performed in private health systems, where as a major medical breakthrough of result in overtreatment of couples who had a the focus on commercial returns has resulted in the 20th century. IVF was developed reasonable chance of conceiving naturally? Is less academic oversight of who receives treat- Sfor women with tubal disease,1 but its indica- it equally effective in these conditions? And, as ment and when.9 Amid this the indications for tions soon began to grow. In the 1990s intra- more is understood about the adverse health IVF have been expanded to include mild male cytoplasmic sperm injection was developed outcomes in IVF children can the risks of IVF subfertility, the effect of ageing on ovarian to treat couples in which the man has poor be justified for these more liberal applications? function, and unexplained subfertility where semen quality,2 which like tubal infertility pre- no absolute barrier to conception can be proved vents sperm from coming into close proximity Rising rates of IVF (table 1). And it is in these groups that use of IVF with an egg. In recent years, however, IVF has One million babies were born in the first 25 years is expanding the most. been applied to other types of subfertility such of IVF between 1978 and 2003. It took only two In the United States, the number of IVF cycles as mild male subfertility, endometriosis, and more years for the tally to reach two million in offered annually increased from 90 000 in 2000 unexplained subfertility. The birth of many 2005, with over five million estimated to have to 150 000 in 2010, but the proportion with healthy children has enhanced provider and been born by the end of 2013.3 In developed tubal problems as an indication fell from 25% to patient confidence in the safety of IVF. But countries with public health systems 2-3% of the 16%.10 In the UK the proportion of IVF cycles for does applying IVF to wider forms of infertility births each year are through IVF, rising as high tubal problems fell from 19% to 12% between as 5% in Denmark and Belgium.4 This is despite 2000 and 2011, although the number of cycles KEY MESSAGES the fact that an observational study showed that remained at around 7000 (table 1).11 The figures The scope of IVF has expanded in the last 95% of 350 couples planning a first pregnancy for unexplained subfertility tripled from 6204 to two decades to embrace a wider range of conceive within 24 months.5 19 552 cycles. Similar shifts have been reported indications, including unexplained subfertility The reasons for the rise in IVF are complex. in the Netherlands.12 The evidence underpinning the use of IVF for Women may plan to have children later and some of these newer indications is weak some are choosing to freeze their eggs.6 A lack IVF and unexplained infertility Outcomes in children conceived through IVF of confidence, among both subfertile couples The value of IVF for tubal blockage and severe seem to be poorer than in those conceived and their doctors, that conception will eventu- male factor infertility, where a live birth rate of naturally ally occur naturally can lead to access to IVF 20-30% per cycle offers the only chance of con- We need to evaluate which couples have a within two to three years of trying to conceive, ception, is not in dispute. However, the evidence reasonable chance of natural conception and the lure of new technology and access to for newer indications such as unexplained For those needing help, the effectiveness and more patient friendly IVF programmes make it subfertility is less clear. Unexplained sub- safety of IVF should be investigated afresh more appealing.7 Evidence has also undermined fertility accounts for 25% to 30% of all couples BMJ | 1 FEBRUARY 2014 | VOLUME 348 15 ANALYSIS Table 1 | Evidence of effectiveness of IVF treatment for different types of infertility and change in indications Table 2 | Potential harms of IVF in singleton between 2000 and 2011 in the United Kingdom11 pregnancies compared with natural conception No (%) of IVF cycles Odds ratio (95% CI) Reason for fertility problem Evidence of effectiveness 2000 (n=35 450) 2011 (n=60 473) Perinatal outcomes Two sided tubal pathology Effective: no chance of conception 6771 (19)* 7 470 (12%)* Preterm birth (<37 weeks)26 35 1.5 (1.5 to 1.6) 1 2 without medical assistance 26 35 Severe male infertility 9777 (28)† 19 643 (33%)† Very preterm birth (<32 weeks) 1.7 (1.5 to 1.9) 26 35 Obstructive male infertility † † Low birth weight (<2500 g) 1.7 (1.6 to 1.8) Very low birth weight (<1500g)26 1.9 (1.7 to 2.2) Anovulation 7% 6% Perinatal mortality26 1.9 (1.5 to 2.4) Unexplained subfertility IVF treatment effective in subfertility 6204 (18) 19 552 (32) Small gestational age26 1.4 (1.3 to 1.5) >4 years; no more effective than less One sided tubal pathology * * 26 36 invasive alternatives in subfertility Congenital malformations 1.7 (1.3 to 2.1) Mild male subfertility <2.5 years; effectiveness unknown for † † Long term outcomes 18 Endometriosis subfertility 2.5-4 years 886 (3) 2 550 (4) Cerebral palsy36 2.8 (1.3 to 16) 33 Poor ovarian reserve No comparative effectiveness data NA NA Generalised vascular dysfunction Increase available Advanced maternal age NA NA Diastolic/systolic blood pressure 61/109 v 59/105 (mm Hg)34 Other or mixed factors 12 691 (25) 11 252 (12) 35 Fat deposition Increase or no change * One sided and double sided tubal pathology were reported together. Fasting glucose35 Increase or no change † Severe male infertility, obstructive male infertility, and mild male subfertility reported together. pr esenting for IVF, many of whom will conceive It is not just a question of whether to intervene tiple births by requiring single embryo trans- before treatment.12-14 In a cohort of 500 Dutch in unexplained subfertility, but when. Economic fer, multiple transfer is still common in many subfertile couples with on average almost two modelling studies indicate that, in younger parts of the world, including the United States years of unexplained subfertility, 60% conceived women with no obvious cause of infertility, IVF and Asia, where multiple birth rates are 20% to naturally after the initial assessment in the fer- is not cost effective within three years of trying 30%.29 Furthermore, studies suggest that tility clinic.15 Other observational studies have to conceive.21 How- single embryo trans- confirmed natural conceptions in couples with ever, experimental fer, which involves subfertility for two to three years.16 17 and observational IVF extended embryo A Cochrane review comparing IVF with research often does culture and trans- expectant management in women without tubal not mention how long fer of a blastocyst, problems identified one trial of 51 women with couples have been try- is associated with a unexplained infertility who had been trying to ing to conceive. Forty 50-70% additional conceive for an average of four years.18 19 The five of the 71 (63%) risk of preterm birth trial reported live birth rates of 29% in women randomised trials of and congenital randomised to one cycle of IVF versus 1% in IVF in 2009 and 2010 m alformations.30-32 the expectant management group. Although did not state length LTD/SPL IMAGING MEDICAL CANE DU Concern has also this may seem like a success for IVF, the women of infertility. National The evidence for newer explanations been raised about in this trial had been trying to conceive for four fertility registries in such as unexplained subfertility is the long term health years, which is much longer than is current Sweden, Australia, less clear. Unexplained subfertility of children born practice in many countries. A randomised clini- Belgium, New Zea- accounts for 25-30% of all couples through IVF. Other- cal trial comparing intrauterine insemination land, Canada, and the wise healthy chil- and ovarian hyperstimulation with expectant United States also do not collect data on dura- dren conceived by IVF may have higher blood management in couples who had an average tion of infertility. pressure, adiposity, glucose levels, and more of two years’ unexplained subfertility found In the UK the National Institute for Health and generalised vascular dysfunction than children a pregnancy rate of 25% after six months and Care Excellence changed its recommendation conceived naturally (table 2). These effects seem 75% after three years in both groups.17 It seems regarding the timing of access to IVF in couples to be related to the IVF procedure itself rather that a short delay in treatment does not affect with unexplained infertility where the woman is than to underlying subfertility.33-36 Animal stud- ovarian reserve in such a way that more couples younger than 40 from three to two years.22 How- ies have shown epigenetic and developmental will end up childless. ever, it did not provide any references to justify abnormalities after assisted reproduction, which Another randomised trial (FASTT) in the US the threshold.