National Infertility Group Report January 2013

6. Clinical effectiveness of IVF

87. Overall, 24% of IVF cycles in Scotland result in the birth of a live baby. The success rate of treatment is, however, significantly affected by maternal age and health behaviours.

88. Infertility is caused by both male and female factors. Many causes of infertility are not preventable, but there are known factors which contribute to a proportion of cases. The most significant is age, and female fertility declines steeply after the age of 35. In order to reduce the likelihood of fertility problems, and to have a better chance of successful treatment, women should aim, if possible, to have their first child before age 35.

89. Other factors which may influence male or female fertility include a healthy Body Mass Index, minimal alcohol intake, not smoking and avoidance of sexually transmitted infections. These can also significantly influence fertility treatment success. Health promotion messages may need to increase awareness of these effects, and both NHS Health Scotland and Infertility Network Scotland are carrying out work on pre-conception care and fertility risk respectively, which will help highlight these issues. More detail on these factors is set out below.

6.1 Factors affecting fertility, maternal and infant health

6.1.1 Obesity

90. The increasing prevalence of obesity is a major health problem. A recent Health Survey for England²¹ found that one-quarter of both men (23.6%) and women (23.8%) are obese, with a body mass index (BMI) of ≥30 kg/m². In total, 50% of women of childbearing age are either overweight (BMI 25-29.9 kg/m²) or obese and 18% are obese at the start of pregnancy.

91. This is evidence that obesity impacts negatively on almost all aspects of IVF treatment, e.g. a poorer ovarian response, oocyte retrieval is more challenging and fewer oocytes are retrieved. These and other factors combine to make pregnancy rates significantly lower in women with a BMI of >30. Available data suggest that as little as 5-10% weight loss can improve fertility outcomes.

92. Maternal obesity has become one of the most commonly occurring risk factors in obstetric practice. Obesity in pregnancy is usually defined as a Body Mass Index (BMI) of 30 kg/m² or more at the first antenatal consultation. BMI is a simple index of weight-for-height and is calculated by dividing a person's weight in kilograms by the square of their height in metres (kg/m²). Currently, 20-40% of women gain more than the recommended weight during pregnancy, resulting in an increased risk of maternal and fetal complications.

93. More than half of women who die during pregnancy, childbirth or the puerperium are either obese or overweight. The maternal complications associated with obesity also include miscarriage, hypertensive disorders such as pre-eclampsia, gestational diabetes mellitus, infection, thromboembolism, caesarean section, instrumental and traumatic deliveries, wound infection and endometritis.

94. The fetal risks associated with obesity include stillbirths and neonatal deaths, macrosomia, neonatal unit admission, preterm births, congenital abnormalities and childhood obesity with associated long-term risks. Excessive weight gain in pregnancy is also associated with persistent retention of the weight gained beyond pregnancy in the mother and an increase in obesity in children at 2-4 years. The health risks to the mother and baby of obesity and excessive weight gain pose significant demands on the healthcare system, with an increased need for additional care and resources in both primary and secondary care settings.

95. The joint Royal College of Obstetricians and Gynaecologists (RCOG)²² and Centre for Maternal and Child Enquiries²³ (CMACE, formerly CEMACH) guidelines and the National Institute for Health and Clinical Excellence (NICE) guidance recommend that women with a BMI of ≥30 kg/m² should have consultant care rather than midwifery-led care, which places a massive burden on maternity unit resources. Obese women spend an average of 4.83 more days in hospital, resulting in a fivefold increase in the cost of antenatal care. The costs associated with newborns are also increased, as babies born to obese mothers have a 3.5-fold increased risk of admission to the neonatal intensive care unit (NICU). Obesity now costs the NHS around £1 billion a year and the UK economy a further £2.3 billion of indirect costs. Reducing maternal and childhood obesity, through effective obesity treatment programmes, could result in significant advantages for the NHS and society.

6.1.2 Smoking

96. Smoking is associated with reduced fertility, although this has not always been widely recognised. The evidence is consistent, through a range of pathways affecting both male sperm production and many female aspects including hormone levels and egg development. Female smokers are more likely to have infertility, and delayed conception is more common with female exposure to active or passive smoking.

97. There is compelling evidence of a negative effect of smoking on IVF outcome, which has been shown to apply to females in relation to active and passive smoking, and in addition there is evidence of reduced success with male smoking. The impact of passive smoking is only slightly less than active smoking and effects are reversed after about one year.

98. Smokers may need twice the number of cycles as non-smokers to conceive and the effect is comparable to an increase in female age of 10 years. Female smoking has also been found to double the risk of pregnancy loss in assisted conception pregnancies. Pregnancy complications and outcomes include higher miscarriage rates, placental complications, fetal growth restriction, preterm birth, stillbirth and early neonatal death. Risks can be reversed by smoking cessation.

6.1.3 Substance misuse

99. Any substance misuse during pregnancy will reach the developing baby and may cause harm.

6.1.4 Alcohol

100. Every pregnant woman in Scotland is given a copy of the NHS Health Scotland and Scottish Government publication Ready, Steady, Baby²⁴ which states that there is no 'safe' time for drinking alcohol during pregnancy and no 'safe' amount. Drinking no alcohol in pregnancy is the best and safest choice.

6.1.5 Maternal age

101. A woman's ability to conceive a child reduces with age - the younger she is the higher the chance of success. In the year from 01/01/2010 to 31/12/2010, for women having IVF using fresh embryos created with their own fresh eggs, the percentage of cycles started that resulted in a live birth (national averages) was:

• 32.2% for women aged under 35
• 27.8% for women aged between 35-37
• 21% for women aged between 38-39
• 13.7% for women aged between 40-42
• 5.3% for women aged between 43-44
• 2% for women aged 45 and over

102. These figures show clearly that IVF is most successful in women aged under 35. Several recent reports show that couples are starting their families later and possibly view IVF as a viable treatment option in their late 30s and early 40s. These studies show that public perception of IVF is that it is far more successful than it actually is, particularly in older women. Women need to be made more aware of the steady decline in their fertility from age 30, and especially in the steep decline from age 35. Appendix G sets out the cost effectiveness of IVF by age.

103. The tables at Appendix H set out the proportion of births due to IVF or ICSI, and show that these treatments account for 3.55% of all first births in Scotland. 433 out of 3181 (13.6%) of first babies born to women between the ages of 35 and 39 are due to IVF or ICSI and 64 out of 634 births (10.1%) in women over the age of 40¹⁶. Treatment results in a live birth in approximately 25% of those undergoing the first fresh embryo transfer, but this is significantly higher in younger women and significantly lower in older women. The success of treatment reduces with a second fresh cycle, and continues to reduce with subsequent treatments.

6.2 How many cycles should be provided?

104. The New England Journal of Medicine published an article in 2009, Cumulative live-birth rates after in vitro fertilization²⁵ based on couples accessing six cycles of IVF treatment. It demonstrated the live birth rates in relation to each cycle based on an optimistic cumulative live birth rate assuming that patients who did not return for treatment had the same chance of a pregnancy resulting in a live birth as those who remained in treatment. The conservative birth rate assumes that patients who did not return for treatment did not have a pregnancy resulting in a live birth.

105. Six thousand, one-hundred-and-sixty-four women undergoing 14,248 cycles were included in the study which showed the live birth rates in the table below:

Table 7. Cumulative live birth rate after successive treatment cycles

No of cycles	Conservative live birth rate	Optimistic live birth rate
1	25	25
2	37	40
3	45	53
4	49	62
5	50	68
6	51	72

106. These data would indicate that providing three cycles of IVF should result in a 45-53% chance of a live birth rate. Since the publication of this study in 2009, national UK data have shown a continued trend upwards in success rates after IVF and thus one would expect that cumulative live birth rates will continue to rise.

107. Definitions used in these data are historical and not necessarily indicative of improvements which may be seen in the future based on the new definition of a cycle of IVF as outlined in this report. However, the Group was of the view these data remain helpful. As mentioned later in the report, NHS Boards are advised to keep a careful eye on the increasing numbers of patients who have multiple frozen embryo transfers and the subsequent cost.

6.3 Should we treat couples with existing children?

108. To ensure a fully equitable service for infertility patients throughout Scotland, anyone with a fertility problem who could benefit from treatment and who fit the criteria based on medical evidence, should be treated, including those whose partner has had a child from a previous relationship. The NHS in Scotland should aim to ensure that all inequities relating to infertility treatment are removed and set a deadline for achieving this.

6.4 Waiting list management

109. To manage the waiting list most efficiently patients should be allowed to continue with treatment once they have reached the top of the waiting list.

110. The use of IVF as a fertility treatment should not be regarded as a single cycle opportunity for conception. Effective fertility treatment requires repeated exposure to the opportunity to conceive. This principle applies to the treatment of anovulatory infertility or the use of donor insemination and should therefore apply to IVF. To return a woman to the end of a queue for treatment between cycles only serves to increase her age at the time of exposure. The link between increased female age and reduced chance of success is well recognised. In clinical effectiveness terms it is better for NHS entitlement to be realised in the shortest time frame possible. Couples should therefore be returned to the top of the queue if repeat cycles are required.

111. The Group recommends that patients currently on the waiting list who will no longer meet the new criteria from 1 April 2013, be kept on a 'holding list' for a period of (at least) one year and, during that time, be supported by their NHS Board to make lifestyle changes that will, ultimately enable them to receive treatment.

112. All new patients from 1 April 2013, without exception, must meet new access criteria recommendations.

113. NHS Boards, and in particular, the four NHS Centres providing treatment, should work with the patient stakeholder group, Infertility Network Scotland¹⁴, to ensure that patients are kept informed of changes to treatment pathways.

114. In 2010, NHS Lothian altered its treatment pathway and eligibility criteria for IVF patients. Some of these changes anticipated recommendations outlined in this report.

115. As it was recognised that some couples undergoing or waiting for treatment could be affected by these changes, thought was given on how to handle the transition. In a manner similar to that proposed in this report, it was decided that those already undergoing treatment would be not affected, while those waiting for treatment were advised of the change and, where appropriate, directed to support to address their smoking or BMI status. As these lifestyle changes can be difficult, couples were not removed from the waiting list but retained their 'place in the queue' in the expectation that these changes would have been successfully made by the time treatment was offered. Extra time was allowed for patients to make the change had they not successfully done so by the time they reached the front of the queue.

116. Infertility Network Scotland¹⁴ had kept abreast of the changes in NHS Lothian and, further to the support provided by the service, were able to help couples work through why these changes had been introduced, how these changes affected them and what options were available. It is believed that the communication with patients by both the service and Infertility Network Scotland made the transition to the new pathway and criteria more understandable than it may have otherwise been.

6.5 The role of support organisations

117. The public needs to be better informed about fertility issues in general and, in particular, what factors might affect fertility, how best to preserve it and what services are available for infertility treatment, support and information.

118. The Scottish Government is funding Infertility Network Scotland¹⁴, an organisation which provides help, information and support to patients (both present and past), to assist with this. The National Infertility Group believes that NHS infertility services should be much more person-centred and recognises the varying and sometimes distressing effects patients and their families face in both accessing care and in coming to terms with the consequences of treatment failure.

119. Infertility Network Scotland's core role is to support patients undergoing treatment, and to work with NHS Boards to ensure a better patient experience.

120. Health Boards were surveyed in September 2009²⁶ to establish details of their provision of infertility services and what eligibility criteria were being used in each Health Board area. Following this, Infertility Network Scotland met with all Health Boards who were not meeting the current Government recommendations for patients needing to access fertility services with a view to establishing what plans they had to meet these recommendations. Staff from Infertility Network Scotland offered to provide patient representation at any Health Board meetings to discuss fertility services. Health Boards were surveyed recently, to establish what positive changes there had been for patients since the first survey, and Infertility Network Scotland is in the process of collecting these responses.

121. Health Boards should consult with organisations which represent patient views at meetings where provision of IVF services is being materially reviewed or changed.

122. There can be many hurdles to overcome before reaching the stage of having infertility treatment, as well as during and after treatment, whatever the outcome. Infertility Network has much experience of giving support to this group of patients and reports that emotional distress caused by infertility is heightened dramatically when patients find themselves unable to access the treatment they need, and find that access criteria and waiting times differ depending on where they live in Scotland.

123. Part of Infertility Network UK, the AceBabes network¹⁴ provides targeted help and support on a wide range of issues, not only to those people who have had successful fertility treatment, but also to those who found their families through other parenting options, including adoption.

124. Around one-third of those suffering from infertility will never become parents and More To Life, another part of the charity, offers ongoing support to those couples whose treatments have been unsuccessful and are exploring what a life without children will mean for them and the best way of coping with that.

6.6 The important implications of single embryo transfer and the increase in frozen embryo transfers

125. There are 'hidden' costs associated with IVF. For example, in women who conceive twins (or more), the need for hospital based antenatal care, complicated vaginal deliveries and caesarean sections is higher and is associated with more frequent and longer maternal and neonatal hospital admissions. This can result in higher costs to the NHS with the 'care' cost of a twin pregnancy estimated at approximately three times the cost of a singleton pregnancy. Singletons born as a result of IVF are also more likely to require neonatal care. The average cost of caring for a baby in neonatal intensive care in the UK is around £1,000 a day²⁷.

126. There is strong evidence that the rise in recent years in the prevalence of twin births in the UK is related to fertility treatment, particularly IVF, in addition to an independent effect of rising maternal age. Data from the Human Fertilisation and Embryology Authority (HFEA)²⁸ shows in 2009 the multiple IVF birth rate following fresh embryo transfer in the UK was 22.4%. In comparison, one in eighty women who conceive naturally has a multiple birth.

127. The direct link between the number of embryos transferred to the uterus during IVF treatment and the chance of twin pregnancy is beyond dispute. An analysis of the factors contributing to high multiple pregnancy rates after IVF acknowledged that contracting arrangements for NHS-funded care influenced uptake of single embryo transfer policies within clinics.

128. The Human Fertilisation and Embryology Authority (HFEA) has introduced a graduated policy²⁸ insisting on all clinics in the UK achieving a reduction in multiple pregnancy rates to 10% of all births following IVF over a 3-year period. The final target which came into effect from October 2012 is 10%.

129. Elective single embryo transfer will undoubtedly reduce the incidence of twin pregnancy. However, there are concerns amongst providers that this will reduce pregnancy rates and potentially result in patients deciding to move to centres abroad who do not operate such a policy in the hope of improving their chances of pregnancy. All centres in the UK have to meet the HFEA target regardless of whether they are NHS or private centres. There is recent robust evidence (BMJ 2010; 341:c6945)⁹ that the pregnancy rate over two cycles (fresh plus frozen embryo transfer) using single embryo transfer is as good as with a single cycle where two embryos are transferred with minimal risk of twin pregnancy. This concern will therefore be reduced if the definition of a cycle is recognised as set out above.

130. The four tertiary units in Scotland are supportive of the need to address the public health concerns of multiple pregnancies, and believe that a common approach will help reduce the number of multiple pregnancies in Scotland. The principles at Appendix I underpin the advice which patients should receive about the appropriate number of embryos to transfer in a treatment cycle.

131. Recognising the importance of reducing risk to both mothers and children and requirements on reducing multiple births from the Human Fertilisation and Embryology Authority, NHS Lothian changed its treatment pathway for infertility in 2010.

132. This approach was drawn from the recommendations of a UK-wide expert group in 2006. This group, chaired by Professor Peter Braude, recommended that single embryo transfer should become the norm. The case for a transfer of a single blastocyst, in good prognosis patients, on day five or six is overwhelming, and frozen cycles should be used after each fresh embryo transfer to achieve equivalent pregnancy rates without the risks of multiple pregnancies.

133. The new approach was adopted despite a small anticipated reduction in success rates, as the change was felt to be a clinically appropriate given the high risks associated with multiple pregnancy.

134. However, 2 years on, this anticipated fall in success rates has not occurred. Indeed initial clinical data show the change in the pathway and the use of additional frozen embryos has led to a higher proportion of couples commencing a cycle successfully becoming pregnant in 2011 than had been the case prior to the change. The use of the subsequent frozen embryos appears to have more than compensated for the drop in pregnancy rate caused by moving significantly from the transfer of two embryos to one.

135. NHS Boards are advised to keep a careful eye on the increasing numbers of patients who have multiple frozen embryo transfers and the subsequent cost. This should be considered as part of the review in March 2015.

136. A recent report in the Lancet²⁹ (November 2012), recognised single embryo transfer in IVF as an important step in reducing early/ premature birth in developed countries.

137. Infertility Network Scotland¹⁴ developed a patient factsheet³⁰ on Single Embryo Transfer which is supplied to all four NHS IVF units in Scotland.

138. Further information on the benefits of elective single embryo transfer are set out on the HFEA website One at a time³¹.