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Keywords:

  • Artificial reproduction;
  • high-order multiple-pregnancy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

High order multiple pregnancies have substantial morbidity and mortality. Fertility treatment is commonly responsible for their conception and is available globally with variable regulation. We investigated cross-border fertility treatment in these pregnancies in a UK fetal medicine unit, recording mode of conception, country of fertility treatment, reason for non-UK treatment and fetal reduction. Over an 11-year period, 109 women had a high order multiple pregnancy. Ninety-four women (86%) conceived with fertility treatment of whom 24 (26%) had this performed overseas. Cross-border fertility treatment poses an increasing challenge to obstetricians. National data on its occurrence is urgently needed.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Since the development of assisted reproductive technology (ART) in the late 1970s, and specifically in vitro fertilisation (IVF) techniques, the prevalence of multiple pregnancies has greatly increased in the United Kingdom and elsewhere. There is a consensus among the medical community that multiple pregnancy, particularly triplet and other high-orders, represents a serious complication of fertility treatment. The European Society of Human Reproduction and Embryology (ESHRE) Capri workshop group have highlighted high order multiple pregnancy complications: pre-eclampsia 11%; hospitalisation 57%, premature rupture of the membranes 13%, prematurity 13%; intrauterine death 13.5% and neonatal mortality within the first 28 days of life 21.3%.1 The perinatal and maternal morbidity and mortality associated with high order multiple pregnancies has led regulatory bodies such as the Human Fertilisation and Embryology Authority (HFEA) in the UK to develop rules to standardise fertility therapies. Since March 2004, the HFEA has limited the number of embryos that may be transferred following IVF and Intra-Cytoplasmic Sperm Injection (ICSI) to a maximum of two, other than in specified exceptional circumstances.

Assisted reproductive technology regulation is also tightly organised and operated in some other European countries such as Belgium for example, where the law links treatment insurance with the number of embryos which may be transferred and the age of the recipient. This has halved the multiple pregnancy rate.2

In other European countries, however, and outside the EU, there is often national control of ART practices and no statutory limit to the number of embryos transferred. In these countries, the rate of triplet and higher multiples remains high. For example; out of all 225 507 IVF/ICSI cycles reported to ESHRE in 2004, there were 49 843 involving three embryo transfers and 7511 involving four embryo transfers. In that year, in France and Germany, the two biggest ART nations in Europe, the proportion of three embryo transfer cycles was 18.7% and 27.1%, respectively, compared to 5.5% in the UK. Although the technique of embryo reduction is available in most circumstances, as the ESHRE Capri workshop concluded: ‘embryo reduction involves extremely difficult decisions for infertile couples and should be used only as a last resort’.

We observed that women with triplet and higher order multiple pregnancies presenting to our UK tertiary centre, multiple pregnancy clinic had received fertility treatment overseas. We investigated the extent of cross-border reproductive care in our patients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This is a retrospective study of women with high order multiple pregnancy, defined as more than two viable embryos on ultrasound examination, referred to the specialist multiple pregnancy clinic before 14 weeks gestation at the Fetal Medicine Unit, University College London Hospital (UCLH), London, UK between February 1996 and July 2007. Cases were identified by searching the electronic computer database on which all ultrasound data are entered (Viewpoint software, GE Healthcare, Milwaukee, WI, USA) using the search strategy ‘multiple pregnancy >2’. Women referred to this specialist clinic have been managed by the same fetal medicine consultant (ERJ) since its inception in January 1996.

During their appointment women were asked information about the method of conception (natural or assisted), the type and location of any fertility treatment and the reason for undergoing treatment outside the UK. The use of clomiphene was recorded because unlike the UK, in many other countries it is available over the counter. Women had a detailed dating scan, and ultrasound scan details were entered into the Viewpoint database. All couples were counselled regarding the obstetric and neonatal risks associated with high order multiple pregnancy and were offered selective embryo reduction.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

There were 116 women referred to the specialist multiple pregnancy clinic at UCLH within the study period with a viable triplet or higher order multiple pregnancy, confirmed on ultrasound examination in the first trimester of pregnancy. One woman who was not eligible for NHS antenatal care returned to her home country for delivery after selective embryo reduction was performed and she was subsequently excluded from analysis; the remaining 115 women were eligible for and received NHS antenatal care. We were unable to get accurate information on whether the women were eligible for NHS fertility treatment because of changes in eligibility over the time period studied. Information on the number of embryos transferred in IVF cycles at assisted conception centres was also not available. Complete data were not available in six cases (5.2%) and these women were excluded from the study leaving 109 women for full analysis.

Fifteen (14%) women conceived spontaneously, while the remaining 94 women (86%) disclosed that they had received fertility treatment (Table 1). Over one-fifth of all triplet and higher order multiples women (n = 24, 22%) received fertility treatment outside the UK. One in four women who had fertility treatment (n = 24, 26%) had received it overseas.

Table 1.   Type and location of fertility treatment of women with high order multiple pregnancies
Type of fertility treatmentLocation of fertility treatmentn (%)
UKOutside UK
Clomiphene citrate9413 (13.8)
Ovulation induction and IUI505 (5.3)
IVF all562076 (80.9)
IVF without ICSI521769 (73.4)
IVF with ICSI437 (7.4)
Total (% of total receiving fertility treatment)70 (74.5%)24 (25.5%)94 (100)

Triplet pregnancies accounted for 89 pregnancies. There were four women with quadruplet and one with quintuplet pregnancy — all of whom underwent embryo reduction. Three of these women had received fertility treatment in the UK (all quads), of whom two reduced to twins and one to a singleton. There were one each of quintuplet and quadruplet pregnancies in the overseas-treated women, both of whom reduced to twins.

The countries outside the UK where fertility treatment was sought were: Algeria (n = 2); Belgium (n = 2); Cyprus (n = 1); France (n = 1); Germany (n = 3); Greece (n = 1); India (n = 1); Irish Republic (n = 1); Israel (n = 4); Japan (n = 1); Lebanon (n = 1); Jordan (n = 1); Spain (n = 1); South Africa (n = 1); Nigeria (n = 1); Turkey (n = 1) and the USA (n = 1).

Most women did not give reasons for having their treatment overseas, but of those who did, they cited: the high cost of treatment in the UK; that the country was their home; a better success rate because of higher number of embryo transfers overseas; faster speed of treatment and the availability of an acceptable ethnic oocyte donor. Some women who were eligible for NHS treatment nevertheless opted to have IVF performed overseas.

Forty-four women (40.4%) underwent selective embryo reduction. The remaining 65 women (59.6%) declined selective embryo reduction and the pregnancies were monitored expectantly in the specialist multiple pregnancy clinic.

Compared to women having UK treatment, women receiving fertility treatment overseas were significantly less likely to have embryo reduction (eight out of 24 overseas-treated women, 33%, compared with 36 out of 70 UK treated women, 51.4%, P < 0.005 chi-squared test). Only one woman out of the 15 spontaneously conceived triplet pregnancies decided to have embryo reduction.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This study is the first to examine the topic of type and location of fertility treatment in multiple pregnancy. We show that in a tertiary level specialist multiple pregnancy clinic, over the last decade, one-quarter of all women with high order multiple gestations who had assisted conception obtained their treatment outside the UK. These women were significantly less likely to have embryo reduction than those who were treated in the UK. Over a fifth of all women with triplet or other high order multiple gestations conceived from fertility treatment performed outside the UK.

Over the last decade, the powerful parental drive for a successful pregnancy, irrespective of the risks associated with a multiple pregnancy seems to have driven NHS patients to seek ART treatment abroad. To avoid the negative connotations associated with terms such as ‘fertility’ or ‘procreative tourism’, ESHRE uses the term ‘cross-border reproductive care’ to describe this movement of candidate healthcare recipients from one country or jurisdiction to another to obtain fertility treatment. Access to good health care, freedom of movement and freedom to reproduce are important concerns to patients and care providers. Freedom of movement also applies to healthcare providers who may move to practise across borders within EU nation states. However, safety issues must remain paramount. Despite counselling on the risks of continuing with a higher order multiple pregnancy, women receiving treatment overseas were less likely to opt to reduce a pregnancy. The reason for this is unclear, but it could be related to differences in the cultural beliefs or the counselling received at the time of fertility treatment about fetal reduction procedures, between women treated in the UK and overseas. Our observation that women who have invested expectations, emotions and money, seeking treatment outside their own borders are less likely to reduce a high order pregnancy adds strength to the argument for information campaigns by government, patients and professional organisations, in order to reduce risk for vulnerable intended parents and their offspring.

This study provides the first information about the extent of cross border reproductive care resulting in multiple pregnancies in the UK. The limitation of the study is that it is retrospective and our ascertainment may not be complete. We relied on women’s memories of the ART stimulation regimens they received, and other barriers such as different languages and variation in informed consent procedures overseas may mean that women may not have fully understood the details of the treatment they received. The numbers of high order multiple pregnancies seen in our unit is not fully representative because of its location in central London with its mobile population, where there are a high number of IVF units, and because it offers specialist procedures such as selective embryo reduction. Our unit may be more likely to see the consequences of cross border reproductive care, and the percentage of women who conceived by fertility treatment outside the UK could be an overestimate of the national situation. The issue of access to an acceptable ethnic oocyte donor, however, is not limited to our unit but has been noted by other UK hospitals outside London (personal communication — Brian Liebermann, Manchester). It is also possible, that we underestimated the proportion of high order multiple gestations conceived by ART in general and those conceived outside the UK for a number of reasons. These include a reluctance on some women’s part to reveal fertility treatment, suspicion that such information could affect entitlement to free NHS antenatal treatment, or not fully understanding what fertility treatment had been given. These are sensitive issues for patients and would suggest the need for a careful prospective study.

The introduction of the Department of Health 18-week target from GP referral to hospital treatment by December 2008 may accelerate the fertility treatment process for some couples. It will have little impact, however, on couples ineligible for NHS fertility treatment and they may be more likely to consider cheap and fast ART which is increasingly available overseas.

In 2003/2004, the Department of Health reported 130 Triplet deliveries out of 575 900 deliveries in England, a rate of 22.6 per 100 000 deliveries.3 For the same year the ESHRE database reported only 22 triplet deliveries resulting from IVF or ICSI cycles for the whole of the UK. The spontaneous incidence (10 per 100 000 deliveries) would give an expected figure of about 58 triplets in that year, leaving a surplus of approximately 50 triplet deliveries in England. These additional pregnancies could be because of the use of Clomiphene (use unregulated by the HFEA); analysis or definition error, or that some triplets resulted from treatment obtained overseas. Our results suggest that overseas treatment may well account for a significant proportion.

As part of its overall strategy to reduce the iatrogenic multiple birth rate, the HFEA is introducing regulations on ART which will, in many IVF cycles, limit the number of embryos transferred to one. Couples may choose to have ART outside the UK because they are more likely to obtain a pregnancy with a multiple transfer. The recent European Union proposal to enshrine the right to cross-border health care may increase the volume of cross-border reproductive care by obliging member states to fund cases where initial treatment was obtained in another EU country.

High order multiple pregnancies have financial implications for the NHS with additional antenatal care, such as serial ultrasound examinations and need for maternal hospitalisation for severe complications. Obstetric complications such as pre-eclampsia and postpartum haemorrhage can be compounded by the relatively high maternal ages seen in women receiving fertility treatment. The oldest woman to receive treatment overseas in our clinic was 48 at the time of referral, with a triplet pregnancy. The most recent Confidential Enquiry into Maternal Death showed a relative risk of 2.5 (95% CI 1.4–4.5) for maternal mortality in multiple pregnancy.4 The report contains anecdotal information on the practice of women obtaining fertility treatment abroad, but concedes that there are no published data on this topic. The NHS also shoulders increased neonatal costs where the greater risk of very preterm birth (and concomitant low birthweights) in high order multiple pregnancies results in high levels of dependency after birth. In a 2006 paper, Ledger and colleagues estimated the costs of triplet pregnancies within the first year of life to be approximately ten-fold greater than a singleton pregnancy, in 2002 figures this amounted to over £32 000.5 More importantly, however, is the longer term impact for individuals born from these pregnancies, where there is a 6.5-fold increase in the rate of cerebral palsy compared with a singleton pregnancy, and the emotional and psychological burden on parents simultaneously caring for more than one baby is considerable.6 The ESHRE report of 2000 suggested a 50% risk of couples separating within a year of delivery.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Fertility treatment outside the UK was responsible for over a quarter of fertility-treated high order multiple pregnancies seen in a UK specialist multiple pregnancy clinic. Reasons our patients gave for seeking overseas ART included the high cost and slow local access to ART in the UK, the limited number of embryo transfers in the NHS, as well as ethnically acceptable oocyte donors. Women who conceived after fertility treatment were significantly less likely to opt for embryo reduction if they underwent treatment outside the UK.

Cross border reproductive care is an under recognised and unregulated phenomenon that is likely to increase as ART technology becomes ever more and possibly more attractive outside the UK. There is a need for national data on this phenomenon. Governments and relevant regulatory and professional bodies should seek consensus on harmonising safe and ethical fertility treatment across jurisdictions.

Disclosure of interests

We have no relevant financial, personal, political, intellectual or religious interests in this matter.

Contribution to authorship

Eric Jauniaux and Francoise Shenfield conceived the idea of this study, guided its evolution and edited the content. Anna David participated in the collection of data and edited the content. Alastair McKelvey collected and analyzed the data and wrote the content.

Details of ethics approval

We wrote to the local ethics committee, who confirmed that the study did not need to undergo the formal ethical application process.

Funding

This study did not receive any specific funding.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

We should like to record the assistance of Melanie Davies FRCOG.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
  • 1
    Multiple gestation pregnancy. The ESHRE Capri Workshop Group. Hum Reprod 2000;15:185664.
  • 2
    Ombelet W, De Sutter P, Van der Elst J, Martens G. Multiple gestation and infertility treatments: registration, reflection and reaction – the Belgian project Hum Reprod Update 2005;11:314.
  • 3
    Government Statistical Office. NHS Maternity statistics, England, 2003–2004. ISBN 1841829552.
  • 4
    Lewis G. Saving Mothers’ Lives 2003–2005. Report. A report of the UK confidential enquiries into maternal deaths. Chap. 1. London, UK: HMSO.
  • 5
    Ledger WL, Anumba D, Marlow N, Thomas CM, Wilson EC, Cost of Multiple Births Study Group (COMBS Group). The costs to the NHS of multiple births after IVF treatment in the UK. BJOG 2006;113:215.
  • 6
    Keith LG, Oleszczuk JJ, Keith DM. Multiple gestation: reflections on epidemiology, causes, and consequences. Int J Fertil Womens Med 2000;45:20614.