Assisted conception and multiple pregnancies: methods of reducing multiples from assisted reproduction

Increase in the utilization of assisted reproductive technology (ART) over the past two decades has led to a significant increase in the incidence of multiple births. Following IVF, the chance of conceiving twins is 20-times that of higher-order multiples and 400-times higher than in the general population [1]. Figures from the USA (Society for Assisted Reproductive Technology) registry for the year 2002 indicate that 58% of all IVF births were singletons, 29% were twins and 7% were triplets or more [2]. Comparable figures from Europe in 2001 show that 75% of babies conceived through ART were singletons, 24% were twins and 1.5% were triplets. Worldwide, about 50,000 children are born annually as a result of IVF treatment and this number is set to rise further in the next few years. Thus, there are serious concerns about the impact of the global growth in ART on future healthcare needs.

In comparison with singletons, twins have a sixfold and triplets a 10–20-fold increased risk of mortality [1]. There has traditionally been a tacit acceptance that iatrogenic multiple pregnancy is a necessary price that couples and clinicians must pay in order to ensure the success of invasive, expensive and emotionally demanding fertility treatment. In some cases, twins are even perceived to be a desirable end product of ART by couples, as well as by healthcare providers [3]. It is only in recent years that there has been growing awareness that the aim of fertility treatment is not merely to achieve conception but to ensure the delivery of a healthy infant.

A number of observational studies have confirmed the fact that an elective double embryo transfer policy substantially reduces the risks of triplets without affecting overall live birth rates [4–6]. In 2001, 64% of all transfers in Europe involved single or double embryos [7] but in the USA, the corresponding figure was 37% [2]. The proportion of IVF-related triplet deliveries in Europe during this period was 1.5% compared with 3.8% in the USA [2,7]. While the problem of triplets and higher-order multiples has been largely addressed in many European centers, almost half of all IVF babies continue to be twins. While the actual risks are lower in comparison with higher-order multiples, the sheer number of twin pregnancies raises substantial concerns regarding maternal and fetal wellbeing. Suggested options for the elimination of twins include selective fetal reduction, single blastocyst transfer and elective single embryo transfer (eSET). Selective fetal reduction in twins carries a risk of miscarriage and poses serious ethical and legal questions [8]. Blastocyst transfer (i.e., replacing embryos on day 5 rather than day 2–3 post oocyte retrieval) involves transferring fewer but higher quality embryos that have survived in culture up to the blastocyst stage. This technique has been demonstrated to be successful [9] but requires special expertise and cannot be routinely offered by all laboratories. Failure to grow to blastocyst stage limits the number of embryos available for transfer and can compromise the live birth rate per cycle started. Also, universally agreed criteria for the selection of blastocysts for transfer are yet to be clarified [10]. A Cochrane Review has failed to demonstrate any advantage of blastocyst transfer over conventional (day 2–3) transfer, in terms of pregnancy rate per woman. The combined odds ratio (OR) in favor of day 2–3 transfer was 0.80 (95% confidence interval [CI]: 0.57–1.29) [11].

Elective single embryo transfer

A systematic review of randomized controlled trials comparing elective double embryo transfer with eSET has been undertaken [12]. The literature currently includes five published trials where day 2–3 eSET was compared with double embryo transfer [13–17]. Compared with single embryo transfer, double embryo transfer in a fresh IVF/intracytoplasmic sperm injection (ICSI) treatment cycle led to a significantly higher pregnancy rate (OR: 2.18; 95% CI: 1.72–2.77; test for overall effect: p < 0.00001) and live birth rate (OR: 1.94; 95% CI: 1.47–2.55; test for overall effect: p < 0.00001) per woman. The multiple pregnancy rate was significantly lower in women who had eSET (OR: 0.05; 95% CI: 0.02–0.13; p = 0.00001). The largest and most recent trial compared two policies: transferring two fresh embryos versus transferring a single fresh embryo followed by a single frozen–thawed embryo [18]. There were no significant differences in the cumulative live birth rates (OR: 1.19; 95% CI: 0.87–1.62; p = 0.3) between the two groups. Multiple pregnancy rates were significantly higher in women who had elective double embryo transfer (OR: 62.83; 95% CI: 8.52–463.57; p = 0.00005).

These results indicate that after fresh IVF treatment the risk of multiple pregnancy, including twins, is lower following eSET than after elective double embryo transfer, as are the live birth and pregnancy rates. However, an eSET policy involving a fresh IVF cycle followed by a frozen embryo replacement cycle reduces the risk of multiples while achieving a live birth rate comparable to that achieved by transferring two fresh embryos. There are, however, no data on cumulative live birth rates associated with fresh followed by subsequent frozen eSET versus fresh and subsequent frozen double embryo transfer.

Reducing the number of embryos transferred in the course of IVF treatment is a certain way of limiting multiple pregnancies. Current evidence suggests that this can be achieved without compromising live birth rates per woman. In women under the age of 38 years with a good prognosis (first or second IVF cycle, a number of good quality embryos available for transfer), eSET should be considered as a way of avoiding twins without compromising treatment success [19].

Limiting the number of embryos transferred

Any change in health strategy can be either voluntary or enforced by legislation. Voluntary change is possible only if service providers and consumers are convinced that the new policy offers advantages that outweigh any potential disadvantages.

Current evidence does not support a universal policy of embryo replacement in all women undergoing IVF. eSET should be reserved for women who are at significant risk of multiple gestation [16]. This includes those who are relatively young, in their first or second IVF cycle and possess a number of good quality embryos [20]. Others should receive two embryos, and many would argue for a three embryo transfer policy in women over the age of 40 years. Accurate determination of embryo quality is also a crucial component of an eSET policy.

Cryopreservation

The outcome of an eSET policy can be substantially improved in terms of cumulative live births when used in conjunction with an efficient and reliable embryo cryopreservation program [21,22]. While human IVF embryos can be frozen successfully, the rates of survival after thawing vary substantially from clinic to clinic and live birth rates are reduced in frozen cycles. There are few controlled data to show that the protocol favored by most clinics is optimal. Most clinics freeze pronucleate and early cleavage-stage embryos and report that 30–80% survive thawing. Such damage is not inconsistent with development to term but intact embryos have a greater potential for implantation and development [23]. There is a need to develop alternative cryopreservation protocols that will lead to improved outcomes in frozen cycles.

Perception of success in IVF

Outcomes in IVF are conventionally expressed in terms of a live birth per fresh cycle. Outcomes of subsequent frozen cycles are reported separately. It comes as no surprise that expressing outcomes per fresh cycle can underestimate the success of eSET by half. It has been suggested that expressing outcomes as live births per woman makes better practical and statistical sense [24]. Proponents of eSET have argued that the best outcome should be either singleton live birth or term singleton live birth [25].

Consumer choice

Clinicians may feel that a high twin rate in IVF is unacceptable [26], but many couples have different views. Some women, especially mothers of IVF twins, may actually see twins as a desirable outcome [27,28]. Others who are paying for their treatment may feel that having twins represents a cost-effective way of completing their family. Improved methods of communicating risks to couples do not always change couple’s opinions [29]. Fewer than a third of UK women in their early thirties, embarking on their first IVF cycle, felt that a hypothetical policy of eSET was acceptable if it meant slightly reduced pregnancy rates [29]. Some women waiting for IVF treatment view severe child disability outcomes associated with double embryo transfer as being more desirable than having no child at all [30]. Women embarking on IVF may be influenced more strongly by considerations of ‘treatment success’ than by future risks to their offspring.

Financial arrangements

Couples who are charged either for multiple fresh IVF cycles (resulting in a transfer of the single best embryo) or for freezing and thawing of embryos are understandably reluctant to consider eSET. By contrast, the eSTET policy has worked well in European settings where IVF is subsidized. In July 2003, the Belgian government agreed to reimburse IVF/ICSI costs for all women under the age of 43 years for a maximum of six cycles, provided all women at risk of twins underwent eSET [31]. Early results suggest a steady decline in the number of embryos transferred as well as IVF-related multiples (from 34% in 1996 to 24% in 2001) [19,31]. The financial argument is stronger in healthcare systems where the source of funding for IVF is the same as that for obstetric and neonatal costs. The existing system in the UK, whereby many couples pay for IVF while the cost of neonatal care is borne by the National Health Service, is apt to discourage some couples from accepting eSET.

Legislation

It is clear from the European experience that legislation is a potent factor in changing practice in IVF [32]. Saldeen and Sundstrom have presented data on IVF success rates in Sweden during three periods: pre-legislation, during a transitional period and post-legislation [33]. Moving from a 25 to a 72% eSET rate within a single clinic in Sweden dramatically reduced twin rates without detriment to ongoing pregnancy rates.

There is a need to improve the safety of ART by reducing the rate of iatrogenic multiple pregnancies. In IVF, limiting the number of embryos transferred appears to be the most effective way of avoiding unwanted multiples. In women at high risk of twins, eSET can lead to high cumulative live birth rates. Regulation of assisted reproduction is more likely to be successful in the presence of adequate funding arrangements.

Financial disclosure

The author has no relevant financial interests related to this manuscript, including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.