Abstract
Worldwide 95% of the adults express their desire for a child. Between 8 and 12% of reproductive-aged couples worldwide have problems conceiving. The probable global average for infertility is estimated to affect 9% of women. In some regions of the world, the rates of infertility are much higher, reaching up to 30% in some populations [1]. Over the past decade, there has been a significant increase in the number of centres offering Assisted Reproduction Techniques (ART). The number of ART cycles performed worldwide has increased clearly over time: a 5–10% increase per annum. The International Committee for Monitoring Assisted Reproductive Technologies reported >1,251,881 procedures with ART in their World Report on Assisted Reproductive Technologies for 2007 [2]. This Committee yearly summarises the data collection set from 2,419 of 3,354 (72.1%) known ART clinics in 55 countries. In 2007, in the United Kingdom, availability of ART was estimated to have been at 766 cycles per million inhabitants. Availability of ART treatments varies by country from 12 (Guatemala) to 4,140 (Israel) treatments per million population. The latter is the result of substantial economic support for patients undergoing in vitro fertilisation (IVF). Australia, New Zealand, and European countries, especially northern Europe, also strongly support ART treatments. The overall worldwide delivery rate per fresh aspiration stood at 20.3% in 2007, ranging from 8% to 33%. For frozen-embryo transfer (FET), delivery rates were 18.4%, resulting in a cumulative delivery rate of 25.8%. In the United Kingdom in 2013, a delivery rate of 26% per cycle started was noted [3]. In Europe, the delivery rate after cycle of intrauterine insemination (IUI) with husband’s semen was 8.9% and 13.8% after IUI with donor semen [4].
1 Assisted Reproduction Worldwide: Availability and Outcomes
Worldwide 95% of the adults express their desire for a child. Between 8 and 12% of reproductive-aged couples worldwide have problems conceiving. The probable global average for infertility is estimated to affect 9% of women. In some regions of the world, the rates of infertility are much higher, reaching up to 30% in some populations [1]. Over the past decade, there has been a significant increase in the number of centres offering Assisted Reproduction Techniques (ART). The number of ART cycles performed worldwide has increased clearly over time: a 5–10% increase per annum. The International Committee for Monitoring Assisted Reproductive Technologies reported >1,251,881 procedures with ART in their World Report on Assisted Reproductive Technologies for 2007 [2]. This Committee yearly summarises the data collection set from 2,419 of 3,354 (72.1%) known ART clinics in 55 countries. In 2007, in the United Kingdom, availability of ART was estimated to have been at 766 cycles per million inhabitants. Availability of ART treatments varies by country from 12 (Guatemala) to 4,140 (Israel) treatments per million population. The latter is the result of substantial economic support for patients undergoing in vitro fertilisation (IVF). Australia, New Zealand, and European countries, especially northern Europe, also strongly support ART treatments. The overall worldwide delivery rate per fresh aspiration stood at 20.3% in 2007, ranging from 8% to 33%. For frozen-embryo transfer (FET), delivery rates were 18.4%, resulting in a cumulative delivery rate of 25.8%. In the United Kingdom in 2013, a delivery rate of 26% per cycle started was noted [3]. In Europe, the delivery rate after cycle of intrauterine insemination (IUI) with husband’s semen was 8.9% and 13.8% after IUI with donor semen [4].
With wide regional variations, single embryo transfer (SET) represented 23.4% of the fresh transfers, with 5 countries in which SET rates were >50%: Sweden (69.9%), New Zealand (61.3%), Australia (59.6%), Finland (57.8%), and Belgium (50.2%). In South Korea and several countries in Latin America and the Middle East, the mean number of embryo transfers (ETs) remained at >3 embryos. In the United Kingdom, the proportion of elective single ETs (eSETs) has increased substantially: in 2008, fewer than 5% of embryo transfers were eSET, but by 2014 this had increased to 29% [3, 5].
Worldwide, the proportion of deliveries with twins and triplets from fresh transfers was 22.3% and 1.2%, respectively [2]. In the United Kingdom, the overall multiple pregnancy rate was 27% in 2008 and fell to 16% in the first half of 2014 [3]. In Europe, twin and triplet delivery rates associated with IUI cycles were 9.6%/0.5% and 8.5%/0.2%, following treatment with husband and donor semen, respectively [4].
In 2007, 229,442 babies born as a result of an ART treatment were reported worldwide. In the United Kingdom in 2013, live birth rate per cycles started (fresh and frozen treatment cycles) was 26% [3]. Overall in 2014, 4% of the babies born in Europe were from ART; in the United Kingdom, this was 2%.
2 Multiple Pregnancies
Multiple pregnancies are the most common in patients who are being treated with fertility medication to induce ovulation (up to 10% multiples and 1% have triplets or more). The use of drugs to induce superovulation with multiple oocytes produced, caused the vast majority of the increase in multiple pregnancies (up to 30% of pregnancies after gonadotrophin treatments are multiples). IVF and Intracytoplasmic sperm injection (ICSI) treatment also contributed in the increase of multiple pregnancies because of transfer of more than one embryo. The single biggest risk of a fertility treatment is a multiple pregnancy; hence the single most important factor responsible for the increase in specific risks for mother, babies and the family. Mothers have an increased risk of hypertension (20% vs. 1–2%); pre-eclampsia (30% vs. 2–10%); and diabetes (12% vs. 4%) during the twin pregnancy. Risks during or after birth include C-section, death of the mother (×2 increase), and a higher incidence of stress and depression after giving birth.
Vanishing twin pregnancies are associated with pregnancies with an adverse perinatal outcome like lower birth weight or small for gestational age, lower Apgar scores, and higher risk for perinatal mortality.
Babies from a twin or triplet pregnancy have an increased risk: very premature and premature birth (twins: 50% before 37 weeks; triplets: 90% increase); extremely low and low birth weight; admission to a neonatal intensive care unit (40–60% vs. 20%); perinatal mortality (3–6 times higher for twins; 9 times higher for triplets); cerebral palsy (1 in 80 twins versus 1 in 434 for singletons). All complications result in an increased cost for pregnancy care and more care after birth because of increase of learning difficulties, slower language development, impaired sight, and congenital heart disease (7.4% of twin pregnancies). A family with twins or triplets will endure higher costs for pregnancy care, for the delivery, and for care after birth. A higher stress level has been observed in these families as well as intense bereavement support to cope with loss or handicaps [6–11]. With approximately 13,000 IVF babies being born each year in the United Kingdom, this contributes significantly and disproportionately to the national multiple birth rates and presents a significant public health concern.
3 Strategies to Prevent Multiple Pregnancies
The main strategy to reduce the multiple birth rate is to transfer one single healthy embryo at a time, even when more are available. Only with a collaborative and multidisciplinary approach that involves clinicians, laboratory staff, nurses, counsellors, professional bodies, governments, and patients, this can be achieved.
3.1 Clinic
It is imperative that prevention of multiple pregnancies starts with the correct diagnosis of infertility and the correct choice of treatment mode for infertility: non-ART, cycle monitoring with planned intercourse, IUI, IVF, or ICSI. Health and lifestyle advice should to be part of the clinical advice.
Clinicians should identify those patients who are at risk of multiple pregnancies. The National Institute for Health and Care Excellence (NICE) guidelines [12] clearly advocate eSET and propose several identifiers: For women under the age of 37 years undertaking their first treatment cycle, these include maternal age, obstetric and gynaecological, history, previous treatment history, ovarian response or reserve, the number of embryos created and quality of embryos or blastocysts available for transfer, and cryopreservation. Maximising oocyte and embryo quality is an essential part of an effective eSET strategy.
A focus should remain on optimising superovulation regimens: the optimal number of good quality oocytes and embryos to achieve a live birth is between 6 and 15 mature oocytes [13]. A Cochrane review of GnRH antagonists in assisted reproduction suggests that overall the antagonist protocol gave a 1.5% lower LBR and 2% lower CPR compared with the agonist protocol. Care should be taken since GnRH antagonist use is associated with a lower risk of ovarian hyper stimulation syndrome (OHSS) compared with GnRH agonist. However, excellent cumulative success rates following mild IVF stimulation protocols and SET can be obtained [14].
Patients entering an oocyte donation programme should only have a single embryo transferred; studies demonstrate that delivery rates for these patients are similar to double embryo transfer (DET), but with fewer risks. NICE therefore recommends using an embryo transfer strategy based on the age of the oocyte donor. However, care should be taken since even with SET for these patients, an increased risk for pre-eclampsia during the pregnancy is observed [12, 13].
3.2 Laboratory
Single embryo transfer is only possible when IVF is performed under the best conditions and when optimal embryo culture and embryo selection systems are in place. It is essential that pre-selection of gametes (spermatozoa and oocytes) is in place, since a clear association exists between some sperm and oocyte aberrant morphologies and genetic normality and fertilising potential [15]. As for the culture system for embryos, a systematic review of randomised controlled trials describing the effect of embryo culture media on IVF/ICSI success rates did not reveal a superior culture medium [16]. Different embryo culture systems are in place such as small and large volume box incubators, bench top incubators, and micro fluid systems. To date, no study has clearly demonstrated a distinct advantage of any specific incubator type regarding human embryo development or clinical outcomes [17]. Manual morphological embryo selection is still the most prevalent first-line method for embryo grading in IVF laboratories. The live birth rate is positively associated with increasing cell number up to eight cells on day 3. A negative correlation is demonstrated with miscarriage and increasing fragmentation, asymmetry scores and/or multi-nucleation. Although cryopreservation is a strong marker for good quality embryos, not having cryopreservation does not reliably indicate poor quality. Advances in embryo culture media and incubation systems have enabled the reliable extended culture of embryos to the blastocyst stage of development with transfer on day 5 or 6 of culture. A positive correlation with live birth was found with good quality blastocyst morphology: a large ICM, a pavoid structured trophectoderm, and presence of early hatching. There is a body of evidence that the number of supernumerary vitrified blastocysts correlates positively with the odds of implantation and live birth in good quality single-blastocyst transfers. Fresh transfer outcomes can predict the success of a subsequent cryopreserved transfer utilising blastocysts of the same cohort. Time-lapse monitoring (TLM) has recently emerged as a novel technology to perform a semi-quantitative evaluation of embryo morphology and developmental kinetics in culture. This technique permits the continuous evaluation of early embryo development by automated imaging every 5–20 min. Embryo scoring occurs without removal from the incubator, so embryos are not exposed to changes in light, humidity, temperature, pH, and gas phase that is necessary for serial manual morphological grading. A systematic review of TLM studies could not support the clinical use of this technology for selection of human preimplantation embryos [18].
However, it has been demonstrated that around 50% of morphological normal looking blastocysts on day 5 are genetically abnormal and are aneuploid. Perhaps preimplantation genetic screening (PGS) using the new generation technique genetic tests with comprehensive aneuploidy screening (PGD-A) of all 24 chromosomes could assist in selection of the healthy embryo for transfer. A systematic review of the literature in 2015 showed potential benefits of using PGD-A techniques over morphology-based selection of embryos, in particular, a PGD-A screened embryo had a higher implantation rate than a morphologically screened embryo [19]. It is essential that more prospective randomised controlled studies are performed, to identify clearly which patients can benefit from PGD-A.
Embryo culture and embryo scoring clearly remains a significant challenge in IVF, since to date, none has been shown conclusively to yield improved implantation and live birth rates [15, 20]. The UK Best Practice Guidelines for Elective Single Embryo Transfer rightfully points out that further research is required to define the best embryo culture and embryo selection systems [15].
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