Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 191–199
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
1
Reducing multiple births in assisted reproduction technology Siladitya Bhattacharya, MD, FRCOG a, *, Mohan S. Kamath, MS, DNB b a
Division of Applied Health Sciences, University of Aberdeen, Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Foresterhill, Aberdeen AB25 2ZD, UK Reproductive Medicine Unit, Christian Medical College, Vellore, India
b
Keywords: assisted reproduction technology in-vitro fertilisation multiple pregnancy elective single embryo transfer
Multiple pregnancy, a complication of assisted reproduction technology, is associated with poorer maternal and perinatal outcomes. The primary reason behind this is the strategy of replacing more than one embryo during an assisted reproduction technology cycle to maximise pregnancy rates. The solution to this problem is to reduce the number of embryos transferred during invitro fertilisation. The transition from triple- to double-embryo transfer, which decreased the risk of triplets without compromising pregnancy rates, was easily implemented. The adoption of a single embryo transfer policy has been slow because of concerns about impaired pregnancy rates in a fresh assisted reproduction technology cycle. Widespread availability of effective cryopreservation programmes means that elective single embryo transfer, along with subsequent frozen embryo transfers, could provide a way forward. Any such strategy will need to consider couples’ preferences and existing funding policies, both of which have a profound influence on decision making around embryo transfer. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Assisted reproductive technology (ART) includes procedures that involve in-vitro handling of human gametes or embryos for purposes of establishing a pregnancy [1]. The past 3 decades have witnessed a dramatic increase in the number of women undergoing ART treatment worldwide, with
* Corresponding author. Tel.: þ44 1224 438419; Fax: þ44 1224 438486. E-mail address: [email protected] (S. Bhattacharya). 1521-6934/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpobgyn.2013.11.005
192
S. Bhattacharya, M.S. Kamath / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 191–199
more than 5 million children conceived by means of this treatment [2]. Ovarian stimulation has traditionally been used in ART to produce a number of oocytes, and has the involved replacement of more than one embryo to maximise pregnancy rates. This has led to an increase in the number of twins and higher order multiple pregnancies [3]. Although initially seen as an acceptable outcome of ART, concerns have increasingly been raised about the consequences of such a policy on the health of women and children. Compared with singleton pregnancies, women carrying twins and other multiples are at increased risk of maternal complications, such as preeclampsia, preterm premature rupture of membrane, and caesarean section [4]. A fivefold increase in neonatal mortality occurs after twin delivery compared with singleton delivery, and this risk is higher in higher order multiples [5]. In many parts of the world, a conscious effort has been made to reduce the rates of iatrogenic multiple pregnancy by means of legislation and policy changes. A favourable downward trend in multiple pregnancy rates has resulted from the introduction of single-embryo transfer (SET) policies in some countries, but this is by no means a universal phenomenon [6,7]. In this chapter, we review various strategies for reducing multiple pregnancies in in-vitro fertilisation (IVF), including legislative and policy changes. Burden of the problem: risks of multiple pregnancies after assisted reproductive technology Data from 376,971 European IVF treatment cycles in 2007 show a multiple birth rate of 22.3% (21.3% twins and 1% triplets), similar to rates in 2005 and 2006 (21.8 and 20.8%, respectively) [8]. Figures from the Society for Assisted Reproduction Technology (SART) registry in the USA, based on 108,130 ART cycles, revealed a multiple birth rate of 35.4, of which 31.8% were twin, 3.5% were triplets, and 0.1% were higher order multiple [9]. In the UK, data published by the Human Fertilisation and Embryology Authority (HFEA) for the years 2009 and 2010 show a multiple pregnancy rate of 25.4 and 22.2%, respectively. In 1992, for every 100 deliveries after successful ART treatment, 28 were multiple births, whereas the multiple births figures stood at 23 per 100 deliveries after ART treatment in the year 2006. Risks associated with multiple pregnancies Multiple pregnancy increases the risk of maternal mortality, estimated to be 14.9 out of 100,000 compared with 5.9 out of 100,000 for singleton births [10]. The incidence of complications of pregnancy, such as pregnancy-induced hypertension, is also increased, and the risk of anaemia is doubled; uterine atony, dystocia, increased operative deliveries, and postpartum haemorrhage are all associated with multiple pregnancy [11], as is the incidence of depression [12]. Prematurity occurs in nearly one-half of all multiple pregnancies, and is the main cause of neonatal morbidity and mortality; 42% of twins and 8% of singletons are born before 37 completed weeks [13,14]. Twins face a six-fold and triplets a 10–20-fold increase in risk of mortality compared with singletons [15]. Gestational age and birth weight are inversely related to the number of fetuses. The mean gestation for twins, triplets and quadruplets is 35, 33 and 29 weeks, respectively. Ninety per cent of triplets and higher order multiples weigh less than 2500 g compared with only 6% of all singletons; 78% of triplets and higher order multiples, and 48% of twins will need admission to neonatal intensive care units compared with 15% of singletons [16]. Higher rates of congenital anomaly in children conceived through ART have been reported and are more common in multiple pregnancies; the risk of cerebral palsy is increased three- to seven-fold in twins and ten-fold in triplets [11,17]. Long-term behavioural problems have been found to be higher in children born after multiple births compared with children born as singletons [18]. Prenatal screening poses additional difficulty, and leads to increased anxiety during the antenatal period for women carrying multiples [19]. Multiple gestation requires more frequent clinical and ultrasonographic monitoring compared with singleton pregnancies. Maternal and neonatal complications in multiple pregnancies are presented in Tables 1 and 2. Healthcare costs rise four-fold in twins and ten-fold in triplets compared with costs associated with singleton pregnancies. The health risks associated with preterm birth are important contributors to
S. Bhattacharya, M.S. Kamath / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 191–199
193
Table 1 Comparison of maternal and neonatal complications in singleton and multiple pregnancies. Complications
Singleton
Twins
Triplets
Preeclampsia [15] (%) Gestational diabetes [58] (%) Neonatal intensive care unit admission [16] (%) Perinatal mortality [58] (per 1000 live births) Intracranial bleeding [58] (%) Respiratory distress syndrome [58] (%)
6 3 15 10 0.4 1.6
17 5–8 48 27 1.9 8.0
20–39 >10 78 62 5.6 20.4
increasing costs associated with multiple pregnancies. Data from the USA indicate that the cost per preterm infant is about 51,600 US dollars. In 2005, ART contributed to 4% of all the preterm deliveries in the USA, costing the society over 1 billion US dollars [20]. Chambers et al. [21] studied the cost involved in inpatient admission of singleton and multiple gestation after ART treatment, and compared it with non-ART babies. The costs after ART treatment were 4818 Euros for singleton delivery, 13,890 Euros for twin delivery, and 54,294 Euros for triplet delivery. Strategies to reduce multiple pregnancies after assisted reproductive technology cycles Traditionally, transfer of multiple embryos in IVF with the intention of maximising pregnancy rates was the norm. Subsequently, analysis of the HFEA database suggested that, in the presence of four or more embryos, replacement of three rather than two embryos increased the risk of multiples without increasing the live birth rate. This led to a revision of the policy of transferring three or more embryos [22]. It is important to devise a mechanism to determine the optimum number of embryos to be transferred in a woman, depending upon the clinical characteristics, so that the risk of multiple pregnancy can be minimised, without jeopardising her chances of conception. Three-compared with two-embryos transfer A Cochrane review by Pandian et al. [23] included only one small trial consisting of 45 women, in which a double-embryo transfer (DET) and a triple-embryo transfer were compared. The cumulative live birth rates (48% v 41%) did not differ significantly in the two groups (four cycles of a DET compared with three cycles of a triple-embryo transfer). The multiple pregnancy rate was significantly higher in the triple-embryo transfer group (30% v 0%; P ¼ 0.05) [23,24]. Apart from this, available data on outcomes after a DET policy are from observational studies. The earliest convincing set of results in favour of double (compared with triple) embryo transfer are from an analysis of data from 44,236 cycles within the HFEA database. In women with more than four fertilised oocytes, transfer of three (rather than two) embryos did not enhance live birth rates, but significantly increased the risk of multiple pregnancy (OR1.6; 95% CI 1.5 to 1.8) [22]. Retrospective data from Germany found comparable pregnancy rates after elective transfer of two and three embryos up to the age of 40 years (22% v 22.5%), with multiple pregnancy rate of 16.1% in the double-embryo group compared with 24% in the triple-embryo group [25]. In their study using a donor model, Licciardi et al. [26] showed similar clinical pregnancy rates after the elective transfer of either two or three embryos (57.5% v 55.8%) in recipients. The multiple pregnancy rate was 40.5% in women who received two embryos and 51.0% in women who received three. Table 2 Maternal mortality and perinatal outcome. Complications
Singleton
Multiple pregnancies
Maternal mortality [10] (per 100,000 birth) Pre-term delivery [14] (
Contents lists available at ScienceDirect
Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
1
Reducing multiple births in assisted reproduction technology Siladitya Bhattacharya, MD, FRCOG a, *, Mohan S. Kamath, MS, DNB b a
Division of Applied Health Sciences, University of Aberdeen, Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Foresterhill, Aberdeen AB25 2ZD, UK Reproductive Medicine Unit, Christian Medical College, Vellore, India
b
Keywords: assisted reproduction technology in-vitro fertilisation multiple pregnancy elective single embryo transfer
Multiple pregnancy, a complication of assisted reproduction technology, is associated with poorer maternal and perinatal outcomes. The primary reason behind this is the strategy of replacing more than one embryo during an assisted reproduction technology cycle to maximise pregnancy rates. The solution to this problem is to reduce the number of embryos transferred during invitro fertilisation. The transition from triple- to double-embryo transfer, which decreased the risk of triplets without compromising pregnancy rates, was easily implemented. The adoption of a single embryo transfer policy has been slow because of concerns about impaired pregnancy rates in a fresh assisted reproduction technology cycle. Widespread availability of effective cryopreservation programmes means that elective single embryo transfer, along with subsequent frozen embryo transfers, could provide a way forward. Any such strategy will need to consider couples’ preferences and existing funding policies, both of which have a profound influence on decision making around embryo transfer. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Assisted reproductive technology (ART) includes procedures that involve in-vitro handling of human gametes or embryos for purposes of establishing a pregnancy [1]. The past 3 decades have witnessed a dramatic increase in the number of women undergoing ART treatment worldwide, with
* Corresponding author. Tel.: þ44 1224 438419; Fax: þ44 1224 438486. E-mail address: [email protected] (S. Bhattacharya). 1521-6934/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpobgyn.2013.11.005
192
S. Bhattacharya, M.S. Kamath / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 191–199
more than 5 million children conceived by means of this treatment [2]. Ovarian stimulation has traditionally been used in ART to produce a number of oocytes, and has the involved replacement of more than one embryo to maximise pregnancy rates. This has led to an increase in the number of twins and higher order multiple pregnancies [3]. Although initially seen as an acceptable outcome of ART, concerns have increasingly been raised about the consequences of such a policy on the health of women and children. Compared with singleton pregnancies, women carrying twins and other multiples are at increased risk of maternal complications, such as preeclampsia, preterm premature rupture of membrane, and caesarean section [4]. A fivefold increase in neonatal mortality occurs after twin delivery compared with singleton delivery, and this risk is higher in higher order multiples [5]. In many parts of the world, a conscious effort has been made to reduce the rates of iatrogenic multiple pregnancy by means of legislation and policy changes. A favourable downward trend in multiple pregnancy rates has resulted from the introduction of single-embryo transfer (SET) policies in some countries, but this is by no means a universal phenomenon [6,7]. In this chapter, we review various strategies for reducing multiple pregnancies in in-vitro fertilisation (IVF), including legislative and policy changes. Burden of the problem: risks of multiple pregnancies after assisted reproductive technology Data from 376,971 European IVF treatment cycles in 2007 show a multiple birth rate of 22.3% (21.3% twins and 1% triplets), similar to rates in 2005 and 2006 (21.8 and 20.8%, respectively) [8]. Figures from the Society for Assisted Reproduction Technology (SART) registry in the USA, based on 108,130 ART cycles, revealed a multiple birth rate of 35.4, of which 31.8% were twin, 3.5% were triplets, and 0.1% were higher order multiple [9]. In the UK, data published by the Human Fertilisation and Embryology Authority (HFEA) for the years 2009 and 2010 show a multiple pregnancy rate of 25.4 and 22.2%, respectively. In 1992, for every 100 deliveries after successful ART treatment, 28 were multiple births, whereas the multiple births figures stood at 23 per 100 deliveries after ART treatment in the year 2006. Risks associated with multiple pregnancies Multiple pregnancy increases the risk of maternal mortality, estimated to be 14.9 out of 100,000 compared with 5.9 out of 100,000 for singleton births [10]. The incidence of complications of pregnancy, such as pregnancy-induced hypertension, is also increased, and the risk of anaemia is doubled; uterine atony, dystocia, increased operative deliveries, and postpartum haemorrhage are all associated with multiple pregnancy [11], as is the incidence of depression [12]. Prematurity occurs in nearly one-half of all multiple pregnancies, and is the main cause of neonatal morbidity and mortality; 42% of twins and 8% of singletons are born before 37 completed weeks [13,14]. Twins face a six-fold and triplets a 10–20-fold increase in risk of mortality compared with singletons [15]. Gestational age and birth weight are inversely related to the number of fetuses. The mean gestation for twins, triplets and quadruplets is 35, 33 and 29 weeks, respectively. Ninety per cent of triplets and higher order multiples weigh less than 2500 g compared with only 6% of all singletons; 78% of triplets and higher order multiples, and 48% of twins will need admission to neonatal intensive care units compared with 15% of singletons [16]. Higher rates of congenital anomaly in children conceived through ART have been reported and are more common in multiple pregnancies; the risk of cerebral palsy is increased three- to seven-fold in twins and ten-fold in triplets [11,17]. Long-term behavioural problems have been found to be higher in children born after multiple births compared with children born as singletons [18]. Prenatal screening poses additional difficulty, and leads to increased anxiety during the antenatal period for women carrying multiples [19]. Multiple gestation requires more frequent clinical and ultrasonographic monitoring compared with singleton pregnancies. Maternal and neonatal complications in multiple pregnancies are presented in Tables 1 and 2. Healthcare costs rise four-fold in twins and ten-fold in triplets compared with costs associated with singleton pregnancies. The health risks associated with preterm birth are important contributors to
S. Bhattacharya, M.S. Kamath / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 191–199
193
Table 1 Comparison of maternal and neonatal complications in singleton and multiple pregnancies. Complications
Singleton
Twins
Triplets
Preeclampsia [15] (%) Gestational diabetes [58] (%) Neonatal intensive care unit admission [16] (%) Perinatal mortality [58] (per 1000 live births) Intracranial bleeding [58] (%) Respiratory distress syndrome [58] (%)
6 3 15 10 0.4 1.6
17 5–8 48 27 1.9 8.0
20–39 >10 78 62 5.6 20.4
increasing costs associated with multiple pregnancies. Data from the USA indicate that the cost per preterm infant is about 51,600 US dollars. In 2005, ART contributed to 4% of all the preterm deliveries in the USA, costing the society over 1 billion US dollars [20]. Chambers et al. [21] studied the cost involved in inpatient admission of singleton and multiple gestation after ART treatment, and compared it with non-ART babies. The costs after ART treatment were 4818 Euros for singleton delivery, 13,890 Euros for twin delivery, and 54,294 Euros for triplet delivery. Strategies to reduce multiple pregnancies after assisted reproductive technology cycles Traditionally, transfer of multiple embryos in IVF with the intention of maximising pregnancy rates was the norm. Subsequently, analysis of the HFEA database suggested that, in the presence of four or more embryos, replacement of three rather than two embryos increased the risk of multiples without increasing the live birth rate. This led to a revision of the policy of transferring three or more embryos [22]. It is important to devise a mechanism to determine the optimum number of embryos to be transferred in a woman, depending upon the clinical characteristics, so that the risk of multiple pregnancy can be minimised, without jeopardising her chances of conception. Three-compared with two-embryos transfer A Cochrane review by Pandian et al. [23] included only one small trial consisting of 45 women, in which a double-embryo transfer (DET) and a triple-embryo transfer were compared. The cumulative live birth rates (48% v 41%) did not differ significantly in the two groups (four cycles of a DET compared with three cycles of a triple-embryo transfer). The multiple pregnancy rate was significantly higher in the triple-embryo transfer group (30% v 0%; P ¼ 0.05) [23,24]. Apart from this, available data on outcomes after a DET policy are from observational studies. The earliest convincing set of results in favour of double (compared with triple) embryo transfer are from an analysis of data from 44,236 cycles within the HFEA database. In women with more than four fertilised oocytes, transfer of three (rather than two) embryos did not enhance live birth rates, but significantly increased the risk of multiple pregnancy (OR1.6; 95% CI 1.5 to 1.8) [22]. Retrospective data from Germany found comparable pregnancy rates after elective transfer of two and three embryos up to the age of 40 years (22% v 22.5%), with multiple pregnancy rate of 16.1% in the double-embryo group compared with 24% in the triple-embryo group [25]. In their study using a donor model, Licciardi et al. [26] showed similar clinical pregnancy rates after the elective transfer of either two or three embryos (57.5% v 55.8%) in recipients. The multiple pregnancy rate was 40.5% in women who received two embryos and 51.0% in women who received three. Table 2 Maternal mortality and perinatal outcome. Complications
Singleton
Multiple pregnancies
Maternal mortality [10] (per 100,000 birth) Pre-term delivery [14] (
