The most important outcome of infertility treatment is a birth of a healthy baby. In many countries, in-vitro fertilisation treatments carry a high risk of twin pregnancy, which brings a higher risk to the mother and child than singleton pregnancies. Preterm delivery and low birth weight are the main factors accounting for the excess in neonatal morbidity. The use of elective single embryo transfer combined with cryopreservation can minimise the twin rate. Recent studies have shown that repeat single-embryo transfer can produce more live births per oocyte retrieval than double-embryo transfer. Ovulation-induction treatment protocols can also be improved and optimised. Correct counselling is important, as many infertile couples may desire twin pregnancies. Good counselling should include realistic information on the risks of twin gestation and also on later burdens with a multiple birth.
Background
The use of infertility treatments has expanded, and the increased success of these methods has been accompanied by concerns about rising rates of multiple pregnancies. Assisted reproductive techniques (ART), including the use of ovulation-inducing drugs, in-vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), have been criticised for producing high rates of multiple pregnancies, including twins. This criticism is well deserved. The increased efficiency of IVF and ICSI programmes in many centres has produced overall pregnancy rates of 30–35% per cycle, with multiple rates of 25–30%. This means that even one-half of children born after ART may have originated from multiple pregnancies. The most important perinatal risk linked to multiple-order pregnancies is prematurity, which occurs in more than one-half of twin pregnancies, and often results in a number of complications, including low birth weight (low birth weight <2500 g).
The contribution of IVF and ICSI to multiple pregnancies is better known than that of ovulation stimulation alone or combined intrauterine insemination. This is because several countries have established national registries for ART. Some prospective cohort studies on this subject, however, have been published; one of them was undertaken in a large training hospital in the Netherlands to evaluate the contribution of different fertility treatments to the number of multiple pregnancies. Of all pregnancies, 46% were conceived spontaneously, 16% were induced by clomiphene citrate, 2.4% by follicle stimulating hormone and 14% by intrauterine insemination combined with controlled hyperstimulation. In-vitro fertilisation and its related techniques resulted in about one-fifth of all continuing pregnancies, but were responsible for more than one-half of multiple pregnancies. Furthermore, 18% of multiple pregnancies were induced by ovulation-induction protocols, whereas about 11% were conceived spontaneously.
Births resulting from infertility treatment account for around 1–3% of singletons, 30–50% of twins and more that 75% of higher-order multiple births in many European countries. Another reason for the higher rate of multiples is older maternal age, which accounts for 25–30% of the rise in multiple birth rates since 1970. Data from the latest report from the European Society of Human Reproduction and Embryology on ART results in Europe showed a multiple birth rate of 22.3% (21.3% twin and 1.0% triplet) in 2007. The proportion of multiple deliveries had not decreased compared with 2006 (20.8%) and 2005 (21.8%). The clinical pregnancy rates per aspiration and per transfer were 29.1 and 32.8% for IVF, and 28.6 and 33.0% for ICSI. Delivery rate after intrauterine insemination with the husband’s sperm cells was 10.2% in women younger than 40 years with twin deliveries in 11.7% and triplets in 0.5%.
In many European countries, the number of multiple pregnancies has increased considerably during the past 20 years ( Fig. 1 ). In Finland, the same trend has been true; furthermore the effect of IVF practices on this change has been analysed ( Fig. 2 ). In the USA between 1998 and 2003, the number of twin births increased by 17%, whereas the number of higher-order multiple births was unchanged. According to the same report, since 1998, total births resulting from ART increased by 67%, twin births increased by 65%, triplet births deceased by 8%, and quadruplet births decreased by 35%. In 2003, the estimated percentages of multiple births resulting from ART and ovulation induction were twins 16% and 21%, triplets 45% and 37%, and quadruplets 30% and 62%, respectively. After publication of the Society for Assisted Reproductive Technologies and the American Society for Reproductive Medicine recommended limits on number of embryos transferred, the ratio of higher-order multiple births to total ART births decreased substantially.
Risks of multiple pregnancies
Multiple pregnancies are associated with considerable risks for the mother and off-spring as well as excess obstetric and neonatal costs. Fortunately, twin pregnancies constitute most multiple pregnancies.
Twin pregnancies fall into two categories: dizygotic twins, which result from the fertilisation of two eggs, and monozygotic twin pregnancies, which arise from the fertilisation of a single egg. Zygosity and chorionicity are important determinants for off-spring outcomes in multiple pregnancies. Monozygotic, monochorionic twins have a fivefold to tenfold increase in antenatal and perinatal complication. Therefore, it is important to determine the chorionicity accurately at the first-trimester ultrasound examination. The proportions of monozygotic and dizygotic twins are different in spontaneously conceived twins compared with ART twins. Most ART twins are dizygotic, but it is important to notice that the use of various ART seems to increase the risk of monozygotics, too. In a Japanese study, blastocyst culture was associated with a significantly increased monozygotic twinning risk (OR, 2.04; 95% CI, 1.29 to 4.48), whereas embryo freezing, type of stimulation protocol used, intracytoplasmic sperm injection fertilisation, or zona removal did not influence its incidence. Other small studies have reported the same increase in monozygotic twinning with other forms of ART, including ICSI and frozen embryo transfer.
Compared with singleton pregnancies, multiple pregnancies carry more risks for the mother and the unborn children. Of these risks, prematurity is the most important, affecting 64% of twin deliveries in ART pregnancies in 2004. In addition, prenatal and neonatal complications can result in health problems later in the children’s lives.
Maternal morbidity
Many risks to the health of the mother are well-documented. Multiple gestation pregnancies increases the risk of maternal mortality compared with singleton pregnancies. The most important causes for maternal deaths are eclampsia and excessive blood loss. Multiple pregnancy is an independent risk factor for these life-threatening events (e.g. obstetric haemorrhage and pre-eclampsia [OR 2.21, 95% CI 1.24 to 3.96]). A population-based report confirmed that a higher plurality is associated with increased risks of many pregnancy complications (e.g. diabetes, hypertension and excessive bleeding). Higher maternal age further increases these risks.
Maternal morbidity is related to the number of fetuses. A dose-response relationship was observed for pregnancy-associated hypertension, diabetes mellitus, and placental abruption, with higher odds ratios in women with quadruplet and higher-order multiple gestations than in women with triplet pregnancies.
Neonatal outcome
Perinatal complications increase morbidity of neonates from twin pregnancies. Mortality rates are also increased: stillbirths, early neonatal, late neonatal and infant mortality are higher in multiple pregnancies, increasing with the number of fetuses.
Preterm delivery and low birth weight are the main factors accounting for the excess in neonatal morbidity. In general, twin pregnancies are at tenfold risk of resulting in growth-restricted infants compared with singletons. Perinatal morbidity in twin pregnancies is related to intrapair birth weight discordance. Many multiple gestation neonates require treatment and extended care in neonatal intensive care units, and about one-half of twins and 80% of triplets are admitted to neonatal intensive care units. Morbidity includes intraventricular haemorrhage, sepsis, necrotising enterocolitis and respiratory distress syndrome.
Preterm twins have a higher incidence of respiratory distress syndrome than preterm singletons, and other neonatal complications affect more often twins than singletons. The increased morbidity of neonates from multiple pregnancies is reflected as an extended need for intensive care: 15% of singletons, 48% of twins and 78% of triplets were treated in neonatal intensive care units. Corresponding results are reported in a Finnish study, which showed that 13.4% of IVF singletons and 38.2% of IVF twins required hospitalisation during the neonatal period. Perinatal mortality was four- to five-fold higher in twins than in singletons.
Long-term outcome
In general, an increased risk of neurological sequelae occurs in multiple pregnancies. The risk for cerebral palsy is five- to 10-fold. A Danish systematic review of IVF and ICSI twins concluded that IVF twins had similar neonatal outcomes as non-IVF twins. They had similar long-term outcome as non-IVF twins, with no differences in the rates of cerebral palsy, chronic disease, surgery or hospital admissions. According to the same review, IVF twins had considerably higher risks for most short- and long-term outcomes, including neurological impairment and poorer cognitive development than IVF singletons.
The psychosocial aspects are important, too. The transition to parenthood is a period of change and stress, and even more for the parents of twins. They have to cope with two infants whose needs may be demanding as a result of prematurity, perinatal complications or disability. This may cause feelings of insufficiency and uncertainty, and can lead to increased parental stress, depression and anxiety. After spontaneous conception, more depression has, indeed, been reported in mothers after multiple births. Maternal anxiety and stress may also affect psychosocial well-being of the whole family. Furthermore, the birth of twins can be challenging for the previous children in the family and can increase the workload and stress of the parents even more. It is evident that twin parenthood is the main factor impairing the mental health in parents with ART twins. In a Finnish study, twin parenthood, but not ART, had a negative effect on the mental health of both mothers and fathers during the transition to parenthood.
Risks of multiple pregnancies
Multiple pregnancies are associated with considerable risks for the mother and off-spring as well as excess obstetric and neonatal costs. Fortunately, twin pregnancies constitute most multiple pregnancies.
Twin pregnancies fall into two categories: dizygotic twins, which result from the fertilisation of two eggs, and monozygotic twin pregnancies, which arise from the fertilisation of a single egg. Zygosity and chorionicity are important determinants for off-spring outcomes in multiple pregnancies. Monozygotic, monochorionic twins have a fivefold to tenfold increase in antenatal and perinatal complication. Therefore, it is important to determine the chorionicity accurately at the first-trimester ultrasound examination. The proportions of monozygotic and dizygotic twins are different in spontaneously conceived twins compared with ART twins. Most ART twins are dizygotic, but it is important to notice that the use of various ART seems to increase the risk of monozygotics, too. In a Japanese study, blastocyst culture was associated with a significantly increased monozygotic twinning risk (OR, 2.04; 95% CI, 1.29 to 4.48), whereas embryo freezing, type of stimulation protocol used, intracytoplasmic sperm injection fertilisation, or zona removal did not influence its incidence. Other small studies have reported the same increase in monozygotic twinning with other forms of ART, including ICSI and frozen embryo transfer.
Compared with singleton pregnancies, multiple pregnancies carry more risks for the mother and the unborn children. Of these risks, prematurity is the most important, affecting 64% of twin deliveries in ART pregnancies in 2004. In addition, prenatal and neonatal complications can result in health problems later in the children’s lives.
Maternal morbidity
Many risks to the health of the mother are well-documented. Multiple gestation pregnancies increases the risk of maternal mortality compared with singleton pregnancies. The most important causes for maternal deaths are eclampsia and excessive blood loss. Multiple pregnancy is an independent risk factor for these life-threatening events (e.g. obstetric haemorrhage and pre-eclampsia [OR 2.21, 95% CI 1.24 to 3.96]). A population-based report confirmed that a higher plurality is associated with increased risks of many pregnancy complications (e.g. diabetes, hypertension and excessive bleeding). Higher maternal age further increases these risks.
Maternal morbidity is related to the number of fetuses. A dose-response relationship was observed for pregnancy-associated hypertension, diabetes mellitus, and placental abruption, with higher odds ratios in women with quadruplet and higher-order multiple gestations than in women with triplet pregnancies.
Neonatal outcome
Perinatal complications increase morbidity of neonates from twin pregnancies. Mortality rates are also increased: stillbirths, early neonatal, late neonatal and infant mortality are higher in multiple pregnancies, increasing with the number of fetuses.
Preterm delivery and low birth weight are the main factors accounting for the excess in neonatal morbidity. In general, twin pregnancies are at tenfold risk of resulting in growth-restricted infants compared with singletons. Perinatal morbidity in twin pregnancies is related to intrapair birth weight discordance. Many multiple gestation neonates require treatment and extended care in neonatal intensive care units, and about one-half of twins and 80% of triplets are admitted to neonatal intensive care units. Morbidity includes intraventricular haemorrhage, sepsis, necrotising enterocolitis and respiratory distress syndrome.
Preterm twins have a higher incidence of respiratory distress syndrome than preterm singletons, and other neonatal complications affect more often twins than singletons. The increased morbidity of neonates from multiple pregnancies is reflected as an extended need for intensive care: 15% of singletons, 48% of twins and 78% of triplets were treated in neonatal intensive care units. Corresponding results are reported in a Finnish study, which showed that 13.4% of IVF singletons and 38.2% of IVF twins required hospitalisation during the neonatal period. Perinatal mortality was four- to five-fold higher in twins than in singletons.
Long-term outcome
In general, an increased risk of neurological sequelae occurs in multiple pregnancies. The risk for cerebral palsy is five- to 10-fold. A Danish systematic review of IVF and ICSI twins concluded that IVF twins had similar neonatal outcomes as non-IVF twins. They had similar long-term outcome as non-IVF twins, with no differences in the rates of cerebral palsy, chronic disease, surgery or hospital admissions. According to the same review, IVF twins had considerably higher risks for most short- and long-term outcomes, including neurological impairment and poorer cognitive development than IVF singletons.
The psychosocial aspects are important, too. The transition to parenthood is a period of change and stress, and even more for the parents of twins. They have to cope with two infants whose needs may be demanding as a result of prematurity, perinatal complications or disability. This may cause feelings of insufficiency and uncertainty, and can lead to increased parental stress, depression and anxiety. After spontaneous conception, more depression has, indeed, been reported in mothers after multiple births. Maternal anxiety and stress may also affect psychosocial well-being of the whole family. Furthermore, the birth of twins can be challenging for the previous children in the family and can increase the workload and stress of the parents even more. It is evident that twin parenthood is the main factor impairing the mental health in parents with ART twins. In a Finnish study, twin parenthood, but not ART, had a negative effect on the mental health of both mothers and fathers during the transition to parenthood.
Prevention of multiple pregnancies in ovulation induction and ovarian stimulation
Ovarian stimulation is variably carried out with gonadotrophin (mostly recombinant), clomiphene (selective oestrogen receptor modulator), letrozole (aromatase inhibitor), or their combinations. All promote the growth and development of ovarian follicles. Ovulation triggering, commonly accomplished with human chorionic gonadotrophin, is usually timed by ultrasound monitoring. Intrauterine insemination is combined with ovulation induction, especially in cases of mild male infertility or unexplained infertility. All these forms of treatment have increases multiple pregnancy rates during recent years.
Clomiphene citrate is a fertility drug that can increase the number of mature oocytes for possible fertilisation. It is used for the treatment of anovulation (e.g. in women with polycystic ovarian syndrome and also in women with unexplained infertility). Clomiphene citrate treatment carries a risk of 10% chance of multiple pregnancies. In a recent systematic review investigating whether ultrasound monitoring during clomiphene treatment reduced multiple pregnancy rates, no basis was found for amending the evidence-based use of ultrasound to monitor the ovaries during stimulation with clomiphene. On the other hand, no indication that treatment with clomiphene is safe without ultrasound monitoring was identified.
The off-label use of letrozole is a more recent ovulation-induction method, the superiority of which over clomiphene has been examined. Pregnancy rates of 11.5–26.3% per cycle have been achieved in prospective, randomised trials. Notably, no high-order gestations were reported. Four of the five trials cited proved free of twin gestations as well. Modest if growing experience is also accumulating in the combined use of letrozole and gonadotrophin. Reviews of potential teratogenicity seem to have found little evidence for concern.
McClamrock et al. reviewed the gestational plurality associated with high-dose gonadotrophin (≥150 IU gonadotrophin) regimens in a series of prospective randomised trials. Programmes using high-dose gonadotrophin protocols gave rise to twin and high-order pregnancy rates as high as 28.6% and 9.3%, respectively. The corresponding per-cycle pregnancy rates ranged from 7.0 to 19.2%.
The plurality of birth associated with ovulation stimulation may not be entirely preventable. As recently as 2005, ovulation stimulation combined with insemination and ovulation induction has been estimated to contribute as much as 22.8% to the national multiple birth cohort. Low-dose (≤75 IU) gonadotrophin regimens with pregnancy rates of 8.7–16.3% per cycle together with absent high-order gestation have been reported in prospective randomised trials. In a Cochrane systematic review, low-dose protocols were advised as pregnancy rates with the low-dose regimen were similar to those with the high-dose regimen. Low-dose gonadotrophin protocols also produced fewer multiples and fewer episodes of ovarian hyperstimulation syndrome. Well-designed, randomised-controlled trials are needed. One example might be the ongoing multicentre Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation trial of gonadotrophin or clomiphene versus letrozole.
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