The health risks associated with transferring multiple embryos for maternal and foetal health
When making the decision on how many embryos to transfer during ART, it’s important to understand risk factors associated with transferring more than one single embryo for the health of both mother and foetus. Multiple pregnancies, particularly twins, are commonly associated with conception via IVF because multiple embryo transfer is commonly indicated as an effective strategy by some clinics to improve the likelihood of a successful pregnancy. However, compared with singleton pregnancies, twin pregnancies are significantly linked with increased adverse effects for both mother and foetus. Interestingly, these adverse effects are more likely to occur in twin pregnancies that are an outcome of IVF than those who conceived twins naturally. From an obstetric lens, risk factors include increased perinatal morbidity and mortality, preterm birth, low birth weight and admission to the neonatal intensive care unit. Maternally, age is a critical independent factor for obstetric outcomes, regardless of IVF or natural conception but there are some things to consider for women with advanced age including how embryo quality impacts the success of multiple embryo transfer and whether or not it should be recommended.
For many IVF clinics around the world the advice is to transfer single embryos due to the known adverse outcomes of transferring multiple embryos but also due to the increase in hospital resources and economic burden associated with multiple births, particularly during the neonatal period and first year of life. Interestingly however, men and women tend to underestimate the risks of complications associated with multiple embryo transfers and multiple gestations. A 2014 study found that of the 1,049 subjects that participated in the survey, the majority of participants answered that they would like to have two embryos transferred (53.7%); followed by three embryos (35.0%), and one embryo (11.3%). In addition, it’s often not discussed the impact of multiple-embryo transfer on the mothers mental health and that mothers of ART multiple births were significantly more likely to have depression and stress than other mothers of ART singletons.
A 2021 study found that maternal outcomes in the IVF group had higher risk than the non-IVF group for gestational hypertension, eclampsia and preeclampsia, gestational diabetes, placenta previa, placental abruption, placenta accreta, preterm birth, caesarean delivery and postpartum haemorrhage. Among IVF-conceived twin pregnancies the most common risks were caesarean delivery, low birth weight, preterm birth, gestational diabetes, gestational hypertension, preeclampsia and eclampsia, dystocia and postpartum haemorrhage. An elevation of these risks was shown with increasing maternal age, especially among women older than 35. This study concluded that twin pregnancy, IVF and advanced maternal are all independent risk factors for adverse obstetric outcomes and when they coexist, they aggravate such obstetric risks. From a neonatal perspective, the IVF group had a higher risk than the non-IVF group of foetal growth restriction, low birth weight, very low birth weight and malformation.
Sazonova et al (2013) found that preterm birth, very preterm birth, low birth weight, very low birth weight and small for gestational age were dramatically increased for IVF twins compared with two IVF singletons with the same mother with adjusted odds ratios from 4 to 16. In addition, significantly higher rates of respiratory complications, sepsis and jaundice were detected. In addition, higher rates of pre-eclampsia, preterm premature rupture of membranes and caesarean section were observed. Luke et al (2021) also found similar findings where researchers analysed data from a large, multi-state study of IVF births, linking IVF treatment information with birth certificate and birth defect registry data. Their findings suggest a correlation between transferring excess embryos and increased risks of non-chromosomal birth defects, low birth weight, and prematurity. The study highlights the importance of considering these risks when deciding on the number of embryos to transfer during IVF treatment. The analysis also accounts for the "vanishing twin syndrome," where one or more embryos are lost during pregnancy. As early as 1997 research by D’ Souza et al showed that ‘the outcome of IVF treatment leading to multiple births is less satisfactory than that in singletons because of neonatal conditions associated with preterm delivery and disabilities in later childhood’.
The 2024 update of the ESHRE guidelines regarding the number of embryos to transfer during IVF/ISCI provided 35 recommendations on the medical and non-medical risks associated with multiple pregnancies. These recommendations include 25 evidence-based recommendations of which 24 were formulated as strong recommendations and one as condition as well as 10 good practice points. Whilst the recommendations were mostly strong, of the evidence-based recommendations 60% were of very low-quality evidence showing the need for continued research in this area.
When it comes to the risks associated with multiple pregnancies that are more than twins, a 1998 study found that there was a significantly higher maternal and neonatal complication rate in the triplet group compared to singletons and twins, including: threatened miscarriage, pre-eclampsia, antepartum haemorrhage, longer hospital stays and preterm labour. Neonatal morbidity and mortality were also significantly higher in the triplet group.
Whilst some research has suggested that the maternal risks in IVF/ICIS twin pregnancies are comparable with non-IVF/ICIS twin pregnancies, the twin mothers were more likely on sick leave or hospitalised during pregnancy.
Transferring multiple embryos also increases the risk of ectopic pregnancy because each embryo has the potential to implant independently. Li et al (2015), found the lowest likelihood of ectopic pregnancy with single embryo transfer and the highest likelihood when transferring three or more embryos. One study found that double embryo transfer resulted in a significantly higher rate of ectopic pregnancy (4.4%) than single embryo transfer (1.2%). Another study in Austria found that the number of embryos transferred increased the probability of an ectopic pregnancy. However, a systematic review comparing elective single embryo transfer and double embryo transfer showed no statistically significant difference in the ectopic pregnancy rate, likely due to the small sample size.
When looking at different types of ART and the risks associated with multiple pregnancies, Eapen et al (2020) looked at the maternal and perinatal outcomes of twin pregnancies conceived via in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), comparing them to singleton pregnancies resulting from the same procedures. The study performs a meta-analysis of international data, examining various maternal complications (e.g., caesarean delivery, preterm labour, hypertension) and foetal outcomes (e.g., preterm birth, low birth weight, congenital anomalies). The authors conclude that twin pregnancies resulting from IVF-ICSI present significantly higher risks and costs compared to singleton pregnancies, advocating for practices that minimize multiple gestations to optimize patient safety. Gupta et al (2020) also found the higher risks associated with IVF twin pregnancies compared to singleton pregnancies revealing significantly lower gestational ages, birth weights, and higher rates of stillbirth/neonatal death in twin pregnancies. Maternal complications were also more frequent in the twin group, primarily due to increased premature rupture of membranes.
When researching particular risks such as preeclampsia and the impact that number of embryos transferred during ART has on the subsequent diagnosis of preeclampsia. Sites et al (2020), found that transferring multiple embryos increased preeclampsia risk in both singleton and twin pregnancies. The study controlled for various factors like maternal age and prior ART cycles. However, the presence of a vanishing twin or triplet was not significantly associated with increased preeclampsia risk. The findings suggest that single embryo transfer may reduce preeclampsia risk.
Women of advanced age are at increased risk of experiencing lower success rates with ART, however a retrospective cohort study investigated the clinical outcomes of double-embryo transfers in frozen embryo transfer cycles for women of advanced maternal age found that transferring two high-quality embryos improved outcomes for women aged 38 and older. Researchers analysed data from nearly 8200 cycles, categorizing patients into three age groups. The study compared clinical pregnancy rates, implantation rates, live birth rates, and multiple pregnancy rates across the age groups and embryo quality classifications. The study suggests tailored embryo transfer strategies based on age and embryo quality to optimize pregnancy outcomes while minimizing multiple births.
A 2012 study in The Lancet examined the impact of maternal age on outcomes in in-vitro fertilization (IVF). Researchers analysed UK IVF data to determine the optimal number of embryos to transfer, comparing live birth rates, multiple births, and adverse outcomes (low birth weight, preterm birth) between women under 40 and those 40 and older. The findings suggest that transferring three or more embryos should be avoided at all ages. For one or two embryo transfers, the decision should consider the woman's age and other prognostic factors, as older women have a lower absolute risk of live birth with multiple embryo transfer, but a higher relative risk of live birth compared to younger women.
Looking into type of transfer i.e. frozen vs fresh, a Swedish study compared obstetric and perinatal outcomes in singleton births following single-embryo transfer (SET) and double-embryo transfer (DET). The study found a higher risk of adverse outcomes, particularly neonatal death, low birth weight, and preterm birth, associated with DET, especially when using frozen embryos or blastocysts. However, the absolute risks remained low, suggesting that while SET is preferable, DET may still be a viable option for women with reduced fertility. The study acknowledges limitations such as a lack of embryo quality data giving another nod to the importance of embryo quality and its impact on success but also reduction in risk of other adverse effects such as ectopic pregnancy.
In addition, a 2017 retrospective cohort study investigated predictive factors for live birth following blastocyst transfer in women aged 40-43. Researchers compared cumulative live birth rates (LBRs) after elective single blastocyst transfer (eSBT) and double blastocyst transfer (DBT). Blastocyst quality and transferring two blastocysts were significant predictors of live birth; however, cumulative LBRs were similar between eSBT and DBT groups, with eSBT resulting in significantly fewer multiple births. The study suggests that for women with high-quality blastocysts, eSBT is a viable option without compromising overall LBR. Limitations included the study's retrospective nature and potential bias.
Whilst some studies concluded that double-embryo transfer could increase live birth in older women, it was concluded in a 2020 study by Arab et al that ‘single embryo transfer should be offered even in women ≥ 40 years of age or transferring lower quality embryos since transferring more did not increase outcomes in this group, and SET is likely the safest path.’ This reflects the conclusion of other studies that whilst transferring double embryos could increase the possibility of a live birth, more so in older women, the quality of embryo really does impact the success as well as the health of the pregnancy and beyond and therefore choosing whether to transfer more than one embryo should be a very personalised decision with risks vs benefits discussed.
When comparing live birth rate and improved perinatal outcomes, Mejia et al found that single-embryo transfer was associated with a higher cumulative live birth rate and significantly improved perinatal outcomes, including reduced multiple births, higher birth weights, and lower rates of preterm birth and perinatal mortality. Although single-embryo transfer resulted in slightly more embryo transfer cycles to achieve a live birth, the benefits outweighed the drawbacks, particularly for younger patients with a good prognosis.
Lastly, a 2022 systemic review and meta-analysis by Ma et al investigated the benefits and risks of single embryo transfer (SET) versus double embryo transfer (DET) in assisted reproductive technology. The study analysed data from 85 studies, revealing that SET reduced multiple pregnancies but also lowered live birth rates, particularly in women under 40 with good-quality embryos. Subgroup analyses explored the impact of maternal age and embryo quality. The researchers concluded that SET is generally preferable for younger women with good-quality embryos, while DET might be considered for older women or when only poor-quality embryos are available. Further research is needed, especially for older women.
To conclude, the risks associated with transferring multiple embryos should not be ignored and should be reviewed on a personalised basis, with a thorough review and advice of the risks vs benefits to both mother and foetus.
References
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