Why are single embryo transfers usually recommended?

Prior to the fresh or frozen embryo transfer process, physicians and patients must decide how many embryos, and which specific embryo(s), to transfer. Patients are usually advised to transfer a single embryo to minimize risks to themselves and the baby.

Embryo transfer is the last step of in vitro fertilization, during which an embryo is placed into the uterus to achieve a pregnancy.ⁱ Fresh embryo transfer is usually performed on either Day 3 or Day 5 following egg retrieval and fertilization (Day 0),ⁱⁱ though embryos can also be cryopreserved (frozen) and transferred in a subsequent cycle(s). Using previously cryopreserved embryos is called a frozen embryo transfer (FET).

Single embryo transfers (SETs) are preferred because they are far more likely than multiple embryo transfer to lead to singleton gestation (a single pregnancy), rather than a multiple gestation pregnancy (i.e., twins, triplets, etc.).ⁱⁱⁱ A 2022 systematic review demonstrated a 16.7 percent chance of multiple gestation pregnancy after IVF when two embryos were transferred, compared to a 0.7 to 1.0 percent chance of multiple gestation after IVF with a single embryo transfer.^iv This data has been supported by other studies as well.^v

Singleton pregnancies offer decreased risk to both mother and baby, as discussed below. In addition, the costs to the healthcare system are significantly decreased for single pregnancies and increased for twin or triplet pregnancies, including during delivery and postnatal care (especially due to increases in neonatal intensive care).^vi,vii,viii

Risks of twin and multiple pregnancies

Single gestation pregnancies are preferred because they carry a significantly lower risk of maternal and fetal complications than multiple gestation pregnancies.^ix,x A summary of the complications occurring most commonly in multiple gestation pregnancies is outlined below.

Maternal complications

The mother is at risk for certain complications including postpartum hemorrhage, hypertensive disorders of pregnancy and heterotopic pregnancy.

• ‍Postpartum hemorrhage: Multiple gestation pregnancies are more likely to result in severe bleeding after delivery, a condition known as postpartum hemorrhage. This risk is due to more extreme distention/stretching of the uterus required to accommodate multiple fetuses, which can lead to impaired uterine contractions after delivery, which are required to stop bleeding.^xi
• ^‍Hypertensive disorders of pregnancy: The incidence of gestational hypertension (high blood pressure), preeclampsia, and eclampsia are increased in multiple gestation pregnancies. In one 2021 study, the incidence of hypertensive disorders in singleton pregnancies was 6.5 percent, compared to 12.7 percent in twin pregnancies, and 20.0 percent in triplet pregnancies.^xii Complications resulting from these disorders, such as kidney failure, heart attack, preterm delivery, restricted fetal growth, and stroke are also increased in multiple gestation pregnancies.^xiii
• ^‍Heterotopic pregnancy: This problem occurs when one pregnancy is intrauterine (within the uterus), while another is ectopic (implants somewhere other than the uterus, i.e., in the fallopian tube). While the intrauterine pregnancy is viable, the ectopic pregnancy is not. It may cause life-threatening bleeding for the mother if the pregnancy ruptures.^xiv

Neonatal complications

There are also risks for the fetuses in twin and multiple pregnancies including preterm delivery, twin-twin transfusion syndrome, and more.

• ‍Preterm delivery: There is an increased risk of preterm delivery in multiple gestation pregnancies. One study demonstrated that in twin pregnancies, the rate of preterm birth at less than 37 weeks was 5.7 times higher than in a singleton pregnancy; delivery at less than 32 weeks was 7.1 times more likely in twin compared to single pregnancies.^xv The resultant prematurity of a preterm delivery can cause significant neonatal morbidity such as breathing and feeding issues, as well as lasting neurologic problems and even neonatal death.^xvi
• ^‍Twin-twin transfusion syndrome (TTTS): This complication can occur in certain types of twin pregnancies, where the twins share a placenta (monochorionic) but have two separate amniotic sacs (diamniotic). In TTTS, the blood flow from the placenta is not shared equally between the two fetuses, meaning one fetus gets more blood flow from the placenta and one has less. This results in one twin being growth-restricted and anemic, with less amniotic fluid (oligohydramnios). The other twin often has too high of a blood volume (hypervolemia), putting them at risk for heart failure, and has excess amniotic fluid surrounding them (polyhydramnios). These abnormalities can cause severe complications for both fetuses and lead to a high rate of fetal demise.^xvii

Other risks include an increased risk of miscarriage, Caesarean section, premature preterm rupture of membranes, low birth weight, and perinatal (newborn) death.^xviii

When should a patient transfer only one embryo?

SETs are almost always recommended, but there are certain situations where fertility clinics are even more unlikely to allow the transfer of two embryos. The American Society for Reproductive Medicine (ASRM) has clear committee guidelines outlining standard practices for embryo transfer.

Maternal age

One important factor is age. When transferring an embryo that has not been genetically tested, if an individual is less than 35 years of age, ASRM guidelines strongly encourage that only one embryo be transferred. For females aged 35 to 37 years, there should be a strong consideration for selecting SET only. For females above the age of 37 who are using their own eggs, more consideration may be given to transferring more than one embryo, which is discussed below in the section on multiple embryo transfer.^xix

This age-based stratification is supported by a study by Wang et al (2022), which arranged patients by age and investigated the first cycle of cleavage-stage (Day 3) frozen embryo transfer where two embryos were transferred. They found these results:^xx

• ‍Patients under 35 years old: Live birth rate per cycle was 59.6 percent; rate of multi-pregnancy was 35.2 percent
• ‍Patients 36 to 37 years old: Live birth rate was 48.2 percent; rate of multi-pregnancy was 27.1 percent
• ‍Patients over 38 years old: Live birth rate was 33.3 percent; rate of multi-pregnancy was 18.9 percent

While this study did not assess blastocyst (Day 5 embryo) transfer, the results demonstrate that patient age is often the predominant consideration when deciding to transfer only a single embryo.^xxi

Embryo genetics

Embryo quality, based on genetic testing, is another important consideration when deciding how many embryos to transfer. Preimplantation genetic testing for aneuploidy (PGT-A) can be used to determine whether an embryo has the correct complement of chromosomes (euploid) or not (aneuploid). One randomized study of 205 couples demonstrated that the transfer of a single euploid embryo had the same pregnancy rate as the transfer of two untested embryos, but with a significantly lower rate of twin pregnancy.^xxii Thus, euploid embryos are considered favorable for transfer, and ASRM guidelines recommend that only one euploid blastocyst should be transferred, regardless of age.^xxiii

Embryo grading

IVF clinics also use embryo grading — or methods of rating the quality of the embryo on factors such as their rate of replication and appearance under a microscope — to further quantify risk of multiple gestation with higher order embryo transfer. Another scenario where SET is strongly advised is when there is more than one high-quality embryo available for transfer. This recommendation is based on evidence that transferring two high-quality blastocysts leads to multiple gestation pregnancies in up to 50 to 60 percent of cases.^xxiv

Cycle number

The number of prior embryo transfers an individual has attempted and how many have led to successful pregnancies is also an important factor. The ASRM practice committee strongly recommends SETs for the first or second IVF cycle, especially if an individual has had a previous successful IVF cycle.^xxv

Gestational carrier

When the embryo is going to be transferred to a gestational carrier (surrogate), a single embryo transfer is strongly recommended to minimize the risks of multiple gestation pregnancies for the gestational carrier.^xxvi,xxvii

Other reasons

There are many personal reasons that individuals may decide to transfer only a single embryo. Some of these reasons include previous pregnancy complications, a strong desire to avoid a twin pregnancy or twin parenting, and concerns about increased healthcare expenses associated with multiple gestation pregnancies.^xxviii

When is single embryo transfer mandatory?

While a SET is typically recommended, there are certain circumstances where it may be mandatory. For example, clinics may have a policy for mandatory SET for certain age groups to minimize maternal and neonatal risks of multiple gestation pregnancy. In addition, SET is often considered mandatory for patients with certain anatomic anomalies including a unicornuate uterus or uterine didelphis, and individuals with significant health problems such as heart disease, lupus, kidney issues, or high blood pressure. The reason is the risk of complications from a multiple gestation pregnancy is unacceptably high in these patients.

Also, in some regions or countries where universal healthcare or private insurance covers IVF costs, there are regulations where only SETs are permitted, with some exceptions for advanced maternal age. These policies are in place to avoid the increased healthcare costs incurred by twins and higher order multiples.^xxix Similarly, in countries with privatized insurance, such as the U.S., some healthcare insurance policies mandate a SET to similarly lessen the chance of higher costs.

Interestingly, studies demonstrate that patients in states where insurers are required to cover IVF are more likely to use SET compared to states where patients pay out-of-pocket for IVF, likely because the additional FET costs are less of a factor for individuals with adequate insurance coverage.^{xxx,xxxi,xxxii} In one study, live birth rate was found to be higher and multiple birth rates found to be lower in states with IVF insurance coverage compared to states without mandated coverage.^xxxiii

Why do patients transfer two or more embryos?

There are various cases where patients and their providers decide that the potential benefits of transferring two or more embryos outweigh the risks. Patients are most likely to consider a double or multiple embryo transfer to increase the chance of success. When transferring two or more genetically untested embryos, there is a higher likelihood of pregnancy and live birth for that IVF cycle, compared to SET.^xxxiv However, it is important to note that the increased success rates are per transfer and may not reflect an improved cumulative live birth rate. In other words, multiple embryo transfer has higher odds of success on that specific transfer, but that fact does not necessarily mean that there is a higher odd of pregnancy when considering all transfers resulting from the same egg retrieval. Each embryo has its own capacity to lead to pregnancy, so if the second embryo is transferred later, the overall chance of pregnancy is expected to be the same. The research comparing success rates in single versus double (or more) embryo transfers is discussed later in this article.

There are several reasons why patients consider transferring multiple embryos, including medical, financial, and personal factors.

Medical reasons for transferring two or more embryos

The risk for a twins or triplets pregnancy is often lower for untested embryos at older ages, with transfer of low-quality embryos, and in the setting of repeated implantation failure (RIF). In these situations, the patient may choose to transfer more than one embryo to increase the odds of successful transfer.

For females using their own eggs, resultant embryos are more likely to be aneuploid and fail implantation as they get older, especially after the age of 40.^xxxv As such, there is lower risk for multiples occurring with embryo transfer with advanced age if the embryos are not genetically tested,^xxxvi meaning that physicians and patients are more likely to be comfortable transferring two or more embryos.

According to ASRM guidelines, for patients with untested embryos (no PGT) and other unfavorable conditions, the following number of cleavage stage (Day 2 to 3) embryos or blastocysts (Day 5 to 6) can be considered for transfer:^xxxvii

• ‍^‍‍Ages 35 to 37 years: Up to three cleavage-stage embryos; up to two blastocysts
• ‍Ages 38 to 40 years: Up to four cleavage-stage embryos; up to three blastocysts
• ‍Ages 41 to 42 years: Up to five cleavage-stage embryos; up to three blastocysts

Unfavorable conditions include cases where there are no high-quality embryos available, there is lack of embryos for cryopreservation, or there were previous failed transfers.

Another scenario where it may be appropriate to transfer an extra embryo is in patients that have a favorable prognosis, but have had multiple unsuccessful cycles, such as recurrent implantation failure (RIF).^xxxviii

Financial, logistical, and other considerations for transferring two or more embryos

Aside from medical reasons for transferring multiple embryos, there are also various financial and logistical reasons that an individual may consider. The costs associated with future embryo transfers — the procedure, transfer medications, embryo cryopreservation fees, time away from work, travel costs — often deter patients from choosing elective single embryo transfer. A double or triple embryo transfer allows patients to avoid these costs again, which can be a significant incentive for individuals paying out of pocket for IVF.

Although patients themselves may incur higher costs, SET is more cost-effective for the healthcare system, since the cost of multiple gestation pregnancy is very high.^{xxxix,xl,xli,xlii} One 2020 health economics study investigating cost-effectiveness in a U.S. state with no fertility coverage showed that SET can result in significant savings for the medical system. The study found that SET saves approximately $3.5 million USD per 250 patients; however, they found that costs to the patient were higher in SET ($23,036), compared to double embryo transfer (DET) ($20,535).^xliii

Some patients may be concerned about cryopreservation of embryos, and therefore prefer the transfer of multiple embryos at once to prevent the need to freeze embryos. However, the process of vitrification with rapid cooling has been shown to produce very high post-thaw survival rates (i.e., above 97 percent).^xliv,xlv Therefore, SET should still be considered in cases where cryopreservation is the primary concern.

In some countries, there are additional considerations that may justify transferring more than one embryo. For example, in locations with limited embryo storage facilities, high costs for storage, or religious concerns about the fate of additional embryos, these factors may justify transferring multiple embryos.^xlvi

Note: Some insurance policies and fertility clinics may include stipulations about the number of embryos that can be transferred per cycle.

Success rates of embryo transfer with single vs. multiple embryos

Multiple factors impact the success rates of transferring a single embryo versus multiple embryos during a single transfer cycle. When transferring two or more embryos, there is an increased chance of pregnancy and live birth for that cycle (per transfer rate), compared to SET.^xlvii

A Cochrane review (2020)^xlviii found that a female with a 46 percent chance of live birth following one IVF cycle with double embryo transfer (DET) of untested embryos had a 27 to 36 percent chance of live birth following one IVF cycle with single embryo transfer (SET). Therefore, there was a reduced rate of pregnancy following SET compared to DET for a single cycle of IVF (as expected). The risk of multiple gestation pregnancy was found to be higher in the DET group.

In one large study of over 180,000 good prognosis cases, DET increased the chance of success by 10 to 15 percent over SET, but significantly increased the risk of multiples; the rate of twin births was 2 percent in SET and 49 percent in DET.^xlix

Similar higher live birth rates following DET have been shown in studies using cleavage-stage embryos (Day 2 or Day 3 embryos). One study demonstrated that cleavage-stage SET had a lower single cycle live birth rate (27 percent) compared to DET (42 percent), but also had a five times higher rate of singleton gestation versus multiple gestation.^l,li

However, transferring multiple embryos in one transfer does not improve the cumulative success rate of an IVF cycle. In other words, considering the total odds of live birth using all embryos from a single IVF cycle, evidence shows that SET has similar success rates to DET while having the added benefit of lower risk for multiples.^{lii,liii,liv,lv} For example, the same Cochrane review described above^lvi also looked at cumulative live birth rates. The study found that the live birth rate after one cycle of DET (42 percent) was similar to the cumulative live birth rate of repeat cycles of SET (34 to 46 percent).^lvii

A 2022 meta-analysis of 12 studies (almost 200,000 females) compared one DET with two cycles of SET.^lviii They found that the cumulative live birth rate was similar with two cycles of SET, compared to one cycle of DET. As expected, SET also resulted in a lower incidence of multiple gestation pregnancies, prematurity, and low birth rate.^lix Another large retrospective cohort study even showed that choosing SET on the initial cycle was associated with higher cumulative live birth rates (74 percent) compared to individuals initially choosing DET (57 percent).^lx These studies demonstrate that each embryo has its own capacity to lead to pregnancy.

Conclusion

While a single embryo transfer is promoted in most situations, research across multiple peer-reviewed journals has highlighted various instances when a patient and/or practitioner may feel that transferring more than one embryo would be beneficial. Patients should speak to their healthcare provider about the options that best fit their unique situation.