Embryo Transfer

When a patient has multiple embryos available, they must decide how many embryos to transfer for each transfer. The decision carries major implications for the person who's delivering's health, the health of the offspring, the likelihood that transfer leads to a live birth, and yes, the family’s future finances. We’ll tackle each of these these in this chapter.

At the start we'd like to highlight that we believe most every doctor and clinic has the singular goal of helping ensure a healthy pregnancy and delivery. As patients it's easy for us to assume additional motives without having closely considered the issue. As an example, some of us wonder whether our doctor insists upon a single-embryo transfer to raise the odds we'll need to pay for an additional transfer to conceive. As you'll see in the next lesson, there are critical medical reasons for such a recommendation. Our hope is that this course helps you and your doctor have a productive discussion on this easily-misunderstood, yet critical, subject.

According to the CDC, when a single embryo is transferred there is a 1% chance of a twin or multiple gestation birth. When multiple embryos are transferred, 27% of births are twins or multiple gestation. The risk that a multiple-embryo transfer leads to a multiple-gestation birth is higher for younger women (say, under age 35) than for older women (e.g. over age 38).

Carrying multiple fetuses is dangerous as rates of infant mortality and cerebral palsy increase manifold to the mid-single digits per child. Twins also bring an increased risk of miscarriage, stillbirth, preterm birth, developmental delay, preeclampsia, and gestational diabetes. The risks of complications to the mother during delivery rise in a similarly alarming fashion. This is a well-characterized phenomenon based on large datasets.

Multiple gestation births are born prematurely 57% of the time for twins and 96% of the time for triplets. This matters because the baby’s brain develops significantly in the last month of gestation, with a 50% increase in cortical grey matter forming in that stretch. Below are data from a meta-analysis of 12 of the better-run studies from various countries around the world analyzing the association between prematurity and cognitive ability: each study clearly shows an undeniable association.

Singletons From Multiple-Embryo Transfer

Even when single babies (known as “singletons”) are born from IVF, their welfare can be closely associated with how many embryos were used in that transfer. If the mother transferred one embryo, that singleton baby is less likely to be born prematurely and less likely to demonstrate intrauterine growth restriction than a singleton born from a multiple-embryo transfer. Below you can see results for eSET (elective single embryo transfer), and DET (double embryo transfer) segmented by whether a single, or multiple, heart beat(s) were detected.

Day 3 vs Day 5 & ASRM Guidelines

Your clinic may insist upon transferring embryos that have only been grown to Day 3, not to Day 5 or 6. Day 3 embryos (known as "cleavage" stage embryos) are less developed, and generally speaking, less reliable in leading to a birth.

In 2017 ASRM revised its guidelines to cap the number of embryos a woman should receive per transfer. We’ll cover those guidelines in the next section but the nature of the embryos (Day 3 versus Day 5 or 6) as well as other factors (e.g. the woman’s age) figure prominently into the recommendations. However, ASRM does not ask all patients receive single-embryo transfer because in many cases multiple-embryo transfer has benefits. We’ll cover these in the next chapter.

When describing how the decision of “single versus multiple-embryo transfer” impacts the likelihood of a live birth, we think it’s important to look at this on a “per transfer” and “per cycle” basis.

To clarify, when a woman has an embryo, or embryos, placed into her uterus that is known as a “transfer.” To create those embryos, the woman has her eggs retrieved and that begins a “cycle”: all of the transfers done using eggs (embryos) created from that cycle’s retrieval are considered part of that “cycle.” In the diagram below, three transfers took place, all belong to one cycle.

Per Transfer: Multiple Embryo Transfer = Higher Live Birth Rates

When a patient elects to transfer multiple embryos in a transfer, there is a higher likelihood that transfer will lead to a live birth than if she has one embryo transferred. Thus, pursuing a “multiple embryo per transfer” strategy often reduces the number of transfers needed to have a live birth. This can shorten the time (often by a few months) and lower cost (often by a few thousand dollars) needed to have a child.

Per Cycle: Multiple Embryo Transfer ≠ Higher Live Birth Rates

While it may take “single embryo per transfer” patients more transfers to achieve a live birth, when all of the embryos in a cycle are transferred, their live birth rates per cycle are likely no different. Thus neither approach reliably lowers the number of cycles needed to have a child.

“Per Transfer” In More Detail

When women include more embryos in a transfer, the likelihood that transfer will work increases. This is true in most circumstances, and it’s especially true for women as they get older or who may have had few (if any) embryos "implant" after multiple transfers (known as "recurrent implantation failure"). Below you will see this in the CDC’s breakdown of 2013’s Live Birth Rate per transfer broken down by age.

Another important caveat is that it appears when a single, PGT-approved embryo is transferred, the live birth rates per transfer are similar to that when two, non-PGT tested embryos are transferred. As you'll see below, it's best practice to transfer only one PGT-approved embryo per transfer.

Importantly, this data comes from a single clinic and is based on a small number of patients (<200). It’s unclear if these results are in any way generalizable to other clinics or to a broader population of patients not seen at this clinic. All the same, the comparable Live Birth Rates are striking, especially in context of the lower twin rate and lower percentage of deliveries that end up in the NICU.

Per Cycle In More Detail

Patients who elect to transfer a single embryo have additional embryos to transfer if the first transfer fails. When a team from Sweden in 2004 included births from those subsequent transfers, and compared them with the live birth rates from “multiple embryo per transfer” patients, they saw no statistically-significant difference in outcomes. And yes, the twin rate was far lower.

There can be many interpretations of this data. Our interpretation is that when there is a finite number of available embryos (e.g. from a single cycle), transferring one embryo at a time, or multiple at a time, does not alter the live birth rate when all embryos are used. This leads us to believe “single” or “multiple” embryo strategies are largely equivalent on a per cycle basis.

If we are indeed wrong, we believe it may be on account of a few factors.

• Patient Attrition: We assume patients in the “one embryo per transfer” camp return for another transfer after each failure. If they do not, good embryos may go unused and this limits that patient’s chances for a live birth from that cycle. Each subsequent transfers costs $3,000 in the United States, R$5,000 in Brazil, and Rs. 50,000 in India and some patients run out of money, or conviction, in the IVF process.
  
  
• “Fail Faster”: If a patient has no viable embryos, transferring more embryos earlier will help the patient learn their fate faster. It may help the patient start a new retrieval cycle months earlier (especially helpful in older patients) and as a result that subsequent cycle may be more likely to succeed.
  
  
• Poor Data: Disappointingly the data on the subject is from trials conducted only in younger patients (under age 36 or 38) and using outdated laboratory technology. However, until we see updated data, this is the best information we have.

Many single-embryo transfers fail and another question is whether on the next transfer one, or multiple, embryos should be transferred. Unfortunately there is little data on the subject and you should confer with your doctor if they have a strategy for this circumstance and the logic or data to support it.

For myriad of reasons, your clinic may insist upon transferring embryos that have only been grown to Day 3, not to Day 5 or 6. Day 3 embryos are less developed, and generally speaking, have a lower-likelihood to lead to a live birth and thus multiple births. Transferring multiple Day 3 embryos is of lower risk from a multiple-birth perspective than transferring multiple Day 5 or 6 embryos. Thus, keep in mind the nature of the embryos you are transferring when determining how many to transfer.