Frozen embryo transfer: natural vs. artificial cycle

It is now more than 30 years since the first live birth after transfer of a frozen (cryopreserved) embryo (Zeilmaker et al., 1984). The ability to successfully freeze embryos had a profound impact on assisted reproductive technologies.

It improved efficacy, encouraged the transfer of fewer embryos into the uterus and hence reduced complications arising from prematurity. Recent research indicated frozen embryo transfer babies do better than babies from fresh embryos.

In recent years, the number of frozen embryo transfer cycles has increased dramatically. This is due to several reasons:

1. Many centers are recommending elective single embryo transfer in young patients with good quality embryos
2. Prevention of severe ovarian hyperstimulation syndrome
3. Elevation of progesterone level on day of hCG trigger
4. Embryos being screened using pre-implantation genetic screening (SMART IVF)
5. Slow growing embryos
6. Some centers are routinely freezing all embryos as frozen embryo transfers have better outcomes (less prematurity, less low birth weight babies, less intrauterine growth retardation)

It is critical that the uterine lining (endometrium) be “receptive” for the embryo(s) to implant. Several protocols have been utilized for preparing the endometrium. In “natural cycle” frozen embryo transfer (NC-FET) cycles, the moment of ovulation is used as a marker for timing of thawing and transfer of embryos.

In “artificial cycle” FET (AC-FET), the patient is treated with estrogen and progesterone (to mimic the natural cycle). Estrogen is started with menses to promote growth of the uterine lining and suppression of ovulation. When the lining is adequate, progesterone is started (mimicking ovulation) allowing the planning of embryo thawing and transfer.

Which frozen embryo tranfer protocol is better, NC-FET or AC-FET?

This very question was addressed by a group of Dutch researchers (Human Reproduction, Advance Access Publication, May 13, 2016). Groenewoud et al. conducted a multicenter prospective randomized trial comparing AC-FET and NC-FET. They included patients that were between 18 – 40 years of age, had regular menses (26 – 35 days) and had frozen embryos. Patients with uterine anomalies, those with contraindications to the use of medications and those using donor gametes were excluded.

Patients randomized to the NC-FET group were monitored by serial ultrasounds from Day 10 to 12 of their menstrual cycle. When the lead follicle was 16 – 20 mm in diameter, hCG trigger (Pregnyl 5,000 units or Ovitrelle 250 mg) was given. Embryo transfer was performed 3 – 4 days later for cleavage stage embryos and 6 – 7 days later for blastocysts.

Results of the study

Over a 5-year period (February 2009 – April 2014) 1032 patients were included in the study. The patients were young (mean age 33.5 y) and mean duration of infertility was 3 years. The Live birth rate (LBR) per patient after NC-FET was 11.5% (57/495) versus 8.8% in AC-FET (41/464). The embryo survival rate was around 72% i.e. many patients did not have embryo transfer as the embryo did not survive thawing.

The LBR per embryo transfer in NC-FET cycles was 14.5% (57/394) and 12.1% (41/340) in AC-FET cycles. Thus both protocols had a similar live birth rate.

What can we conclude about frozen embryo transfer?

Both protocols can be used for FET.

At InVia, we prefer to use AC-FET as it is easier to monitor patients on this protocol and much easier to plan the date of embryo transfer. Since embryo transfer is done on the 6^th day after starting progesterone, we can start progesterone in such a way that embryo transfer can be scheduled accordingly.

With NC-FET, it is not always possible to judge when the lead follicle will be 16 – 20 mm in diameter and hence scheduling FET can be difficult.

We will usually use NC-FET only in patients who have failed a couple of attempts of AC-FET, have thin lining or have premature elevation of progesterone level in programmed cycles.

We have much higher live birth rate with FET at InVia. In our 2014 pregnancy success rates, the LBR for FET was 50.9% in women < 35y, (n = 112), 40.5% in age 35 – 37, (n = 37), and 8/17 in age 38 – 40 (n=17). There were 5 cycles in older patients with no pregnancies.

The high success rates for FET at InVia can be explained by the following:

At InVia, we culture embryos to the blastocyst stage (5 or 6 days after egg retrieval) before freezing. We thus end up freezing only good quality embryos.

We use a technique called vitrification, which is superior to the slow-freezing techniques used by Groenewoud et al. The embryo survival rate is almost 99% (it was only 72% in the study).

To see a fertility specialist who is a board-certified physician with excellent success rates, make an appointment at one of InVia’s four Chicago area fertility clinics.