Bruce D. Pier, MD1Logan M. Havemann, MD1Ryan J. Heitmann, DO1,2
1Division of Reproductive Medicine, Madigan Army
Medical Center, Tacoma, WA2Center for Reproductive Medicine, West Virginia
University, Morgantown, WV
Corresponding Author:Bruce D. Pier, MD
Division of Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
Madigan Army Medical Center
Tacoma, WA 98431
email: bruce.d.pier3.mil@mail.mil
telephone: 253-968-3276
Shortened Running Title: Reprogram the Frozen Embryo Transfer
The views expressed in this manuscript are those of the authors and do
not reflect the official policy or position of the Department of the
Army, Department of Defense, or the United States Government.
Many advances have been made in the area of assisted reproductive
technologies (ART) over the last 40 years. Ultimately, the cumulative
success of these advancements comes down to the interaction of a
competent embryo and a receptive uterine endometrium during the optimal
window of implantation. Advancements in cryopreservation techniques has
allowed for the separation of the in-vitro fertilization process into
oocyte retrieval with cryopreservation of either oocytes or embryos
followed by the embryo transfer at a to-be-determined time in the future
(termed “freeze-all”). Common reasons for the increased use of
freeze-all strategies include, but are not limited to, use in PGT-A,
risk reduction for those at high risk of OHSS due to hyper-response,
elevated progesterone on the day of oocyte maturation trigger,
identification of uterine (polyps, fibroids, adenomyosis) or tubal
(hydrosalpinx) anomalies, and random start ovarian stimulation, most
commonly done for fertility preservation in newly diagnosed cancer
patients.1-3
Adverse pregnancy outcomes have been noted with both fresh and frozen
(FET) embryo transfer cycles.4 Determining the optimal
treatment paradigm, fresh or frozen transfer, to optimize live
birth/delivery outcomes is still a highly debated topic . Outcome
differences evaluating different FET endometrial preparation protocols
is one area predominately studied via retrospective
data.1 Herein, we discuss both hormonal or programmed
along with natural FET cycles and offer a call for high quality
randomized trials to help advance our knowledge of this complex topic.
The number of ART cycles have increased globally over the last decade,
with over 1,200,000 cycles performed in the United States and Europe
combined in 2016.5,6 The use of frozen embryo transfer
has seen a drastic increase during this time, with some estimates
suggesting a tripling in women over 40 in the United States between
1996-2013.7 As the increase in FET cycles has taken
place, studies initially demonstrated a lower incidence of small for
gestational age (SGA) infants born after a frozen embryo transfer. This
represents a very attractive finding given data demonstrating increased
SGA seen in fresh embryo transfer cycles. This finding, however, has
been tempered in recent years, as data now suggests increasing rates of
maternal hypertensive disorders of pregnancy (mHTN) and infants born
large for gestational age (LGA) following frozen embryo
transfer.4 A recent review from our group reviewed the
possible pathological rationale for these findings, with perhaps the
most compelling evidence suggesting the loss of the corpus lutuem in
programmed frozen embryo transfer cycles as the leading cause of the
association between FET and LGA/mHTN disorders.8
Frozen embryo transfers are performed three to five days post-ovulation
during the natural menstrual cycle (deemed a natural transfer), or with
a programmed menstrual cycle using exogenous estradiol and progesterone
supplementation. Programmed FET cycles are especially useful for
patients with irregular menses, but are used in all patient types given
the ease of scheduling of transfers juxtaposed with the possible
unpredictable nature of scheduling natural cycle FETs. A recent study by
Alur-Gupta el al, demonstrated similar live birth rates after programmed
or natural FET cycles. However, only 10% of the 1028 transfers in this
study were done with a natural cycle preparation. 9 A
recent retrospective study from Sweden investigated differences in
obstetrical outcomes with programmed cycles without a corpus luteum,
compared to natural or modified FET cycles. Natural cycles represented
over 60% of all cycles evaluated and demonstrated that programmed FET
cycles were associated with increased rates of mHTN, cesarean section,
post-partum hemorrhage, post-term birth and macrosomia when compared to
natural/modified FET. The difference in postpartum hemorrhage (PPH) was
particularly striking, with 19.4% of patients in the programmed cycles
experiencing PPH compared to 7.9% in the natural cycle
cohort.10 Similarly, a recent study by Makhijani et
al, demonstrated a 2-fold increase in mHTN in programmed cycles compared
to natural cycles, and concluded that natural cycle FET should be the
first-line option given to patients undergoing FET.11
What leads to the differences observed? Research has also been conducted
to provide pathophysiologic rationale to this association. A recent
review by Singh et al discussed the role of the corpus luteum in early
pregnancy, concluding programmed cycles and subsequent lack of a corpus
luteum, suppress the production of vasoactive compounds which may
increase the risk of pre-eclampsia. Specifically, the absence of
circulating relaxin and vascular endothelial growth factor in early
pregnancy likely contributes to abnormal placentation during programmed
FET cycles, which may represent the cause for increased obstetrical
complications observed after these cycles.12
It is unclear from published data the true prevalence of programmed FET
cycle use in the United States, but anecdotally, our experience is the
use of programmed cycles is similar to the data presented by Alu-Gupta
el al.9 While research to date does not demonstrate a
definitive relationship between programmed FET and LGA/mHTN, the
literature seems to present a strong enough cause for our community to
rethink the high use of programmed FET cycles. We present the need for
more high quality research, particularly with randomized controlled
trials, to substantiate these findings before completely abandoning the
programmed cycle. Even so, given the possible decrease in LGA/mHTN
pregnancy complications, it would seem beneficial for infertility
clinics across the world to strongly considering using natural FET
cycles over programmed cycles whenever possible.