Natural cycle frozen-thawed embryo transfer in young women with regular menstrual cycles increases the live-birth rates compared with hormone replacement treatment: a retrospective cohort study

Natural cycle frozen-thawed embryo transfer produces a higher chance of live birth than hormone therapy for endometrial preparation in young women with regular menstrual cycles.

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Volume 113, Issue 4, Pages 811–817

Authors:

Xitong Liu, M.D., Wenhao Shi, M.D., Juanzi Shi, Ph.D.

Abstract:

Objective

To determine the optimal endometrial preparation protocols of frozen-thawed embryo transfer (FET) in young women with regular menstrual cycles.

Design

Retrospective cohort study.

Setting

Public fertility center.

Patient(s)

Infertile women with regular menstrual cycles undergoing FET.

Intervention(s)

Natural cycle (NC) treatment for patients with proven ovulation in previous cycles or who refused medication (n = 308), or hormone treatment (HT) for patients who could not be frequently monitored (n = 1,538).

Main Outcome Measure(s)

Live-birth rates.

Result(s)

The live-birth rates were 61.73% in the NC group and 55.11% in the HT group. The effect size of the endometrial preparation on live-birth rates was evaluated in prespecified and exploratory subgroups in each subgroup, and multivariable logistic regression analysis was used to determine which variables could be independently associated with the live-birth rate. The HT patients had a lower chance of live birth in all subgroups: endometrial thickness on the day of progesterone administration, triple-line endometrial pattern, female age at embryo transfer, fertilization type, and protocol in the fresh cycle. Multivariable analysis showed NC to be associated with an increased likelihood of live birth compared with HT.

Conclusion(s)

Natural cycle treatment has a higher chance of live birth than HT for endometrial preparation in young women with regular menstrual cycles.


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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

2 Comments

Go to the profile of Barbara
Barbara 7 months ago

Dear Editor, dear authors,

We read with great interest the paper of Liu et al, entitled "Natural cycle frozen-thawed embryo transfer in young women with regular menstrual cycles increases the live-birth rates compared with hormone replacement treatment: a retrospective cohort study", which was recently published in Fertility & Sterility (1).

In recent years, the number of frozen embryo transfer cycles (FET) performed has increased significantly, contributing to approximately 30% of ART cycles worldwide (2). However, despite this increase, the optimal endometrial preparation for FET is a matter of ongoing controversy due to conflicting study results. Published articles evaluating different cycle regimen for FET, do have fundamental deficiencies due to ascertainment bias and improper endometrial preparations, neglecting the basic physiology of the so-called window of implantation.

Reliable data, not only towards the pregnancy rates, hence also towards the miscarriage rates and the  obstetric and perinatal outcomes, are of utmost importance especially as recently published data point towards a higher incidence of pregnancy induced hypertension and pre-eclampsia in FET cycles with an absent corpus luteum (3). As the main body of studies (4,5) on FET approaches have looked purely into achievable pregnancy rates and not into the live birth rates, the retrospective study of Liu et al. (1) covers an important topic. However, the presented data have to be critically appraised due to underlying faults in the retrospective study design.

While the title indicates the comparison of a "Natural Cycle" (NC) to a "Hormonal Replacement Cycle" (HRT), actually the herein presented approach compares not a "NC", instead a modified NC as part of the patients received hCG for ovulation induction and the luteal phase was medicated by using daily intramuscular (i.m.) progesterone injections from the day of ultrasonographic confirmed ovulation. In the same journal, our group published in 2010 a randomized controlled study, describing the inferiority of the managed natural cycle as compared to a true natural cycle (6). Moreover, it has to be noted that different patterns of follicular fluid evacuation during ovulation have been described previously, rendering ultrasonographic disappearance of a follicle as an unreliable "ovulation marker" (7). Consequently, luteal phase initiation may not be precise leading to a possible embryo transfer (ET) timing outside the "window of implantation". Asynchrony between the endometrium and the embryo developmental stage will result in failed implantation or possibly to a miscarriage.

Endometrial receptivity is driven by the secretory transformation of the endometrium under the influence of progesterone after preceding estrogen exposure. The route of progesterone administration influences distinctly the rise of serum progesterone and its subsequent effect on the endometrium, with IM progesterone injection resulting in early and high peak levels in blood due to its rapid absorption (8). In the study of Liu et al. (1), embryo transfer was scheduled at "3 days for cleavage-stage embryos and at 5 days for blastocyst stage embryo" in the NC group and at "4 days for cleavage-stage embryos and at 6 days for blastocyst stage embryo" in the HRT group, introducing another bias into the study.

A further flaw of this study is that patients with an hCG induced ovulation were summarized together with patients with a spontaneous ovulation. In a natural cycle, a small increase in progesterone level is seen before the LH surge (9). In hCG-triggered cycles this physiologic process will be absent, leading to a different early luteal phase. Moreover, hCG administration itself may have an impact on the endometrial receptivity due to the hCG receptors being present in the endometrium (10). Under physiologic conditions, the endometrium will not be exposed to hCG before the implantation of the embryo. As hCG also exerts control over the endometrial vascular endoethelial growth factor which is a key regulator of both neoangiogenesis and vascular function, these factors taken together may influence the implantation and ongoing pregnancy rates as the initiation of neoangiogenesis is an essential process for placenta formation (10).

Unbiased data to evaluate the ART outcomes after different approaches of endometrial preparation for FET cycles are critical due to the increase number of FET cycles, hence randomized controlled trials, avoiding study bias are warranted. In future, clinical researchers should be more careful in their publications with the definition and terminology of a “Natural cycle”.

 

References:

  1. Liu X, Shi W, Shi J. Natural cycle frozen-thawed embryo transfer in young women with regular menstrual cycles increases the live-birth rates compared with hormone replacement treatment: a retrospective cohort study. Fertil Steril 2020, E-pub ahead of print
  2. https://ivf-worldwide.com/survey/frozen-thawed-embryo-transfer/results-frozen-thawed-embryo-transfer.html
  3. von Versen-Höynck F, Schaub AM, Chi Y-Y, Chiu KH, Liu J, Lingis M, et al. Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum. Hypertension. 2019;73(3):640–9.
  4. Groenewoud ER, Cantineau A, Kollen BJ, Macklon NS, Cohlen BJ. What is the optimal means of preparing the endometrium in frozen–thawed embryo transfer cycles? A systematic review and meta-analysis. Hum Reprod Update 2013;19(5):458–470.
  5. Ghobara T, Gelbaya TA, Ayeleke RO. Cycle Regimens for Frozen-Thawed Embryo Transfer. Cochrane Database Syst Rev 2017;7(7):CD003414
  6. Fatemi HM, KyrouD, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin–induced natural cycle. Fertil Steril 2010; 94 (6), 2054-8.
  7. Hanna MD, Chizen DR, Pierson RA. Characteristics of follicular evacuation during human ovulation. Ultrasound Obstet Gynecol 1994;4(6):488-93
  8. de Wit H, Schmitt L, Purdy R, Hauger R. Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women. Psychoneuroendocrinology. 2001;26(7):697-710.
  9. Devoto L, Fuentes A, Kohen P, Céspedes P, Palomino A, Pommer R, et al. The Human Corpus Luteum: Life Cycle and Function in Natural Cycles. Fertil Steril. 2009;92(3), 1067-79
  10. Licht P, Fluhr H, Neuwinger J, Wallwiener D, Wildt L. Is human chorionic gonadotropin directly involved in the regulation of human implantation? Mol Cell Endocrinol 2007;15:85–92

 

Lawrenz B1,2, Melado L1, Fatemi HM1

1 IVF department, IVIRMA Middle East Fertility Clinic, Abu Dhabi, United Arab Emirates

2 Obstetrical Department, Women´s university hospital Tuebingen, Tuebingen, Germany

Go to the profile of Michael Awadalla
Michael Awadalla 4 months ago

Dear authors,

I enjoyed reading your recent paper “Natural cycle frozen-thawed embryo transfer in young women with regular menstrual cycles increases the live-birth rates compared with hormone replacement treatment: a retrospective cohort study.” We reviewed the article as a division during our weekly fellowship conference and found it timely since we have had more patients undergoing natural FET cycles recently.

Could you please provide more details on the endometrial preparation protocols used?

Specifically, what time of day was IM progesterone administered in the natural cycle protocol and in the hormone treatment protocol? What time of day did most frozen embryo transfers occur? How many hours were there (or what was the approximate range) between the first IM progesterone administration and embryo transfer in the NC and HT protocols for cleavage and blastocyst-stage embryo transfers?

We would appreciate the clarification because the first day of progesterone administration could be designated as day 0 or day 1 depending on one’s preferred terminology. When we discussed the paper, it seemed to some like the HT protocol used a longer time of progesterone exposure prior to transfer than the NC protocol. To others, the wording seemed to indicate that for the NC protocol (see below) the first day of progesterone was designated day 0 and for the HT protocol the first day of progesterone was designated day 1 so that the total time of progesterone exposure is equal in both groups. I’m including the wording from the paper below for reference.

Natural cycle protocol: “Frozen-thawed embryo transfer was scheduled at 3 days for cleavage-stage embryos and 5 days for blastocyst-stage embryos.”

Hormone treatment protocol: “Frozen-thawed embryo transfer was scheduled at 4 days for cleavage-stage embryos and 6 days for blastocyst-stage embryos.”

I’m also including a brief overview of common terminology used to describe frozen embryo transfer cycles below since some readers may be more familiar with some terms and less familiar with others. There is definitely a lot of variation in protocols used and even in how some terminology is applied in different studies.

 

Overview of Frozen Embryo Transfer Cycle Terminology:

Frozen embryo transfer cycles can be divided in to natural cycles where the patient ovulates and produces a corpus luteum and artificial cycles where ovulation does not occur and there is no corpus luteum produced.

Cycles where the patient ovulates and produces a corpus luteum can be completely natural without any medication administration. Three common modifications to a completely natural cycle are follicle stimulation, triggering of ovulation with HCG, and luteal phase support. Follicle stimulation can be performed with exogenous gonadotropins or more commonly with oral agents (clomiphene or letrozole). These cycles are often referred to as “stimulated cycles.” The term “modified natural cycle” seems to be most commonly used to describe cycles in which HCG is used to trigger ovulation, however theoretically this term could be used to describe any modification to a completely natural cycle. Lastly, luteal phase support with progesterone supplementation (intramuscular and/or vaginal) can be administered as the only medical intervention in a cycle or in combination with follicular stimulation and/or ovulation trigger. There are definitely lots of variations to natural and modified natural cycles which makes comparing data from different studies somewhat challenging.

Cycles with no corpus luteum have been described as programmed cycles, artificial cycles, hormonal replacement treatment cycles, or hormone treatment cycles.  These cycles can be carried out with or without the use of GnRH suppression.

 

Sincerely,

 

Michael Awadalla

REI fellow

University of Southern California