Natural cycle frozen embryo transfer: a survey of current assisted reproductive technology practices in the U.S

Abstract

Purpose

Emerging data suggests improved obstetric outcomes with frozen embryo transfer (FET) in an ovulatory or natural cycle (NC-FETs), as compared to programmed endometrial preparation. The objective of this study is to better understand practice patterns and provider attitudes regarding the use of NC-FETs in the United States (U.S.).

Methods

In this cross-sectional study, an anonymous 22-question survey was emailed to 441 U.S. Assisted Reproductive Technology (ART) clinics to assess the utilization of NC endometrial preparation for FET, protocols used, restrictions to offering NC-FET, and providers’ perspectives on advantages and disadvantages of NC-FET. Descriptive statistics were used to analyze survey responses.

Result(s)

The survey response rate was 49% (216/441). Seventeen percent of responding clinics did not offer NC-FET. Of the clinics that did not offer NC-FET, 65% had only 1–2 physicians in their practice. Common reasons for not offering NC-FET included “lack of timing predictability for transfer” (81%) and “increased burden on staff/laboratory personnel on holidays and weekends” (54%). Of clinics offering NC-FET, 76% reported < 25% of cycles used the NC for endometrial preparation. Over half (52%) of clinics that offered NC-FET reported having eligibility restrictions for NC-FET. Reported benefits of NC-FET were “patient satisfaction” (18%), “decreased cost of medications” (18%), and “avoidance of intramuscular progesterone” (17%). The attitude towards NC-FET in their clinics was reported as positive by 65% of respondents.

Conclusion

NC-FETs are offered by most U.S. ART clinics but are used only in the minority of FET cycles for endometrial preparation, and use is often restricted.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10815-023-02751-w.

Introduction

Frozen-thawed embryo transfers (FETs) have become increasingly common in the U.S. such that 78.8% of transfers in 2019 used frozen embryos [1, 2]. Contributors to this trend include the increased utilization of embryo cryopreservation for fertility preservation for future use, the expanded use of pre-implantation genetic testing (PGT) as well as the widespread use of embryo vitrification that offers better embryo survival rates [3, 4]. Other benefits of FETs include risk reduction of ovarian hyperstimulation syndrome and growing evidence that uterine milieu at time of embryo transfer may impact cycle and pregnancy outcomes [4, 5]. As the number of FETs increases, debate continues regarding the best endometrial preparation protocol for these transfers. In particular, the differences in obstetric and neonatal outcomes between natural (ovulatory) and programmed (medicated) endometrial preparation remains a topic of active investigation.

In the programmed endometrial preparation cycle, endometrial proliferation is attained with exogenous estrogen and the addition of progesterone supplementation after appropriate endometrial thickness is achieved [6]. Benefits of programmed cycles include more robust data on clinical outcomes, higher predictability, and lower cancellation rate, with its major disadvantages being increased cost and potential adverse effects of exogenous hormone treatment [7–9]. Most notably, intramuscular progesterone in oil injections (IM PIO) has been associated with pain and infection at the site of injection, rare but severe systemic side effects, as well as inconvenience in administration [7]. Conversely, with natural cycle endometrial preparation (NC), endometrial maturation relies on endogenous estradiol and progesterone produced by the dominant follicle with later hormone production by the corpus luteum [8]. Benefits of NC-FET include a lower medication burden, lower costs, and a more physiologic hormone milieu; however, the timing of these transfers is dictated by the menstrual cycle which limits the predictability and control in scheduling.

Emerging data shows potentially improved obstetric outcomes with NC-FETs, as compared to programmed endometrial preparation [8, 10–14]. Most consistently across studies is the reduction of hypertensive disorders of pregnancy and lower risk of cesarean sections with NC-FETs [8, 10–14]. Although some studies have found similar pregnancy rates [9], others have found higher ongoing pregnancy rates in natural cycle preparations [15, 16]. Proposed mechanisms driving these observed differences include differences in the hormonal milieu, specifically the supraphysiological concentrations of estrogen and progesterone in programmed cycles or the absence of a corpus luteum which produces peptides including the vasodilator, relaxin [17, 18]. Differences in endometrial development, altered trophoblast invasion or uterine adaptation to pregnancy could contribute to differences in pregnancy outcomes including hypertensive disorders of pregnancy seen between programmed and natural cycles [19]. It must be noted that most studies published to date are retrospective observational studies focused on populations outside of the United States (U.S.), limiting conclusions and generalizability [10, 11, 13].

Despite the data suggesting potential maternal and neonatal benefits to transfer in a natural cycle, the utilization and provider attitudes towards this type of protocol in the U.S. remain unknown. To better understand U.S. practice patterns, we developed a survey and distributed it nationally to all the U.S. Assisted Reproduction Technology (ART) clinics evaluating the use of natural cycles FETs at their sites. The objectives of this survey-based study are to assess the current rate of utilization of NC-FET, protocols used, restrictions to undergoing NC-FET, and providers’ perspectives on advantages and disadvantages of NC-FET.

Material and methods

An anonymous 22-question survey along with a unique clinic-specific code was distributed to 441 U.S. ART clinics by email (Supplemental material). The language of the survey was designed for reproductive endocrinologists and advanced practitioners of ART clinics, and the survey was developed and tested by multiple reproductive endocrinologists in the study group. For the purposes of this study, NC-FET included all cycles in which endometrial preparation occurred in an ovulatory cycle. The survey was structured to cover four main topics: (1) utilization of NC endometrial preparation for FET, (2) NC-FET protocols used, (3) restrictions to undergoing NC-FET, and (4) providers’ perspectives on advantages and disadvantages of NC-FET. The survey was available online for 12 weeks. The survey did not collect any personal health information. Participation was voluntary, and consent was inferred based on participation. Upon completion of the survey, respondents could include their email address optionally for a chance to win a $100 Amazon gift card selected at random. This study was deemed exempt from further Emory University Institutional Review Board (IRB) review and approval, as it meets the criteria for exemption under 45 CFR 46.104(d)(2) as established by Emory University policies and procedures.

The study participants were selected from those who reported to the 2019 Centers for Disease Control (CDC) and Prevention National ART Surveillance System, which included 448 clinics total. To ensure the most up-to-date information, the CDC list was cross-referenced with the 2021 Society for Assisted Reproductive Technology’s (SART) website clinic list. If a clinic only was part of the CDC list and did not appear on the SART website, we visited the website directly to corroborate if they were still operating. If a clinic had closed, they were removed from the list. Conversely, when searching the SART database by state, if a new clinic reported to SART but was not part of the 2019 CDC report, they were added to the list. After our cross-reference, we ended with a pool of 475 total clinics. Of the 475 total, 3 were removed due to their location being in a U.S. territory, and 31 were removed because they did not have a contact email publicly available. A total of 441 met the inclusion criteria and were contacted via email.

An initial email was sent to medical directors of U.S. ART clinics on 9/6/2021, with a follow-up email on 9/18/21, and a third follow-up on 10/11/21. If there was no response from the medical director two weeks after the third follow-up email, an alternate contact round was attempted wherein, if available, another reproductive endocrinologist practicing at the clinic was contacted with the same unique clinic-specific code. Geographic regions were determined according to the U.S. Census Bureau Regions and Division [20]. Clinic volume data (total cycles) was gathered from the preliminary 2019 CDC annual surveillance system. Question types included multiple choice, “select all that apply,” and free text input (Supplemental material). Free text responses were coded based on themes by one of the authors. Most questions had the option of answering “unknown.” The survey was created and distributed using an online professional survey platform called SurveyMonkey.

Descriptive statistics were used to analyze the complete survey responses. If a clinic submitted multiple responses, the first submission was prioritized and included; the extra submissions from the same clinic were excluded from our analysis.

Results

Respondent clinic demographics

Of the 441 U.S. ART clinics contacted, 216 (49%) completed the NC-FET practice survey. Of the responding clinics, 133 (62%) identified as private, 50 (23%) academic, and 33 (15%) hybrid clinics (private clinics with academic affiliation). Respondents were distributed across all five geographic regions in the U.S. (Table 1). The reported number of physicians on staff per clinic was commonly 1–2 (40%) providers or 3–5 providers (41%). There was a range of clinic cycle volume, ranging from < 250 cycles (13%) to > 1000 cycles (24%) annually. Over half (55%) of clinics responded that > 75% of transfers were FETs (Table 1). The distribution by practice type, geographic region, number of physicians on staff, SART report status, clinic volume, and frozen embryo transfer percentage for responding and non-responding clinics are presented in Table 1.

Table 1.

Characteristics of clinic respondents and non-respondents

A. Clinic respondents				B. Clinic non-respondents
Characteristic	Yes NC offered n = 179	No NC not offered n = 37	Total n = 216	Total n = 225
	n (%)	n (%)	n (%)	n (%)
Geographic region
Northeast	51 (28%)	3 (8%)	54 (25%)	50 (22%)
Midwest	37 (21%)	9 (24%)	46 (21%)	42 (19%)
Southeast	34 (19%)	12 (32%)	46 (21%)	37 (16%)
Southwest	17 (9%)	6 (16%)	23 (11%)	38 (17%)
West	40 (22%)	7 (19%)	47 (22%)	58 (26%)
Practice type
Academic	45 (25%)	5 (14%)	50 (23%)	15 (7%)
Private	102 (56%)	31 (84%)	133 (62%)	183 (81%)
Hybrid	32 (18%)	1 (3%)	33 (15%)	27 (12%)
Number of physicians on staff
1–2	63 (35%)	24 (65%)	87 (40%)	158 (70%)
3–5	77 (43%)	11 (30%)	88 (41%)	50 (22%)
6–8	21 (12%)	1 (3%)	22 (10%)	12 (5%)
8 +	18 (10%)	1 (3%)	19 (9%)	5 (2%)
Reports to SART
Yes	152 (85%)	26 (70%)	178 (82%)	157 (70%)
No	27 (15%)	11 (30%)	38 (18%)	68 (30%)
Total cycles (2019 CDC Prelim data) [2]
1–250	20 (11%)	9 (24%)	29 (13%)	61 (27%)
251–500	33 (18%)	9 (24%)	42 (19%)	38 (17%)
501–750	31 (17%)	4 (11%)	35 (16%)	17 (8%)
751–1000	18 (10%)	1 (3%)	19 (9%)	14 (6%)
1000 +	49 (27%)	3 (8%)	52 (24%)	31 (14%)
Did not report	28 (16%)	11 (29%)	38 (18%)	64 (28%)
What percentage of transfers are frozen embryo transfers (FETs)
< 25%	9 (5%)	2 (5%)	11 (5%)
35–50%	21 (12%)	7 (19%)	28 (13%)
50–75%	52 (29%)	5 (14%)	57 (26%)
> 75%	95 (53%)	23 (62%)	118 (55%)
Unknown	2 (1%)	0 (0%)	2 (1%)

Characteristics of NC-FET cycles in the U.S.

Of the 216 survey respondents, 179 (83%) reported offering NC-FETs. When examined by practice setting, 76.7% of private, 90% of academic, and 96.9% of hybrid clinics offered NC-FET. Of responding clinics not offering NC-FET, 65% had only 1–2 physicians in their practice, whereas, of those offering NC-FET, 65% had 3 or more physicians in their clinics. Of clinics that did not offer NC-FET, 48% had a clinic volume of < 500 total cycles, compared to 29% of clinics that offered NC-FET. Of clinics that reported offering NC-FET, the majority (76%; n = 135) reported NC FETs are utilized in the minority of cycles (< 25%). There were only 6 clinics (3%) that reported > 75% of FET used a NC for endometrial preparation (Table 2A).

Table 2.

Characteristics and attitudes of NC-FET cycles in the U.S. clinics (n = 179)

A. Characteristics of NC-FET survey questions	n (%)
a. If offered, what percentage of FETs are NC-FETs?	n = 179
< 5%	60 (34%)
5–25%	75 (42%)
25–50%	24 (13%)
50–75%	13 (7%)
> 75%	6 (3%)
Unknown	1 (1%)
b. Are there restrictions regarding who can undergo NC-FET?	n = 179
Yes	93 (52%)
No	85 (47%)
Unknown	1 (1%)
c. If there are restrictions of who can undergo NC-FETs, what are they?*	n = 93
Ovulatory cycles/regular menses/no anovulation (no specificity about ovulation induction)	60 (64%)
Ovulatory cycles or if anovulatory, must respond to ovulation induction	13 (14%)
Logistics (lab, patient, clinic schedule, etc.)	10 (11%)
Diminished ovarian reserve/primary ovarian insufficiency	6 (6%)
Not menopausal	7 (8%)
Adequate endometrium	7 (8%)
Age < 40	7 (8%)
Previous failure with medicated cycles	4 (4%)
Must not be a surrogate	3 (3%)
Previous medication side effects/medications contraindications	3 (3%)
Preference	1 (1%)
No answer	2 (2%)
d. Do you allow anovulatory women to undergo NC-FET with ovulation induction?	n = 179
Yes	113 (63%)
No	62 (35%)
Unsure	3 (2%)
No answer	1 (1%)
e. What medication is used for ovulation induction in anovulatory women?	n = 113 (allow anovulatory)
Clomid	4 (4%)
Letrozole	69 (61%)
Both	28 (25%)
Other	12 (11%)
f. What is the most frequently used method of timing transfer in NC-FET cycles in your clinic?	n = 179
hCG trigger	125 (70%)
Ovulation Predicter kit	27 (15%)
Equal split	23 (13%)
Unknown	3 (2%)
No response	1 (1%)
g. If NC offered, do you feel like the rate of NC-FET has increased in your clinic over the last 5 years?	n = 179
Yes	112 (63%)
No	51 (28%)
Unsure	15 (8%)
No answer	1 (1%)
B. Attitudes towards NC-FETs survey questions
h. In light of recent publications regarding benefit of NC-FET on obstetric outcomes, has there been an increase in patient demand for this type of endometrial preparation?	n = 216
Yes	45 (21%)
No	147 (68%)
Unsure	15 (7%)
No answer	9 (4%)
i. In light of recent publications regarding benefit of natural cycle FET on obstetric outcomes, has there been a change in physician attitude favoring this type of endometrial preparation?	n = 216
Yes	97 (45%)
No	88 (41%)
Unsure	26 (12%)
No answer	5 (2%)
j. Do you anticipate an increase in NC-FET use due to recent research regarding favorable outcomes and possible perinatal benefits?	n = 216
Yes	121 (56%)
No	53 (25%)
Unsure	37 (17%)
No answer	5 (2%)
k. What is the attitude towards NC-FET in your clinic?*	n = 216
Positive	110 (51%)
Neutral	33 (15%)
Negative	35 (16%)
Positive, but difficult logistics	31 (14%)
No answer	11 (5%)
l. What are the barriers for offering NC-FET (if any) in your clinic?*	n = 216
None	45 (21%)
Lab	29 (13%)
Logistics/scheduling	121 (56%)
Lack of data	8 (4%)
Other	19 (9%)
No answer	11 (5%)

*Questions “c.,” “k.”, and “l.” were free text response questions; respondents could provide more than one answer. Questions “c.,” “k.”, and “l.” responses were coded based on common themes by one of the authors

Over half (52%) of clinics that offered NC-FET reported having restrictions surrounding which patients can utilize this type of protocol. Of the clinics with restrictions, 60 (64%) reported the most common restriction to be that the patient must have ovulatory cycles. Restrictions related to clinic scheduling (11%), menopausal status (8%), endometrial thickness (8%), age > 40 (8%), diminished ovarian reserve/primary ovarian insufficiency (6%), previous failure with programmed cycle or medications (4%), must not be a surrogate (3%), and a history of previous medication side effects or contraindications (3%) were also mentioned in this free response question (Table 2A).

The most frequently reported method used to time a transfer in NC-FET cycles was a human chorionic gonadotropin (hCG) trigger (70%), followed by ovulation predictor home test (15%) and equal split between both methods (13%) (Table 2A). Notably, 113 (63%) of clinics offering NC-FET allowed anovulatory women to undergo NC-FET, with 69 (61%) using letrozole and 28 (25%) using both letrozole and clomid for ovulation induction (Table 2A).

Reasons for not offering NC-FET

When asked about reasons they did not offer natural cycle endometrial preparation for their frozen embryo transfers, the 37 (17%) survey respondents who reported it as not part of their practice commonly cited “lack of timing predictability for transfer” (30 clinics, 81%) and “increased burden on staff/laboratory personnel on holidays and weekends” (20 clinics, 54%) (Fig. 1).

Fig. 1.

Reasons for not offering natural cycle frozen embryo transfers. Respondents (n=37) had the option to choose more than one answer for this survey question

U.S. ART clinics’ perspectives on natural cycle benefits and negatives

All survey respondents were asked about the most valuable benefits and most notable negatives of NC-FETs, with the option of selecting more than one answer. The most valuable benefits reported were “patient satisfaction” (39 clinics, 18%), “decreased cost of medications” (39 clinics, 18%), and “avoidance of intramuscular progesterone” (36 clinics, 17%) (Fig. 2A). The majority selected “lack of timing predictability for transfer” (70 clinics, 32%), as the most notable negative aspect of NC-FETs, followed by “increased burden on staff/laboratory personnel on holidays and weekends” (58 clinics, 27%) and “inability to coordinate provider/patient schedule for transfer” (45 clinics, 21%) (Fig. 2B).

Fig. 2.

The most valuable A benefits and B negatives of natural cycle endometrial preparation from respondents’ perspective. Respondents (n=216) had the option to choose more than one answer for this survey question

U.S. ART clinics’ attitudes towards NC-FETs

When asked about practice patterns and the effect of recent data demonstrating possible benefit on obstetrical outcomes for natural cycle endometrial preparation, the majority of responding clinics (147 clinics, 68%) reported not seeing an increase in patient demand for NC-FET. However, most (121 clinics, 56%), anticipate an increase of this type of endometrial preparation, and 45% of clinics reported a change in physician attitude favoring NC-FETs. The attitude towards NC-FET in their clinics was reported as generally positive by 141 (65%) of respondents with 33 (15%) reporting a neutral attitude and 35 (16%) reporting a negative towards NC-FET at their clinics (Table 2B).

Discussion

Amid emerging data showing a potential improvement in obstetric outcomes with NC-FETs when compared to programmed cycles [8, 10–14], this survey of U.S. ART clinics, with 216 respondents, represents the first formal attempt to assess utilization and provider attitudes toward NC-FETs at the national level. Of responding clinics, 76.7% of private clinics offered NC-FETs, while 96.9% hybrid and 90% of academic clinics offered this type of protocol; practices with higher volume, more providers, and those with an academic affiliation were more likely to offer NC-FET.

Based on the results of this cohort, we found that even when NC-FET is offered, it is used in the minority of cycles, as 76% of responding clinics that reported offering NC-FET endometrial preparation reported having < 25% of their FETs prepared in a NC. In contrast, large retrospective cohort studies from China and Sweden that compared outcomes between NC-FETs and programmed cycle FETs, reported that between 49 and 68% of all FETs were prepared with NC [10, 13, 14, 21]. Moreover, our findings show that NC-FETs are restricted in over half (52%) of responding clinics that offer NC-FET. The most common requirement (reported by 64% of restricting clinics) was that the patient must have ovulatory cycles. This restriction could potentially exclude many patients, because as cited in the CDC 2019 ART report, 13.9% of patients using ART have ovulatory dysfunction [2]. Interestingly, 8% of clinics reported an age restriction of < 40 years old. This might be explained by some studies finding higher miscarriage rates in women > 42 years old using NC-FET [22]. However, more recent studies have found a lower miscarriage rate, higher live birthrate, and no significant difference in clinical pregnancy in women > 40 years old using NC-FET when compared to programmed cycle outcomes [23, 24].

Our findings revealed that 17% of responding U.S. clinics do not offer NC-FET in their practice. The most common reasons for not offering NC-FET were logistical in nature and likely scheduling related. These logistical reasons are directly influenced by provider availability, which could explain why smaller clinics, with only 1 or 2 physicians on staff, were the most represented on the NC-FET non-offering group (65%). Our findings suggest that smaller clinics may perform only programmed endometrial preparation for FET for scheduling and logistical reasons.

Patient satisfaction, decreased cost of medications, and “avoidance of intramuscular progesterone” were the most notable benefits of NC-FETs reported by all survey respondents. This is supported by studies showing that the biggest disadvantages of programmed cycles are the higher costs and potential adverse effects related to exogenous hormone treatment that are generally avoided with natural cycles [7–9]. The notable negative aspects of this type of endometrial preparation reported by all clinics, including those that do offer NC-FET, have a significant overlap with the reasons why NC-FET non-offering clinics do not offer this protocol, including logistical issues, like lack of predictability, increased burden on staff, and scheduling issues. These problems may be amplified in lower volume clinics with fewer providers and should be taken into consideration when developing systems to bypass these obstacles.

About two-thirds of clinics that offered NC-FET reported the rate of NC-FETs has increased in their clinic over the last 5 years; however, most (68%) of responding physicians do not report an increase in patient demand for NC-FET. Most responding clinics anticipate an increase in NC-FET use (56%) and report a generally positive attitude towards this type of protocol (65%). Notably, 19% of responding clinics that did not offer NC-FET reported “limited data regarding chances of success” as the reason for not offering them. Though there is not yet a consensus on the ideal method of endometrial preparation prior to frozen embryo transfer, emerging, largely retrospective data supports differences in maternal and neonatal outcomes. The results of this survey study report the need for prospective, rigorous trials exploring the benefits of frozen embryo transfer in ovulatory cycles so that clinicians can optimally counsel patients on the risks and benefits of different endometrial preparation methods.

A limitation of our study is the 49% survey completion rate from 441 U.S. ART clinics; however, this is similar to previously published survey-based studies that have assessed different types of ART practices [25, 26]. There is potential for selection bias, as those that responded to the survey may differ from those that did not. A higher percentage of practices that did not respond to our survey were private, had only 1–2 physicians on staff, and did between 1 and 250 cycles per year when compared to the responding clinics. Thus, the results of this study may not be representative of clinics with these characteristics.

Another limitation is that the clinics’ position on a particular issue may not have been well represented by the answer choices available in this survey (options of “Other” and “Unsure” may include a variety of answers) or by the answers provided by a single representative of the practice. The results of this survey study, therefore, may not be a representative overview of physicians’ attitudes and perspectives, as only one individual was surveyed per participating clinic. The free-text responses were coded by common themes by one of the authors, which may introduce some bias into the data. These results are qualitative and should be interpreted as such, as the aim of the study is to assess overall practice patterns and physician attitudes towards NC-FETs and does not elucidate more subtle variations in FET protocols between clinics.

This study provides a national snapshot of current practice patterns and attitudes surrounding NC-FET in the U.S. Moreover, our respondents were diverse in practice type, U.S. geographic region, number of physicians on staff, and clinic volume, which is representative of a broad portion of the U.S. It represents the first formal attempt to anonymously assess the utilization and provider’s attitudes toward NC-FETs at the national level.

Conclusion

While NC-FETs are offered by most U.S. clinics in the responding cohort, they are used only in the minority of FETs cycles for endometrial preparation, and their use is often restricted. Additional prospective, randomized studies comparing the outcomes of FET in an ovulatory versus programmed cycle are needed to clarify the optimal endometrial environment for transfer. If embryo transfer in a natural cycle is further proven to benefit obstetric and neonatal outcomes, clinics will be challenged to address the most common barriers to offering NC-FET described in this study.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

All the authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Natalia Calzada-Jorge, Jacqueline Lee, and Jennifer Kawwass. The first draft of the manuscript was written by Jacqueline Lee and Natalia Calzada-Jorge. All the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

Funding

Emory University School of Medicine’s Department of Gynecology and Obstetrics provided funding for the survey’s respondent incentive, a raffled 100$ Amazon Gift Card.

Materials availability

Data will be made available to the editors of the journal for review or query upon request.

Data Availability

Data will be made available to the editors of the journal for review or query upon request.

Declarations

Ethics approval

This study was deemed exempt from further Emory University Institutional Review Board (IRB) review and approval, as it meets the criteria for exemption under 45 CFR 46.104(d)(2) as established by Emory University policies and procedures.

Competing interests

The authors declare no competing interests.