Keep trying or give up? the future fertility of patients undertaking their first in vitro fertilization with no available embryos

doi:10.21203/rs.3.rs-1961642/v1

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Keep trying or give up? the future fertility of patients undertaking their first in vitro fertilization with no available embryos

https://doi.org/10.21203/rs.3.rs-1961642/v1

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published 23 May, 2023

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In in vitro fertilization (IVF), the patient's probability of subsequent pregnancy after a failed procedure with no transferable embryo is unknown. We conducted a cohort retrospective study evaluating the live birth rate in the subsequent cycles of the patients with no embryo transfer in their first IVF attempt between 2017and 2020. The variables in the first cycle were compared between the patients who conceived in subsequent cycles and who did not. Additionally, for patients who conceived at last, variables related to ovarian stimulation were compared between the first cycle and the pregnancy cycle. According to the inclusion criteria, 529 were enrolled during the study period, of which 230 had successful pregnancies and 192 gave birth to a live infant. Cumulative live birth rates (CPR) per cycle and per patient were 26%, 36% respectively. 99% of the live births were obtained within the first 3 attempts, no pregnancy was achieved beyond 6 cycles. Stimulating variables in the first cycle were not effective in predicting the likelihood of a patient's subsequent pregnancy. Overall, patients who did not have embryos available for transfer in the first cycle had a 36% chance of having a live birth in subsequent attempts, and more than three attempts were not recommended.

Embryos are one of the two most important factors for a successful pregnancy in in vitro fertilization (IVF). For various reasons, such as the heterogeneity of the patients in the ovarian stimulation protocol and laboratory operations, there may be no embryos available for transfer¹. There is little literature concerning the patients who didn’t obtain any embryos for transfer in their first IVF procedure. In our center, the rate of having no embryos for transfer is approximately 4% overally. After the first failure 50% of patients choose to have another try. Evidence suggests that after repeat IVF/ICSI cycles, live birth can be achieved eventually for certain groups ².

However, in China where IVF costs have not been fully covered by public resources, the use of IVF is based on the family financial situation. A considerable number of families will consider seeking the most cost-effective way and avoiding unnecessary financial waste. Additionally, trying again means a drain on physical energy, time, and social resources.

In this study, we intended to provide patients who had not yielded any available embryos for transfer in their first IVF cycle with the realistic information about what outcomes might be expected if they elect to undergo another cycle and the approximate number of cycles required for a given patient to achieve a successful pregnancy and live birth.

This was a single-center retrospective cohort study performed in the Reproductive Center of Northwest Women's and Children's Hospital in Xi’an, Shaanxi province. It was approved by the ethics committee of the Northwest Women’s and Children’s Hospital (number 2018002) and the informed consent was waived because of its retrospective nature with the approval of the ethics committee of the Northwest Women’s and Children’s Hospital. We guaranteed that all methods used in the research were in strict accordance with the requirements and regulations of the Declaration of Helsinki. Women attending our center for their first IVF or Intracytoplasmic sperm injection (ICSI) treatment from January 2017 to December 2020 were included. Inclusion criteria were women who: 1)had no embryos for transfer in their first cycle; 2) had done at least 1 subsequent cycle and had not achieved a pregnancy until all the embryos transferred; 3)or get a pregnancy or live birth in a subsequent cycle.

Ovarian stimulation was started on the third day of menstruation using a combination of Gonadotropin-releasing hormone(GnRH)Agonist/Antagonist with recombinant FSH. Trigger with hCG was administrated when there were more than 3 follicles ≥ 18 mm in diameter. 36 hours later, oocyte retrieval was performed by transvaginal ultrasound-guided vaginal fornix puncture.

oocytes were collected and fertilized with husband's sperm with IVF or ICSI in the laboratory. After 64-68h of culture, morphological embryo assessment was performed according to the Edward RG’s criteria based on the number of blastomeres, homogeneousdegree of blastomeres, and degree of cytoplasmic fragmentation: grade(Ⅰ): The blastomeres are of equal size, transparent, and free of fragments;( Ⅱ): The blastomeres are uneven in size, and the fragmentation rate is < 10% ;( Ⅲ): The blastomeres are uneven in size, and the fragmentation rate is 10%-50% ;( Ⅳ): blastomere size is uneven, fragmentation rate > 50%. GradeⅠ Ⅱ Ⅲ were identified suitable for transferring into the uterus. So having no embryos for transfer meant that there was not a single embryo that met the transfer criteria.

The patients were ordered to keep a full bladder on the day of the embryo transfer. Embryos were placed in the uterus using a catheter (Cook, Ireland) with the guidance of transabdominal ultrasound. In order to ensure the successful landing of the embryo, the mucus in the cervical os was wiped in advance with a cotton swab soaked in warm and humid saline. This operation was carried out with the cooperation of senior physicians, nurses and laboratory experts.

The primary outcomes were clinical pregnancy and live birth. Secondary outcomes were miscarriage. Clinical pregnancy referred to the presence of a gestational sac. Live birth was defined as giving birth at least one live birth (> 24 weeks gestation). Miscarriage meant termination before 28 weeks of pregnancy.

The data of the first cycle and the subsequent cycles were collected and compared. The variable data obtained from gestational cycles were compared with cycles in which not a pregnancy was achieved.

SPSS 22.0 was used to perform the data analysis. To compare continuous variables between two groups, Mann–Whitney U test was used. Categorical variables were compared by chi-square test. Binary regression was used to calculate odds ratios and 95% confidence intervals for pregnancy outcomes to analyze the impact of potential confounders on outcomes. P<0.05 was considered statistically significant.

A total of 27932 people received 34933 cycles during the study period, and 1019 first cycles did not obtain embryos for transfer. According to the inclusion criteria, a total of 556 patients were enrolled, and after removing the missing information, a total of 529 patients entered the final study stage.

Baseline data, ovarian stimulation and embryo fertilization of the first IVF cycle were shown in Table 1. The basic characteristics, the CPR and cumulative live birth rate (CLBR) of each subsequent cycle were shown in Table 2. During the study period, 230 women achieved clinical pregnancies and 192 of them resulted in successful live births. As can be seen, the clinical pregnancy rate and live birth rate reached 34% and 28%, respectively, in the second attempt. The highest cumulative clinical pregnancy rate and cumulative live birth rate per cycle reached 34%, 28%. Similarly, the highest cumulative clinical pregnancy rate and cumulative live birth rate per patient were 43%, 36%.

Table 1

Baseline characteristics of patients undergoing their first cycle with no embryo for transfer.
Number of patients	529
Maternal age (years), mean ± SD	32.32 ± 5.28
Maternal BMI, Kg/m²,mean ± SD	22.82 ± 3.48
Infertility duration(y)	3.93 ± 3.25
No. of oocyte retrieved(n)	5.42 ± 4.36
Fertilization type (%)
IVF	426
ICSI	103
Infertility type (%)
Primary	299
Secondary	230
Basal LH ,IU/L	5.35 ± 4.65
Basal FSH,IU/L	8.47 ± 4.37
Total Gn dose, IU	2579 ± 1041
endometrium thickness, mms	10.82 ± 2.87

Table 2

Reproductive outcomes of patients stratified by cycle rank.
Cycle rank	1	2	3	4	5	6	7	8	9	10
Patients	529	529	133	54	20	10	5	1	1	1
Number of clinical pregnancy	0	180	36	10	2	1	1	0	0	0
Number of live birth	0	155	27	8	1	0	1	0	0	0
clinical pregnancy	0	180/529	36/133	10/54	2/20	1/10	1/5	0	0	0
%	0	34%	27%	19%	10%	10%	20%	0	0	0
Live birth	0	155/529	27/133	8/54	1/20	0	1/5	0	0	0
%	0	28%	20%	15%	5%	0	20%	0	0	0
Cumulative Clinical Pregnancy ( cycle)	0	180/529	216/662	226/716	228/736	229/746	230/751	230/752	230/753	230/754
%	0	34%	33%	32%	31%	31%	31%	31%	31%	31%
Cumulative live birth (cycle)	0	155/529	182/662	190/716	191/736	191/746	192/751	192/752	192/753	192/754
%	0	28%	27%	27%	26%	26%	26%	26%	26%	26%
Cumulative Clinical Pregnancy ( patients)	0	180/529	216/529	226/529	228/529	229/529	230/529	230/529	230/529	230/529
%	0	34%	41%	43%	43%	43%	43%	43%	43%	43%
Cumulative live birth( patients)	0	155/529	182/529	190/529	191/529	191/529	192/529	192/529	192/529	192/529
%	0	28%	34%	36%	36%	36%	36%	36%	36%	36%

Then, for the patients who conceived or not ultimately, their basic characteristics and ovarian stimulation variables were compared (Table3). We can conclude that the patients who get pregnant at last have a younger age(31.06 ± 4.45 Vs 33.29 ± 5.66, P<0.001 ), shorter years of infertility (3.48 ± 2.38 Vs 4.27 ± 3.76, P<0.001), less Gn amount(2471.97 ± 1005.02 Vs 2532.89 ± 1188.95, P = 0.01), and lower E2(2399.08 ± 2144.44 Vs 2527.66 ± 2416.90, P = 0.02 ) and LH(2.66 ± 3.60 Vs 3.88 ± 6.10, P<0.001) levels compared with those who do not in the first cycle.

Table 3

The ovarian stimulation characteristics in the first cycle of the patients who conceived and who did not.
	pregnancy	No pregnancy	P-value
Number of patients	230	299
Duration of infertility, years	3.48 ± 2.38	4.27 ± 3.76	<0.001
Maternal age (years), mean ± SD	31.06 ± 4.45	33.29 ± 5.66	<0.001
Number of oocyte retrieved	5.53 ± 4.13	5.34 ± 4.55	0.16
Mean endometrium thickness, mms	11.09 ± 2.92	10.44 ± 3.11	0.10
Gn amount, (IU)	2471.97 ± 1005.02	2532.89 ± 1188.95	0.01
Gn duration(days)	10.33 ± 3.50	9.77 ± 3.50	0.91
E2	2399.08 ± 2144.44	2527.66 ± 2416.90	0.02
LH	2.66 ± 3.60	3.88 ± 6.10	<0.001

Additionally, we compared the variables in the first and conceiving cycle of the patients who get pregnant at last. Compared with the first cycle, there existed more oocytes (8.40 ± 5.12Vs5.53 ± 4.13,P<0.001) and 2pn(5.17 ± 3.16Vs 1.82 ± 2.33,P<0.001), less Gn duration(9.76 ± 2.47Vs10.33 ± 3.52, P<0.001) in the conceiving cycle.

To date, there have been few reports regarding the subsequent clinical outcomes of the patients who did not achieve any embryos available for transfer in their first attempt. The purpose of our study was to identify potential mechanisms affecting clinical pregnancy and live birth, and to provide some advice to patients who have failed their first IVF treatment. To our knowledge, our study has the largest sample size of its kind on this topic. Our analysis suggested that the probability of subsequent live births was 36% for patients having no embryo for transfer in their first IVF and that the majority of patients would achieve live births within 3 cycles.

One study investigated the question of the pregnancy predictive value of the stimulation characteristic in the first cycle in women of advanced age³. Different from ours, they thought the only statistically significant differences between women who achieved a clinical pregnancy and those who did not were maternal age and number of oocyte retrieved. We believe that a shorter years of infertility, less Gn dosage and lower LH levels in the first cycle, rather than number of oocyte retrieved, predict a greater likelihood of pregnancy in the subsequent treatment.

Another study showed that extending cycles of IVF increased CLBRs and the increase was most evident during the first three cycles². This conclusion is similar to ours, most of the patients can get live birth within 3 cycles.

Interestingly, we found that the CLBR of the patients in this study was similar to that of the POSEIDON 4 group or those with diminished ovarian reserve in the previous study ^4–8. This result may be related to the infertility factors such as the patient's age. Orvieto et al.⁹ found that the factors predicting pregnancy or not were only maternal age and number of oocytes retrieved, different from ours. Although no valuable indicators were found to predict future pregnancy from the first IVF attempt, it was confirmed that age and ovarian response were the most important factors.

The CLBR of the patients in this study was similar to that of the patients with advanced age in a previously published study in which IVF treatment was extended up to 13 times¹⁰. In contrast, it could be seen that 3 cycles were sufficient for most patients, and more cycles meant just a waste of time and resources.

Our present work has some strengths of note. First, this is the first study with the largest sample size to date to explore possible future outcomes for patients who did not have embryos available for transfer in the first cycle. additionally, the nature of retrospective studies may hinder observation bias. Last, our research comes from actual clinical data, not a clinical trial, thus avoiding strict inclusion and exclusion criteria which may result in certain limitations on representation and the authenticity of randomized controlled trials.

The limitations of this study should also be considered. first, because of its retrospective nature, we could not control for potential unknown confounding factors. Finally, since all of this data comes from one IVF treatment center, a larger multicenter study is needed to confirm the results .

In conclusion, our findings indicated that patients who did not have embryos available for transfer in their first cycle still had a 34% chance of pregnancy in subsequent cycles, and for this population, treatment for more than 3 cycles should not be performed even if there was no financial burden.

Author contributions

X.D. designed the study, drafted and revised the manuscript; X.X. helped design the study and revised the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing interests.

Additional information

All data generated or analysed during this study are included in this published article and its supplementary information files.

Correspondence and requests for materials should be addressed to X.X.

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Gu F, et al. Can repeat IVF/ICSI cycles compensate for the natural decline in fertility with age? an estimate of cumulative live birth rates over multiple IVF/ICSI cycles in Chinese advanced-aged population. Aging (Albany NY). 10:14385–14398(2021).
Homburg R, et al. Do stimulation characteristics of the first in vitro fertilization cycle predict pregnancy in women of 40 years old and over? Fertil Steril. 4 Suppl:1311–1313(2009).
Ferraretti AP, et al. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 7:1616–1624(2011).
Abdullah RK, et al. Cumulative live-birth, perinatal and obstetric outcomes for POSEIDON groups after IVF/ICSI cycles: a single-center retrospective study. Sci Rep. 1:11822(2020).
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Polyzos NP, et al. Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI. Reprod Biomed Online. 4:469–474(2014).
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Lebovitz O, et al. The expected cumulative incidence of live birth for patients starting IVF treatment at age 41 years or older. Reprod Biomed Online. 5:533–541(2018).

No competing interests reported.

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You are reading this latest preprint version

Keep trying or give up? the future fertility of patients undertaking their first in vitro fertilization with no available embryos

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