Document Type : Original Article
1 Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon
2 Faculty of Medicine, American University of Beirut, Beirut, Lebanon
The prevalence of infertility is around 9% worldwide (
To the best of our knowledge, CLBR after IVF/intra-cytoplasmic sperm injection (ICSI) cycles has never been reported at a national level in Lebanon, nor in the ME. It is important to determine these rates and how they change with repeated cycles, according to maternal age and type of infertility. It is essential to define an IVF cycle for these patients as the initiation of ovarian stimulation with subsequent fresh embryo transfer.
We aim to determine whether the CLBR increases over multiple successive IVF cycles, providing patients with a better estimation of their chances of a live birth.
The Ethical approval for this study was obtained from the Institutional Review Board at the AUBMC (BIO – 2017- 0331).
This retrospective cohort study was performed on all patients scheduled to have fresh IVF/ICSI cycles at the AUBMC between January 2016 and December 2016. One IVF cycle is defined as a fresh embryo transfer attempt resulting from one episode of ovarian stimulation. All embryo transfers involving the transfer of one or more embryos were included in the study to reproduce the daily practice of assisted reproductive technologies in our region.
Cycles that were excluded are those which were cancelled before the oocyte retrieval or before the embryo transfer, patients who had their IVF cycles after December 2016 and cycles with frozen embryos/frozen oocytes. Cancellation rate was 5%.
Baseline characteristics included different age categories (≤35, 36-39 and ≥40 years) and different types of infertility (male factor, unexplained infertility, ovulatory disorders, endometriosis, low ovarian reserve, tubal infertility and combined factors). Data collected included levels of anti-müllerian hormone and/or day 3 follicle stimulating hormone (FSH) and estradiol.
Patients underwent controlled ovarian stimulation and oocyte retrieval after 10-12 days of stimulation. All cycles included were ICSI cycles. Fresh embryo transfer took place two, three or five days after the oocyte retrieval. All cycles with pre-implantation genetic testing (PGT) or frozen embryo transfer were excluded.
Live birth and CLBRs per cycle were the main outcome measures, stratified by maternal age and type of infertility in up to six IVF cycles. Live birth was defined as a newborn delivered after 24 weeks of gestation. Once a woman succeeded in achieving her first live born baby from IVF, she does not contribute further to the cumulative rates calculation. All women without a live birth in a previous cycle were eligible for a subsequent cycle. The CLBR at one cycle expressed the likelihood of a live birth at that cycle and from all preceding cycles.
For all patients included, descriptive statistics of demographics and treatment characteristics were analyzed. A summary of the statistics was prepared as percentages for categorical variables and is compared using the chi-square test. The mean ± standard deviation (SD) was used for continuous variables and was compared using Student's t test or one-way analysis of variance (ANOVA).
The primary outcome of this study was the CLBR. Patients were not re-enrolled after having a first live birth in a previous IVF cycles.
The live birth rate per fresh IVF treatment was calculated
at different number of cycles, through dividing the number
of women in each cycle who had their first live birth by the
total number of IVF cycles. Conservative CLBR was also
calculated by dividing the total number of women who had
their first live birth up to the corresponding cycle by the
total number of women who ever attempted IVF (
Statistical analysis and computations were performed using Statistical Package for Social Sciences (SPSS IBM version 24 software, AUBMC, Lebanon), and a value of P<0.05 was considered to be statistically significant.
In this cohort study a total of 706 women underwent fresh
IVF cycles at the AUBMC from January 2016 to December
2016. After exclusions, 547 women with 736 fresh ovarian stimulation cycles were included in the analysis (
Flow chart of eligible cycles.
AUBMC; American University of Beirut Medical Center.
Tables 1 and 2 summarize the baseline characteristics of the cohort. Sixty-five percent of the patients undergoing IVF cycles were younger than 35 years of age. The mean duration of infertility was 4.2 years with male infertility being the most frequent diagnosis (42.5%).
Characteristics of the 736 fresh IVF Cycles at the American University of Beirut Medical Center in 2016
|Variables||For all cycles number (%)|
|Thyroid disorder||47 (6.4)|
|Type of infertility|
|Cause of infertility|
|Male factor||311 (42.5)|
|Unexplained infertility||136 (18.6)|
|Combined factors||97 (13.3)|
|Ovulatory disorder||55 (7.5)|
|Low ovarian reserve||48 (6.6)|
|Tubal factor||33 (4.5)|
|Total number of cycles|
|Antagonist protocol||631 (85.7)|
|Long protocol||85 (11.5)|
|Mild stimulation||19 (2.7)|
|hCG trigger||574 (78.0)|
|GnRHa trigger||159 (22.0)|
|Day of embryo transfer|
|Day 2||139 (19.0)|
|Day 3||454 (62.0)|
|Day 5||139 (19.0)|
Spring (March to May), Summer (June to August), Fall (September to November), Winter (December to February). IVF; In vitro fertilization, COS; Controlled ovarian stimulation, hCG; Human chorionic gonadotropin, and GnRHa; Gonadotropin releasing hormone agonist.
Characteristics of the 736 fresh IVF Cycles at the American University of Beirut Medical Center in 2016
|Variables||For all cycles|
|BMI (Kg/m2)||25.5 ± 4.7|
|Duration of infertility (Y)||4.2 ± 3|
|Day 3 FSH (mIU/mL)||7.1 ± 2.6|
|Day 3 Estradiol (ng/mL)||63.5 ± 62.0|
|AMH (ng/mL)||2.1 ± 2.3|
|Number of oocytes retrieved||10.4 ± 7.8|
|Number of mature oocytes||7.4 ± 5.2|
|Number of 2PN zygotes on day 1||5.5 ± 3.9|
|Number of embryos transferred||2.7 ± 0.9|
Data are presented as mean ± SD.
IVF; In vitro fertilization, BMI; Body mass index, FSH; Follicle-stimulating hormone, AMH; Anti-mullerian hormone, and PN; Pronuclear.
Cycles were stimulated with various protocols, with the antagonist protocol being the most commonly used (85.7%). Final oocyte maturation was mainly triggered by human chorionic gonadotropin (hCG) (78% of cycles), while the remaining cycles were triggered by gonadotropin releasing hormone agonist (GnRH) agonist. Transvaginal oocyte collection was performed 35-36 hours after the trigger. The luteal phase was supported by vaginal (micronized progesterone suppositories), intra-muscular and/or oral progesterone (Dydrogesterone).
The average number of embryos transferred per patient
was 2.7, and 81% of the embryo transfers were performed
on day 2 or day 3 with a fresh cleavage-stage embryo. This
resulted in 216 live births (29.3%), where 61.6% were singletons and 38.4% were multiple gestations (Table S1, See
Supplementary Online Information at
The overall CLBR for all treatment cycles and all age
groups is shown in
Conservative CLBR stratified for the different age groups
are presented in
Live birth rates within initiated treatment cycle and conservative cumulative live birth rates across all cycles
|Cycle number||Number of cycles||Number of live births||Live birth rate with-in each cycle, % (95% CI)||Cumulative live birth rates across all cycles, % (95% CI)|
|1||318||105||33.0 (27.8-38.2)||33.0 (27.8-38.2)|
|2||172||49||28.5 (21.7-35.3)||48.4 (42.8-54.1)|
|3||102||27||26.5 (17.8-35.2)||56.9 (51.3-62.4)|
|4||64||16||25 (14.1-35.9)||61.9 (56.4-67.3)|
|5||39||8||20.5 (7.2-33.8)||64.5 (58.9-69.7)|
|6||41||11||26.8 (12.7-41.0)||67.9 (62.5-73.0)|
CI; Confidence interval
CLBRs across all age groups
|Cycle number||Number of cycles||Number of live births||Live birth rate within each cycle, % (95% CI)||Cumulative live birth rates across all cy-cles, % (95% CI)|
|1. Women aged ≤35 years’ old|
|1||243||91||37.4 (31.3-43.6)||37.4 (31.3-43.6)|
|2||117||40||34.2 (25.5-42.9)||53.9 (47.4-60.3)|
|3||62||19||30.6 (18.8-42.4)||61.7 (55.3-67.9)|
|4||29||10||34.5 (16.1-52.9)||65.8 (59.5-71.8)|
|5||18||6||33.3 (9.2-57.5)||68.3 (62.1-74.1)|
|6||10||4||40.0 (3.1-76.9)||69.9 (63.8-75.6)|
|2. Women aged 36-39 years’ old|
|1||43||13||30.2 (15.9-44.5)||30.2 (15.9-44.5)|
|2||32||9||28.1 (11.7-44.6)||51.2 (35.5-66.7)|
|3||22||4||18.2 (0.7-35.7)||60.5 (44.4-75.0)|
|4||20||4||20.0 (0.8-39.2)||69.8 (53.9-82.8)|
|5||11||2||18.2 (0.9-45.4)||74.4 (58.8-86.5)|
|6||9||4||44.4 (3.9-85.00)||83.7 (69.3-93.2)|
|3. Women aged ≥ 40 years’ old|
|1||32||1||3.1 (0.3-9.5)||3.1 (0.3-9.5)|
|3||18||4||22.2 (0.9-43.5)||15.6 (5.3-32.8)|
|4||15||2||13.3 (-6.1-32.8)||21.9 (9.3-40.00)|
|6||22||3||13.6 (-1.9-29.2)||31.2 (16.1-50.0)|
CLBRs; Cumulative live birth rate and CI; Confidence interval.
Conservative CLBR categorized by the different types
of infertility are presented in
This 1-year cohort showed significant CLBRs based
on fresh IVF cycles, even in women older than 40 years
of age. These numbers can help physicians counsel patients about the chances of successful live births in terms
of age and type of infertility with repeated cycles. Because of the health system differences between the ME
and Western countries (financial constraints, lack of insurance coverage, ethical and religious reasons), we assessed the CLBRs in fresh IVF cycles only. We chose 6
cycles, because of the significant reduction in success in
CLBRs after 4 to 6 cycles noted in the literature (
It is believed that the success rate within a cycle decreases with an increase in the number of cycles (
When the cause of infertility was taken into account, the
differences noted in CLBRs were insignificant among patients with male factor, unexplained, tubal and combined
infertility. In addition, couples with a male factor had the
highest CLBRs as it is also outlined in the biggest US
study by Luke et al. (
Only patients with low ovarian reserve had their CLBR
plateauing after the second cycle with only 29.4%, which
is significantly different from the rest of our study cases
mentioned here. With an improvement in cumulative rates
of only 7% after 2 cycles and subsequent stabilizing after
6 consecutive cycles, it may be concluded that assisted
reproductive technologies in patients with low ovarian
reserves may be futile and especially after 3 cycles. Nevertheless, the number of events in this particular group
was too small to draw definite conclusions. These findings contradict previous reports that showed no substantial differences in the CLBRs among women with various
causes of infertility (
These results show that for patients willing to continue
their treatment, the CLBRs after 6 cycles would be 69.9%
(95% CI: 63.8-75.6) at the age of 35 years or younger,
which is close to the live birth rate of 75% in a woman
trying to conceive naturally. However, the CLBR at the
age of 40 years for our subjects is 31.2% (95% CI: 16.1-
50.0), which is slightly lower than the 44% of natural conception (
In a retrospective study on 4810 transfers, the possible
beneficial effects of transvaginal ultrasound-guided ET was
assessed and it was shown that the number of pregnancies
per ET significantly increased when performed under transvaginal ultrasound compared to trans-abdominal (38% vs.
30%, P<0.001). Transvaginal ultrasound may simplify difficult transfers via a better monitoring of the trans-cervical
area improving the overall technique (
The multiple pregnancy rate was 38.4 %, with 83.1%
twins, and 15.7% triplets, reflecting the continuing practice of transferring more than 2 embryos in the ME. The
mean number of embryos transferred in this study was 2.7
(± 0.9). These rates are high when compared to averages
reported in the American and European registries, with
only 25.1% risk of multiple births (
This is the first study in the ME to report CLBRs per cycle following fresh IVF treatment over a one-year period.
We classified our patients according to age and the type
of infertility when to our knowledge other studies have
failed to do so. In addition, we included all patients presenting for their first cycle and undergoing fresh cycles,
thus increasing the generalizability of our results. CLBRs
were calculated on the basis of conservative estimates reflecting that women who do not achieve a live birth at
their first attempt, will have their chances increased after
successive attempts. In our study, we used live birth rates
as a primary outcome while other studies reported pregnancy rates only (
Because of the retrospective aspect of the study, confounders were not reliably controlled, and significant biases affected the outcome. Our study has several other drawbacks. For instance, the cycles that were cancelled before oocyte retrieval were not recorded. This might have led to a minor overestimation of the CLBRs, as patients with severely poor prognosis did not account for the number of cycles and were excluded. However, only 36 patients were deemed ineligible, concluding that our findings are very close to the actual rates and the methodological bias had a relatively small influence on the final results. Patients who usually discontinue treatment are patients with very poor prognosis and are older than 40 years. In our cohort, only 16.3% of the cases were older than 40 years and most women had a high oocyte yield (10.4 ± 7.8). Because of these two important factors, we expect a very small difference between the rates that we calculated and the actual rates. On the other hand, some patients had undergone previous IVF cycles in other centers, adding some bias to the results since different laboratories and techniques may have been used. Furthermore, there was extensive heterogeneity in the different controlled ovarian stimulation protocols used limiting the generalizability of the results.
Our observed results postulate the chances of obtaining a live birth after one or multiple consecutive cycles,
basing our decisions on some realistic expectations of
CLBRs. In addition, it provides hope for older patients
whose CLBRs are not affected by their age up till the
age of 40. This reveals the advancements in reproductive
technologies with the growth of ICSI (
In a region that is highly influenced and controlled by religious beliefs, different barriers exist for using assisted reproductive technologies, preventing the performance of oocyte and sperm donation. Therefore, with these unanticipated findings, couples have no other options except to extend their treatment cycles beyond 4 cycles.
This study provides an approach for estimating the effectiveness of IVF over 6 successive cycles. We showed an increase in the CLBRs over multiple cycles reaching a 67.9% chance of conception after 6 cycles, with variations by age and type of diagnosis. These findings are reassuring for patients insisting to continue with their treatments given the meaningful cumulative chances of success. Thus, barriers to continuation of treatment should be reduced with improvement in couples’ counseling. Moreover, our results show that IVF treatments approach the natural fertility rates in patients younger than the age of 40.
However, the multiple pregnancy rate is still high in this part of the world due to the lack of regulations and policies. The practice is surrounded by an inequity in accessibility to this expensive form of health resource with fluctuation in the proportion of treatment cycles where few patients have the privilege of starting another IVF treatment in the case of a previous failed one.