Natural cycle frozen-thawed embryo transfer—can we improve cycle outcome?

Purpose

Several replacement protocols for frozen-thawed ET (FET) exist, with no advantage of one protocol over the others. In the present study, we aim to evaluate the outcome of natural cycle FET with modified luteal support.

Methods

All consecutive patients undergoing natural or artificial hormone replacement (AHR) day-2/3 FET cycles between May 2012 and June 2015 in our IVF unit were evaluated. While AHR FET cycles were consistent, those undergoing natural cycle FET received progesterone luteal support, and from June 2014, patients received two additional injections, one of recombinant hCG and the other of GnRH-agonist, on day of transfer and 4 days later, respectively (modified luteal support).

Results

Patients’ clinical characteristics and laboratory/embryological variables were comparable between those undergoing natural vs. AHR cycles, during the earlier as compared to the later period. Moreover, while implantation, clinical, and ongoing pregnancy rates were significantly higher during the later period in patients undergoing the natural cycle FET with the modified luteal support (31, 51, and 46 %, respectively), as compared to natural (17, 26, and 20 %, respectively), or AHR FET in the late study period (15, 22, and 17 %, respectively), the natural cycle FET without the additional two injections yielded the same results, as the AHR cycles.

Conclusions

We therefore suggest that in ovulatory patients undergoing FET, natural cycle FET with the modified luteal support should be the preparation protocol of choice. Further large prospective studies are needed to elucidate the aforementioned recommendation prior to its routine implementation.

     

Freeze-all cycle for all normal responders?

Purpose

The purpose of this study is to evaluate the freeze-all strategy in subgroups of normal responders, to assess whether this strategy is beneficial regardless of ovarian response, and to evaluate the possibility of implementing an individualized embryo transfer (iET) based on ovarian response.

Methods

This was an observational, cohort study performed in a private IVF center. A total of 938 IVF cycles were included in this study. The patients were submitted to controlled ovarian stimulation (COS) with a gonadotropin-releasing hormone (GnRH) antagonist protocol and a cleavage-stage day 3 embryo transfer. We performed a comparison of outcomes between the fresh embryo transfer (n?=?523) and the freeze-all cycles (n?=?415). The analysis was performed in two subgroups of patients based on the number of retrieved oocytes: Group 1 (4–9 oocytes) and Group 2 (10–15 oocytes).

Result(s)

In Group 1 (4–9 retrieved oocytes), the implantation rates (IR) were 17.9 and 20.5% (P?=?0.259) in the fresh and freeze-all group, respectively; the ongoing pregnancy rates (OPR) were 31 and 33% (P?=?0.577) in the fresh and freeze-all group, respectively. In Group 2 (10–15 oocytes), the IR were 22.1 and 30.1% (P?=?0.028) and the OPR were 34 and 47% (P?=?0.021) in the fresh and freeze-all groups, respectively.

Conclusion(s)

Although the freeze-all policy may be related to better in vitro fertilization (IVF) outcomes in normal responders, these potential advantages decrease with worsening ovarian response. Patients with poorer ovarian response do not benefit from the freeze-all strategy.

     

Does hysteroscopic polypectomy without cycle cancellation affect IVF?

Endometrial polyp (measuring <2 cm) was diagnosed by transvaginal ultrasonography performed on days 7 and 9 of the cycle in six patients who underwent IVF. These six patients were treated by hysteroscopic polypectomy preceding oocyte retrieval under general anaesthesia after informed consent was obtained. The cause of infertility was male factor in three patients, tubal factor in one, and two cases were unexplained. All patients had undergone ovulation induction and luteal support according to the long luteal protocol. As a result, in three cases pregnancy was achieved (one multiple and two singleton) and three cases were unsuccessful. One of the pregnant women gave birth at term, while the other two pregnancies are still ongoing. There is still no consensus regarding the management of patients diagnosed with endometrial polyp in IVF cycles. Cryopreservation, cycle cancellation and embryo transfer preceding polypectomy is the current management choice. The treatment modalities will be clarified only if embryo transfer preceding polypectomy in the same cycle is proven to be safe. This approach has been used in only six patients so far, and further studies with more patients are needed to confirm these findings.     

Natural cycle IVF: a question of semantics?

Recently there has been much discussion and presentation on IVF protocols using less stimulation or indeed none at all. Our experience with controlled natural cycle IVF over the last few years has convinced us that this is a powerful tool for many patients in the treatment of infertility. The protocol we employ has raised some questions as to whether it is natural cycle or stimulated cycle. We have reported a large series of cycles and seen no stimulatory effects of the medications used to control the cycle, thereby confirming our position that controlled natural cycle IVF is a valid option as an assisted reproduction treatment.     

The neuro control of the ovarain cycle – a hypothesis

Since more than 100?years, it is known that pituitary function depends upon the function of higher centers in the brain. It was already assumed at this time that pituitary extracts could influence the gonads and postulated that their use could have practical applications. In 1926, the ‘gonadal principle’ was discovered revealing the regulation of ovarian function by the pituitary. The two pituitary hormones were called ‘Prolan A’ and ‘Prolan B’ which are responsible for ovarian function especially secretion of the hormones: ‘lutein’ and ‘foliculin’. If the names of Prolan A and B are changed to follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and the names of foliculin and lutein to estrogen and progesterone, it becomes obvious that the pituitary–gonadal relationship, as we know it today, was first described in 1930. Then, the next step was the isolation, sequence and synthesis of gonadotropin releasing hormone (GnRH) responsible for the secretion of gonadotropins (Gn). It could be shown that GnRH pulse frequency has differential effects on Gn secretion: low-frequency pulses of GnRH stimulate preferentially FSH and high frequency LH secretion. The pulse frequency control depends from a subpopulation of kisspeptin neurons within the infundibular region of the hypothalamus with coexpression of neurokinin B and dynorphin A – KNDy neurons showing a negative feedback to estrogen. A second group of kisspeptide neurons in the rostral periventricular area of the third ventricle is devoid of neurokinin-B and dynorphin, mediates positive feedback from estrogen and so induces the midcycle LH-surge. Therefore, the variability in the frequency and amplitude of GnRH pulsatility is central to the differential regulation of LH and FSH and thus ovarian follicle development, the correct selection of a single dominant follicle for ovulation, the LH surge and the luteal phase.     

Second cycle: to hatch or not to hatch?

The objective of this study was to assess the impact of assisted hatching (AH) on pregnancy rate (PR), clinical pregnancy rate (CPR), and implantation rate (IR) after a single failed, fresh, nondonor IVF cycle. Accordingly, we report that patients with one prior implantation failure benefit from AH with improved PR, CPR, and IR in a subsequent cycle.     

Does urinary incontinence occurrence depend on the menstrual cycle phase?

BACKGROUND: The aim was to study an eventual co-variation of menstrual cycle progression and urinary incontinence (UI) occurrence in 20-54-year-old-women, who have regular menstrual cycles, which are not influenced by exogenous sex hormones. METHODS: An age-stratified random sample of of 3900 women, aged 20-59 years, answered a questionnaire on UI. The present analysis included 821 women, who reported regular menstrual cycles un-intervened by sex hormone intake. RESULTS: Five percent of the women reported episodes of UI the day before they answered the questionnaire. Urinary incontinence was unassociated with menstrual cycle characteristics, such as time position from day one in the menstrual cycle, presence and amount of bleeding and the number of sanitary towels or tampons used. There was however, a borderline significant association (P = 0.08) with day 11-15 before the expected next menstrual bleeding. CONCLUSIONS: The present data allow for limited co-variation, if any, to exist in UI occurrence with the natural menstrual cycle phases, including the menstruation itself. A hypothesis of a moderate UI increase associated with ovulation however, merits attention.     

Influence of resveratrol supplementation on IVF–embryo transfer cycle outcomes

Research questionDoes resveratrol, a polyphenolic compound, affect IVF–embryo transfer outcomes?DesignThis single-centre, cross-sectional retrospective study was designed to compare the outcomes of embryo transfer cycles in women receiving resveratrol supplementation (200 mg/day) continuously (RES group) with a control group (non-RES group). Of 8686 embryo transfer cycles, 1409 cycles with poor prognostic factors were excluded, including cycles in women aged ≥43 years and those with poor-quality embryos. The RES group (204 cycles, 102 women) was compared with the non-RES group (7073 cycles, 2958 women).ResultsAfter matching patients by age at the time of oocyte retrieval, grade and developmental stage of embryos, number of embryos transferred, and fresh or vitrified-warmed embryo transfer, multivariate logistic regression analysis showed that resveratrol supplementation is strongly associated with a decrease in clinical pregnancy rate [odds ratio (OR) 0.539, 95% confidence interval (CI) 0.341–0.853] and an increased risk of miscarriage (OR 2.602, 95% CI 1.070–6.325).ConclusionsResveratrol supplementation during embryo transfer cycles appears to be detrimental for pregnancy outcomes. An analysis of the supplementation protocol and randomized controlled studies are needed.     

Is there a role for preparatory cycle in ovum donation recipients?

PURPOSE OF REVIEW: In ovum donation cycles, the role of preparatory cycles to ensure proper endometrial development in the recipient remains controversial. As evidenced in the literature, endometrial receptivity is critical in conception. Therefore, endometrial preparation with exogenous hormones in addition to synchronization of the recipient and donor are essential in achieving a successful outcome. RECENT FINDINGS: There are very limited data specifically examining the benefit of recipients undergoing preparatory cycles prior to their actual egg donation cycle. One study concluded that trial hormone replacement treatment cycles with endometrial biopsies may be useful in older reproductive-age women but not in younger women. Another study showed no difference in pregnancy rates between those who did and did not undergo preparatory cycles. SUMMARY: Since one of the integral elements of preparatory cycles is determining endometrial dating, with relatively conflicting data, these mock cycles may not be as beneficial as expected. Therefore, for those who routinely use preparatory cycles, the potential risks, benefits, and costs of these cycles, increased hormonal exposure, the relatively invasive nature of the procedure, and time prior to performing them must be considered.     

Improvement of accuracy of clinical reports—the case of IVF cycle rank

Purpose

Accurate clinical reports of In Vitro Fertilization Cycle Rank (IVF-CR) are important because of their predictive value of treatment success—clinical pregnancy. Our district currently provides more than a hundred IVF pick-up cycles per month. The study objective was to evaluate and improve the accuracy of IVF units’ reports of IVF-CR.

Methods

Reports of IVF-CR from local IVF units were correlated with administrative data. Couples who were having IVF treatments during the 3-month study period were included in the study. Data were collected before and after an intervention program.

Results

During the study period accurate IVF-CR reporting rate improved from 27% (29 out of 108) to 83% (91 out of 110).

Conclusions

Accuracy of clinical reports of IVF-CR from local units significantly improved after the intervention. It is recommended that national regulatory bodies should issue compulsory guidelines for the recording and reporting of IVF-CR.     

Cryopreserved embryo transfer in an artificial cycle: is GnRH agonist down-regulation necessary?

The use of GnRH agonist downregulation in artificial endometrium priming cycles for cryopreserved embryo transfer was retrospectively investigated to establish whether higher live birth rates resulted. Six hundred and ninety-nine patients underwent 1129 artificial endometrium priming cycles for the transfer of cryopreserved embryos between 1 July 2009 and 1 June 2012. Hormonal supplementation with (group A, n = 280 cycles) or without (group B, n = 849 cycles) GnRH agonist co-treatment was given. Live birth rates were comparable between the two groups per started cycle (14.9% [41/275] in group A versus 15.1% [127/839] in group B) or per embryo transfer (17.5% [41/234] in group A versus 17.6% [127/723] in group B). After logistic regression analysis, the only variables that were significantly associated with live birth rates were day of embryo transfer (OR 0.69; 95% CI 0.48 to 0.98) for day 3 versus day 5 embryos, the number of embryos transferred (OR 2.13; 95% CI 1.58 to 2.86) for two embryos versus one embryo transferred and the endometrial thickness on the day of embryo transfer (OR 1.15; 95% CI 1.05 to 1.25). Live birth rates after cryopreserved embryo transfer in artificial cycles did not increase when a GnRH agonist was administered.     

Initiation of ovarian stimulation independent of the menstrual cycle: a case–control study

Purpose

In the GnRH-antagonist protocol, ovarian stimulation with gonadotropins typically commences on cycle day 2 or 3. Initiation of ovarian stimulation with a spontaneously occurring menstruation, however, poses significant organizational challenges for treatment centres and patients alike. It has previously been demonstrated in the context of fertility preservation that initiation of stimulation in the luteal phase is feasible in terms of retrieval of mature oocytes for cryopreservation. Herein, we report the extension of this concept to a routine IVF setting with the aim of establishing an ovarian stimulation protocol, which can be utilized independent of menstruation. Because of asynchrony of endometrium and embryo in such a setting, all fertilized oocytes have to be cryopreserved for a later transfer.

Methods

This was a prospective, case–control study (trial registration: NCT00795041) on the feasibility of starting ovarian stimulation in a GnRH-antagonist protocol in the luteal phase. Inclusion criteria were: IVF or ICSI; 18–36 years; ≤3 previous IVF/ICSI attempts; BMI 20–30 kg/m²; regular cycle (28–35 days); luteal phase progesterone >7 ng/ml at initiation of stimulation. Exclusion criteria were: PCOS, endometriosis ≥AFS III°, unilateral ovary, expected poor response. Stimulation was performed with highly purified uFSH (Bravelle^®) 300 IU/day and 0.25 mg/day GnRH-antagonist starting on cycle day 19–21 of a spontaneous menstrual cycle and commencing until hCG administration when three follicles ≥17 mm were present. All 2PN stage oocytes were vitrified for later transfers in programmed cycles. Feasibility was defined as the achievement of ongoing pregnancies progressing beyond the 12th gestational week in at least 2/10 study subjects (primary outcome). Secondary outcomes were gonadotropin consumption per oocyte obtained, stimulation duration, and fertilization rates. Study subjects were matched in a 1:3 ratio with concomitantly treated control cases of similar age, BMI, and duration of infertility who were treated in a conventional GnRH-antagonist protocol with 150–225 rFSH or HP-HMG/day.

Results

The study group consisted of ten subjects, mean age 31.4 years, BMI 25.4 kg/m², of which one had fertilization failure. Mean stimulation duration was 11.7 (SD 1.6) vs. 9.1 (SD 1.3) days, mean cumulative FSH dose was 3,495.0 (SD 447.5) vs. 2,040.5 (SD 576.2) IU, and mean number of oocytes was 8.8 (SD 5.0) vs. 10.0 (SD 5.4) in study vs. control group, respectively. Per follicle ≥10 mm, the cumulative FSH dose was 274.5 (SD 130.8) IU vs. 245.2 (SD 232.3) IU in study and control groups, respectively. Cumulative ongoing pregnancy rates were 1/10 (10 %) and 6/30 (20.0 %) in study and control group, respectively (difference: 10 %, 95 % confidence interval of the difference: ?29.2–22.2 %, p = 0.47). Fertilization rate was similar between groups, with 63.5 % (SD 32.9) in the study and 61.3 % (SD 26.7) in the control group, respectively. Serum estradiol levels were significantly lower on the day of triggering final oocyte maturation with 1,005.3 (SD 336.2) vs. 1,977.4 pg/ml (SD 1,106.5) in study and control group, respectively. Similarly, peak estradiol biosynthesis per growing follicle ≥10 mm was lower in the study group (134 pg/ml, SD 158.4 vs. 186.7 pg/ml, SD 84.7).

Conclusions

Per retrieved oocyte, a nearly threefold higher dose of FSH had to be administered when ovarian stimulation had been initiated in the luteal phase. Furthermore, the present study casts doubt on the efficacy of initiating ovarian stimulation in the luteal phase in terms of pregnancy achievement. Thus, this concept is currently not feasible for routine use, and it should also be explored further before using it at larger scale in the context of emergency stimulation for fertility preservation.     

Labor ward workload waxes and wanes with the lunar cycle,myth or reality?

Objective: To test the validity of the statement “We are busy because it is getting close to the full moon” often heard on labor ward, by analysis of birth statistics in relation to lunar cycles.Method: Data for births from spontaneous onset labors for 12 lunar cycles from January 1 to December 31, 1994 was analyzed. Births resulting from induced labors were excluded. Birthrate for each day of the lunar cycle from new moon to full moon (ascending lunar phase) and from full moon to new moon (descending lunar phase) were analyzed using Pearson correlation coefficient. Birthrate at full moon was compared to that at new moon and that at mid ascending lunar phase was compared with that at mid descending lunar phase using t test.Results: There were 3706 spontaneous births during the study period. The average daily birthrate was 10.58 with standard deviation (SD) of 1.27. There was no statistically significant difference in the daily birthrate between the ascending and the descending lunar phases, r = −0.21. Statistical analysis showed no significant difference in the number of births at full moon as compared to that at new moon, P = .44. No difference was found on comparison of number of births during the mid ascending phase to that at the mid descending lunar phase, P = .84.Conclusion: Scientific analysis of data does not support the belief that the number of births increases as the full moon approaches, therefore it is a myth not reality.     

What is the preferred method for timing natural cycle frozen–thawed embryo transfer?

Spontaneous ovulation during a natural menstrual cycle represents a simple and efficient method for synchronization between frozen embryos and the endometrium. The objective was to compare serial monitoring until documentation of ovulation, with human chorionic gonadotrophin (HCG) triggering, for timing frozen embryo transfer (FET) in natural cycles (NC). In a retrospective study, 112 women with regular menstrual cycles undergoing 132 NC–FET cycles were divided into two groups: group A (n = 61) patients had FET in an NC after ovulation triggering with HCG; group B (n = 71) patients had FET in an NC after spontaneous ovulation was detected. The main outcome measure was the number of monitoring visits at the clinic. Patients in both groups were similar in terms of demographic characteristics and reproductive history. Clinical and laboratory characteristics of fresh and frozen cycles were also found comparable for both groups, as were pregnancy and delivery rates. The number of monitoring visits in group A (3.46 ± 1.8) was significantly lower than in group B (4.35 ± 1.4) (P < 0.0001). In patients undergoing NC–FET, triggering ovulation by HCG can significantly reduce the number of visits necessary for cycle monitoring without an adverse effect on cycle outcome. Ovulation triggering can increase both patient convenience and cycle cost-effectiveness.     

The problem of IVF cost in developing countries: has natural cycle IVF a place?

Infertility represents a national health problem in some African countries. Limited financial health resources in developing countries are a major obstacle facing infertility management. IVF is the definitive line of treatment for many couples. Stimulation cycles are associated with risks of ovarian hyperstimulation syndrome and multiple pregnancy. This study evaluates the client acceptability of stimulated versus natural cycle IVF among couples attending one infertility clinic, with respect to cost and pregnancy outcome. Of the patients who were indicated for IVF, 15% (16/107) cancelled, due mostly (12/16, 75%) to financial reasons. The majority of patients who completed their IVF treatment (82/91, 90.1%) felt the price of the medical service offered was high, and 68.1% (62/91) accepted the idea of having cheaper drugs with fewer side effects but with possibly lower chances of pregnancy. Natural cycle IVF has emerged as a potential option that might be suitable for patients worldwide, especially in developing countries.     

Human embryonic stem cell methyl cycle enzyme expression: modelling epigenetic programming in assisted reproduction?

To investigate a possible mechanism for inducing epigenetic defects in the preimplantation embryo, a human embryonic stem cell model was developed, and gene expression of the key methyl cycle enzymes, MAT2A, MAT2B, GNMT, SAHH, CBS, CGL, MTR, MTRR, BHMT, BHMT2, mSHMT, cSHMT and MTHFR was demonstrated, while MAT1 was barely detectable. Several potential acceptors of cycle-generated methyl groups, the DNA methyltransferases (DNMT1, DNMT3A, DNMT3B and DNMT3L), glycine methyltransferase and the polyamine biosynthetic enzymes, SAM decarboxylase and ornithine decarboxylase, were also expressed. Expression of folate receptor alpha suggests a propensity for folate metabolism. Methotrexate-induced depletion of folate resulted in elevated intracellular homocysteine concentration after 7 days in culture and a concomitant increase in cysteine and glutathione, indicating clearance of homocysteine through the transulphuration pathway. These studies indicate that altered methyl group metabolism provides a potential mechanism for inducing epigenetic changes in the preimplantation embryo.     

Does premature luteinization or early surge of LH impair cycle outcome? Report of two successful outcomes

Purpose

To report two successful antagonist IVF cycles; one ending up with pregnancy despite premature luteinization (case 1, aged 35 years), and the other with the retrieval of high quality oocytes despite premature ovulation (case 2, aged 39 years).

Methods

Serum LH was 36 and 47 IU/L on cycle day?7 before antagonist administration, which was then brought to 6.94 and 3.92 IU/L by antagonist administration, and kept below these levels throughout the remaining stimulation in case 1 and 2 respectively. Serum progesterone was 1.42 and 5.5 ng/mL on the day of hCG respectively. Ten metaphase II (MII) oocytes were harvested wherein 3 grade A embryos were transferred in case 1, and seven good quality MII oocytes were retrieved wherein six embryos were cryopreserved in case 2.

Conclusions

More precise cut thresholds for both LH and progesterone are necessary for accurate prediction of the cycle outcomes.