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 artificial cycle method improves the pregnancy outcome in frozen–thawed embryo transfer: a retrospective cohort study

Abstract

The aim of this retrospective cohort study was to investigate which preparation method is optimal for frozen–thawed embryo transfer (FET) treatment. Analyses were performed on 3160 FET cycles, including 654 cycles with a natural cycle (NC) protocol and 2506 cycles with an artificial cycle (AC) protocol. The primary outcome measures were the clinical pregnancy rate (CPR) and the live birth rate (LBR) per transfer. The Student’s t-test, chi-square test and multiple logistic regression were used for statistical analysis. The CPR per transfer was 49.4% in the NC group and 58.6% in the AC group (OR?=?1.270, 95% CI: 1.037–1.554). The LBR per transfer was 42.2% and 50.8% in the NC and AC groups, respectively (OR?=?1.269, 95% CI: 1.037–1.552). Dividing the patients according to the type of transferred embryos, the CPR (67.3% versus 57.0%, p?<?0.01) and LBR (58.8% versus 49.7%, p?<?0.01) were higher after the AC protocol than after NC protocol in patients with blastocyst transfer. The NC and AC protocols yielded comparable CPR and LBR in the patients with cleavage embryo transfer. Our data indicate better pregnancy outcomes after the AC protocol than after the NC protocol. The AC protocol should be recommended in patients who were counseled before receiving FET treatment. Further studies are needed to confirm this finding.     

Letrozole versus clomiphene citrate: which is better for ovulation induction?

Letrozole is at least as effective as clomiphene for inducing ovulation and achieving pregnancy in patients with polycystic ovarian syndrome. Potential advantages of letrozole include reduced multiple pregnancies, absence of antiestrogenic adverse effects, and the subsequent need for less intensive monitoring.     

Administration of a GnRH agonist during the luteal phase frozen–thawed embryo transfer cycles: a meta-analysis

Abstract

At present, the precise role of GnRH agonists during the luteal phase remains uncertain. In the present study, a meta-analysis was used to evaluate the effect of administering a GnRH agonist to during the luteal phase in patients undergoing FET cycles. A literature review was carried out by searching the current content of MEDLINE, Embase, the Cochrane Controlled Trials Register and Ovid. We particularly focused upon implantation rate, CPR per transfer, and ongoing pregnancy rate. All of the trials analyzed involved a GnRH agonist administered during the luteal phase. Six trials involving 1137 women were included in our meta-analysis. All of the cycles analyzed exhibited significantly higher implantation rates, clinical pregnancy rates, and ongoing pregnancy rates in the group of patients administered with a GnRH agonist during the luteal phase compared with the control group that did not receive a GnRH agonist during the luteal phase. Our data, therefore, demonstrate that the administration of a GnRH agonist during the luteal phase can significantly increase clinical pregnancy and ongoing pregnancy rates in FET cycles. The implantation rates, clinical pregnancy rates, and ongoing pregnancy rates can significantly increase in the group of patients administered with a GnRH agonist in natural cycle FET.     

Characterization of early pregnancy placental progesterone production by use of dydrogesterone in programmed frozen–thawed embryo transfer cycles

Research questionWhen and how does the gradual transition of the endocrine control of early pregnancy from the corpus luteum to the placenta, termed luteoplacental shift, take place?DesignProspective analysis of serum progesterone levels in pregnancies (n = 88) resulting from programmed frozen–thawed embryo transfer cycles in which ovulation was suppressed and no corpus luteum was present. Dydrogesterone, which does not cross-react with progesterone in immunoassay or spectrometric assay, was used for luteal phase and early pregnancy support. Progesterone, oestradiol and hCG were measured at regular intervals from before pregnancy achievement until +65 to 71 days after embryo transfer by Roche Elecsys electrochemiluminescence immunoassay (Elecsys ECLIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS).ResultsSerum progesterone remained at baseline levels on first blood analysis +9 to 15 days after embryo transfer and increased only marginally independently from the type of pregnancy up to +16 to 22 days after embryo transfer. From +23 to 29 days after embryo transfer, progesterone increased non-linearly above 1.0 ng/ml and increased further throughout the first trimester with elevated levels in multiples. Oestradiol levels increased in parallel with progesterone; hCG plateaued around +37 to 43 days. Progesterone levels were significant predictors for pregnancy viability from +23 to 29 days after embryo transfer onwards with best accuracy +37 to 43 days after embryo transfer (receiver operator characteristic analysis area under the curve 0.98; 95% CI 0.94 to 1; P = 0.0009).ConclusionsThe onset of substantial progesterone production is the 7th gestational week. Progesterone increase is non-linear, depends on chorionicity and zygosity, and may have predictive potential on the outcome of pregnancies originating from frozen embryo transfer cycles.     

Vaginal progesterone supplementation has no effect on ongoing pregnancy rate in hCG-induced natural frozen–thawed embryo transfer cycles

Objective

The purpose of this study is to assess the effect of luteal phase supplementation (LPS) on pregnancy rates in human chorionic gonadotropin (hCG)-induced natural frozen–thawed (FET) cycles.

Study design

All performed hCG-induced natural FET cycles from January 2006 until August 2007 were retrospectively identified. The study group consisted of 452 cycles: 243 supplemented with progesterone administration (600 mg natural micronized progesterone in three separate doses) and 209 without progesterone. Analysis was limited to cycles where embryos were cryopreserved on day 3. Final oocyte maturation was achieved by hCG when endometrial thickness of ≥7 mm and a follicle of 17 mm were present on ultrasound.

Results

No statistically significant differences were observed in ongoing pregnancy rate between the two groups (22% versus 21%, p = 0.8; difference +1%; 95% confidence interval (CI): −6.5 to +8.7). The non-significant effect of the presence or not of luteal support on pregnancy rate was confirmed by logistic regression (odds ratio (OR): 0.9, 95% CI: 0.54–1.47, P = 0.64). A previous pregnancy following fresh embryo transfer (OR: 6.04, 95% CI: 3.63–10.02, P = 0.001) and increased endometrial thickness (OR: 1.25, 95% CI: 1.11–1.41, P = 0.001) significantly affected the achievement of ongoing pregnancy, whereas the association between embryo score and achievement of pregnancy was marginally significant (OR:0.28, 95% CI: 0.08–0.97, P = 0.05).

Conclusion

There is no convincing evidence to support the use of LPS in hCG-induced natural FET cycles, since there is no luteal phase defect. Further prospective randomized studies are necessary to confirm these findings.     

Outcomes of natural cycles versus programmed cycles for 1677 frozen–thawed embryo transfers

The study compares outcomes for patients with frozen embryos who had frozen–thawed embryo transfer (FET) timed to their natural ovulation cycle versus cycles in which endometrial timing was programmed with oestrogen and progesterone. A total of 1205 patients undergoing 1677 FET cycles between 1 January 2000 and 31 December 2006 were analysed. Comparisons were made for patients undergoing modified natural versus programmed FET cycles, as well as between patients using their own eggs for frozen embryos versus those using donor-egg-derived embryos. Clinical pregnancy (gestational sac on 7 week ultrasound) rates (CPR), as well as miscarriage rates, were significantly higher in programmed FET cycles in patients using their own eggs (106/262, 40.5% per embryo transfer, P = 0.015) However, there was not a difference in delivered pregnancies between cycle types in own egg patients (natural cycle delivery rate 245/862, 28.4%; programmed cycle delivery rate 77/262, 29.4%). Furthermore, CPR were not different in natural (38/129, 29.5%) versus programmed cycles (144/424, 34.0%) for ovum donor recipients, nor were delivered pregnancy rates different in natural (33/129, 25.6%) versus programmed cycles (114/424, 26.9%) for ovum donor recipients. In conclusion, there is no significant difference in delivery rates for FET in natural (278/991, 28.1%) versus programmed (191/686, 27.8%) cycles using both own embryos and donor-egg-derived embryos.     

Lower risk of adverse perinatal outcomes in natural versus artificial frozen–thawed embryo transfer cycles: a systematic review and meta-analysis

This systematic review of literature and meta-analysis of observational studies reports on perinatal outcomes after frozen embryo transfer (FET). The aim was to determine whether natural cycle frozen embryo transfer (NC-FET) in singleton pregnancies conceived after IVF decreased the risk of adverse perinatal outcomes compared with artificial cycle frozen embryo transfer (AC-FET). Thirteen cohort studies, including 93,201 cycles, met the inclusion criteria. NC-FET was associated with a lower risk of hypertensive disorders in pregnancy (HDP) (RR 0.61, 95% CI 0.50 to 0.73), preeclampsia (RR 0.47, 95% CI 0.42 to 0.53), large for gestational age (LGA) (RR 0.93, 95% CI 0.90 to 0.96) and macrosomia (RR 0.82, 95% CI 0.69 to 0.97) compared with AC-FET. No significant difference was found in the risk of gestational hypertension and small for gestational age. Secondary outcomes assessed were the risk of preterm birth (RR 0.83, 95% CI 0.79 to 0.88); post-term birth (RR 0.48, 95% CI 0.29 to 0.80); low birth weight (RR 0.84, 95% CI 0.80 to 0.89); caesarean section (RR 0.84, 95% CI 0.77 to 0.91); postpartum haemorrhage (RR 0.39, 95% CI 0.35 to 0.45); placental abruption (RR 0.61, 95% CI 0.38 to 0.98); and placenta accreta (RR 0.18, 95% CI 0.10 to 0.33). All were significantly lower with NC-FET compared with AC-FET. In assessing safety, NC-FET significantly decreased the risk of HDP, preeclampsia, LGA, macrosomia, preterm birth, post-term birth, low birth weight, caesarean section, postpartum haemorrhage, placental abruption and placenta accreta. Further randomized controlled trials addressing the effect of NC-FET and AC-FET on maternal and perinatal outcomes are warranted. Clinicians should carefully monitor pregnancies achieved by FET in artificial cycles prenatally, during labour and postnatally.     

Predictive value of serum kisspeptin concentration at 14 and 21 days after frozen–thawed embryo transfer

Research questionCan serum kisspeptin levels 14 and 21 days after frozen–thawed embryo transfer predict the early pregnancy outcome of patients?DesignProspective study, with 133 patients undergoing frozen–thawed embryo transfer. Patients were divided into non-pregnant group and pregnant group (including biochemical pregnancy, singleton pregnancy, miscarriage and twin groups).ResultsSerum kisspeptin levels on day 21 were significantly higher than day 14 in singleton pregnancy, miscarriage and twin groups (all P < 0.0001), but not in the biochemical pregnancy group. Similarly, serum human chorionic gonadotrophin (HCG) levels were higher on day 21 compared with day 14 except for the biochemical pregnancy group. Compared with the twin group (296.9 pg/ml), the other four groups showed significantly higher serum kisspeptin levels on day 14 (non-pregnant 548.9, biochemical pregnancy 440.4, miscarriage 434.9, singleton pregnancy group 420.9 pg/ml, P < 0.01, P = 0.016, P = 0.034, P = 0.036, respectively). The miscarriage (762.2 pg/ml), singleton pregnancy (730.8 pg/ml) and twin groups (826.3 pg/ml) had significantly higher kisspeptin levels than the biochemical pregnancy group (397.3 pg/ml) on day 21 (P < 0.001, P < 0.01, P < 0.001, respectively). Serum kisspeptin levels on day 14 were negatively correlated with embryo implantation rate (P = 0.035, R² = –0.880). Serum kisspeptin levels on day 21 have a poor predictive value of miscarriage compared with serum HCG levels (area under the curve = 0.53 and 0.78, respectively).ConclusionsSerum kisspeptin levels on day 14 are negatively correlated with embryo implantation rate. Serum kisspeptin levels on day 21 have a poor predictive value of miscarriage.     

Progesterone for preparation of the endometrium for frozen–thawed blastocyst transfer in vitro fertilization cycles: a prospective study on patients’ opinions on a new subcutaneous formulation

We aimed to evaluate patients’ perspectives on a progesterone subcutaneous formulation for endometrial preparation for frozen-thawed blastocyst transfer. In this prospective study, women with at least one experience with vaginal progesterone, undergone endometrial preparation with oral estradiol valerate and daily subcutaneous progesterone administered from the fifth day before the transfer until the day of the beta-hCG test. Patients completed three questionnaires, at enrollment (Q1), for gathering information on the experience with vaginal treatment and expectations about the subcutaneous route and then at the time of the transfer (Q2) and eight days later (Q3). Main outcome measures were patients' opinions on comfort, ease of use, convenience, overall satisfaction, level of anxiety and pain associated with the administration of subcutaneous progesterone in comparison with their previous experience. Sixty-nine women completed the questionnaires. All vaginal versus subcutaneous comparisons were significantly in favor of the subcutaneous route. When comparing patients’ expectations at Q1 with patients’ opinions at Q2 and Q3, all evaluations, except for one, demonstrated that the patient’s positive expectation was confirmed after 5 and 13 days of treatment. In conclusion, in women with previous experience with vaginal progesterone, the subcutaneous route was associated with significantly increased acceptance.     

Successful birth following transfer of frozen–thawed embryos produced from in-vitro matured oocytes

It is well established that ovarian hyperstimulation syndrome (OHSS) is more frequent in patients with polycystic ovarian syndrome. In-vitro maturation (IVM) of immature oocytes presents a potential alternative for the fertility treatment and prevention of OHSS for these patients. This report describes the case of a 26-year old woman with a successful pregnancy and delivery following the transfer of frozen–thawed embryos derived from in-vitro matured oocytes. She had three failed cycles of ovarian stimulation (using low-dose step-up gonadotrophin protocol) with or without intrauterine insemination cycles, an ovulation-induction cycle with luteal long protocol, two fresh IVM cycle and one frozen–thawed IVM cycle. During the IVF cycle, she developed moderate OHSS and required hospitalization for 3 weeks. Following four unsuccessful IVF or IVM cycles, 15 months after the last cryopreservation, six fertilized oocytes were thawed for a scheduled embryo transfer. Following thawing, four fertilized oocytes survived and cleaved. Four frozen–thawed embryos were transferred. Six weeks after embryo transfer an ongoing intrauterine single pregnancy with fetal heartbeat was confirmed by transvaginal ultrasound. An uneventful pregnancy and delivery via Caesarean section at 39 weeks resulted in the birth of a normal healthy infant.     

Consecutive cycles in in vitro fertilization–embryo transfer

Background.?The decline of female fertility with advancing age is well documented. The aim of this study was to compare the ovarian performance after repeated ovarian stimulation cycles in women of different ages.

Methods.?Four hundred patients who started at least three in vitro fertilization (IVF) cycles during the 5-year period between 1998 and 2002 were identified. The patients were divided into four groups: the 25–30 age group (n?=?90), the 31–35 age group (n?=?150), the 36–40 age group (n?=?110) and the 41–45 age group (n?=?50).

Results.?Comparing subsequent cycles versus the first treatment cycle we found a statistically significantly increased number of ampules of recombinant follicle stimulating hormone (rFSH) needed to reach follicles maturation (p?<?0.001). The number of ampules of gonadotropin required was significantly higher (p?<?0.001) in the groups of advanced age compared with the groups of young women. For women in the 36–40 group and in the 41–45 group we found the number of follicles, the number of oocytes and the proportion of grade A embryos, in every cycle, were significantly lower than in the groups of young women. We compared the characteristics of ovarian stimulation and response of a single age group in different consecutive cycles. We found significant differences (p?<?0.05) only in the number of ampules required.

Conclusions.?Maternal age adversely affected ovarian performance. During repeated IVF cycles we also noted an age-independent decline of ovarian response.     

Two consecutive successful live birth in woman with 17α hydroxylase deficiency by frozen–thaw embryo transfer under hormone replacement endometrium preparation

17α-Hydroxylase deficiency is rare autosomal recessive disorder that manifested by hypertension, hypokalemia, delayed sexual development, primary amenorrhea and infertility. The information regarding infertility care and conception in women with this disorder are extremely limited. We report a 24-year-old Japanese woman with primary amenorrhea who was diagnosed as partial 17α-hydroxylase deficiency caused by homozygous 3?bp deletion in exon 1 of 17α-hydroxylase gene. In vitro fertilization with controlled ovarian stimulation was carried out and all viable embryo were frozen. During ovarian stimulation, serum progesterone levels were markedly elevated, and endometrial growth was impaired. Utilizing frozen-thaw embryo transfer under hormonal replacement (glucocorticoid, estradiol and progesterone), she had successfully given two consecutive live birth. Women with 17α-hydroxylase deficiency with residual ovarian reserve can afford reproductive success by appropriate diagnosis and treatment by assisted reproductive technology.     

Day 6 blastocyst is associated with increased birth weight in full-term singleton newborns after frozen–thawed transfer

Purpose

The purpose of the study is to compare the newborns weight in singleton term birth following transfer of thawed blastocysts–frozen on either day 5 or day 6 after in vitro fertilization.

Method

The retrospective study included 1444 frozen–thawed blastocyst transfer (FBT) cycles resulting in live singleton births between Jan 2013 and Dec 2016. The main outcomes measured were absolute birth weight, z-score adjusted for gestational age and gender, and incidence of large-for-gestational-age (LGA) newborns. Generalized linear model (GLM) and logistic regression were used in multivariate analyses.

Result(s)

Both the absolute birth weight (3416.49?±?404.74 vs 3349.22?±?416.17) and the z-score (0.6?±?0.93 vs 0.41?±?0.93) were significantly higher on day 6 FBT in comparison with day 5 FBT. The incidence of LGA newborns was also increased on day 6 FBT (22.8 vs 14.7%, P?=?0.006). Adjusted for maternal age, BMI, PCOS diagnosis, present of vanishing twin, and embryo quality, the odds ratio (95% confidence interval) for LGA on day 6 FBT comparing with day 5 FBT was 1.76 (1.18–2.64).

Conclusion(s)

Day 6 FBT is associated with increased birth weight and contributes to the incidence of LGA newborns in FBT.

     

HCG administration after endogenous LH rise negatively influences pregnancy rate in modified natural cycle for frozen–thawed euploid blastocyst transfer: a pilot study

Purpose

The aim of the present study was to evaluate whether in a modified natural cycle (modified-NC) for a frozen-thawed single euploid blastocyst transfer, a critical LH value, above which human chorionic gonadotropin (hCG) administration should be avoided, may be defined.

Methods

One hundred and sixty-seven patients underwent modified natural cycle in order to transfer a single frozen-thawed euploid blastocyst. All embryos were obtained by intracytoplasmic sperm injection and were biopsied at the blastocyst stage and analyzed by means of array comparative genomic hybridization (aCGH). Ovulation was induced using 10.000 IU hCG when the mean follicle diameter was at least of 17 mm, independently from LH values. The primary end points were the hCG-positive test and clinical pregnancy. The interim analysis showed that LH value ≥?13 mIU/ml on the day of hCG injection may negatively influence the clinical results, suggesting that in this condition, it should be advisable waiting for spontaneous ovulation.

Results

Among patients who received hCG for ovulation induction, the hCG-positive test and clinical pregnancy rates in modified-NC were significantly lower in cycles with LH?≥?13 mIU/ml in respect to those with LH?<?13 mIU/ml (45.4 vs 73.3 and 36.4 vs 65.9%, in LH?≥?13 and LH?<?13 groups, respectively). In patients with LH value ≥?13 mIU/ml, hCG administration led to significantly lower rates of hCG-positive test (45.4 vs 74.5% in hCG administration and spontaneous ovulation groups, respectively) and clinical pregnancy (36.4 vs 64.7% in hCG administration and spontaneous ovulation groups, respectively). The baseline patient characteristics were comparable in all groups.

Conclusions

The findings of this study highlight that LH elevation ≥?13 mIU/ml prior to hCG administration may negatively affect clinical pregnancy rates in modified-NC for single euploid blastocyst transfer. The LH determination should be routinely performed during follicular monitoring. In the presence of LH level ≥?13 mIU/ml, hCG administration should be avoided, and the embryo transfer should be planned only after spontaneous follicular rupture.