Conception after early IVF pregnancy loss: should we wait?

RESEARCH QUESTION: Is the interval length between an early pregnancy loss and the following treatment cycle a predictor for achieving clinical pregnancy among IVF patients? DESIGN: This retrospective cohort study of 257 women who reinitiated treatment after first-trimester IVF pregnancy loss was conducted at a tertiary, university-affiliated medical centre between 1 January 2014 to 1 January 2018. Women aged 18-40 years, with normal uterine cavity, who experienced first-trimester pregnancy loss at less than 14 weeks after IVF, were included. Miscarriages were classified as spontaneous, biochemical, medical or surgical. RESULTS: Among 257 women, interval to subsequent IVF treatment was not associated with achieving pregnancy. Patients after biochemical pregnancy (72.7 ± 56.4, median 60 days) or spontaneous miscarriage (97.7 ± 93.1, median 66 days) had shorter intervals to next cycle, compared with medical (111.9 ± 103.2, median 65 days) or surgical (123.4 ± 111.1, median 84 days) (Kaplan-Meier, P = 0.03) miscarriages. Logistic regression analysis showed that the chance of subsequent pregnancy was affected by the number of embryos transferred (P = 0.009) and the type of miscarriage. Medical (P = 0.005) and surgical (P = 0.017) miscarriages were related to lower likelihood of pregnancy compared with biochemical pregnancy (reference group). When pregnancy was achieved in the first post-miscarriage cycle, the chance of live birth increased with shorter intervals (median 57.5 days), whereas second miscarriage was related to longer intervals (median 82.5 days) between miscarriage and subsequent IVF cycle (P = 0.03). CONCLUSION: On the basis of this cohort, IVF should not be postponed after pregnancy loss, as shorter intervals were associated with greater likelihood of live birth.

Thawing day 3 embryos and culturing to day 5 may be a better method for frozen embryo transfer.

PURPOSE: Does thawing cleavage embryos and culturing them for transfer as blastocysts improve pregnancy and perinatal outcomes compared to transferring thawed blastocysts? METHODS: Retrospective, observational cohort study performed at two assisted reproductive technology centers, 2014 to 2020. A total of 450 patients with 463 thawed embryo transfer cycles were divided into 2 groups according to the embryonic developmental stage at cryopreservation and transfer: 231 thawed blastocysts (day 5 group) and 232 thawed cleavage embryos that were cultured for 2 days and transferred as blastocysts (day 3-5 group). The two groups were compared for demographics, routine parameters of IVF treatment, pregnancy rates, and perinatal outcomes. RESULTS: Multivariable logistic regression analysis for ongoing pregnancy and delivery demonstrated that the day 3-5 group had a greater likelihood of achieving ongoing pregnancy and delivery compared to the day 5 group (OR 1.58, 95%CI 1.062-2.361, p = 0.024). Perinatal outcomes were comparable between the three groups. CONCLUSION: Our results support culturing post-thaw cleavage embryos for 2 days and transferring them as blastocysts to increase chances of ongoing pregnancy and delivery.

Assessment of a double freezing approach in the management of surplus embryos in IVF.

RESEARCH QUESTION: What pregnancy rates are achieved after transfer of cryopreserved double slow-frozen embryos in IVF cycles? Patients in whom surplus thawed cleaved embryos (day 2 or 3) were grown to the blastocyst stage, re-frozen and then re-thawed for transfer (double freezing) were included. DESIGN: Data were collected on all patients who had undergone the above procedure at the IVF unit of Assuta Ramat Hachayal Hospital, Tel Aviv, during a 7-year period. For each patient in the study group, the two-consecutive, matched-by-age patients treated with frozen-thawed single blastocyst transfer were selected to form a 2:1 ratio control group. All embryos were frozen using the slow freeze protocol. RESULTS: A total of 54 patients had 70 embryos that were re-frozen at the blastocyst stage. Twenty-eight of these blastocysts were thawed and 27 underwent transfer to 25 patients. A single embryo was transferred to 23 patients and two embryos were transferred to two patients. The survival rate of the second thawing was 96.4% (27/28). Clinical pregnancy rate was 16% (4/25) and implantation rate was 14.8% (4/27). In the study group, pregnancies were achieved in 22 out of the 25 patients using IVF treatment, indicating good receptivity of the uterus. In the control group, the implantation/pregnancy rates were significantly higher (44.2% [23/52]; P < 0.01). CONCLUSION: The transfer of twice slow-frozen and thawed embryos does not seem to be a beneficial approach in the planned management of cryopreserved surplus embryos owing to the low pregnancy rate achieved after transfer of the re-frozen blastocyst embryos.

Repeated GnRH agonist doses for luteal support: a proof of concept.

RESEARCH QUESTION: What are the safety and feasibility of repeated subcutaneous doses of gonadotrophin-releasing hormone (GnRH) agonist for luteal support in IVF cycles triggered by a GnRH agonist? DESIGN: In this prospective trial, patients exhibiting oestradiol concentrations of over 2500 pg/ml after use of a GnRH agonist for triggering ovulation were initially randomized to GnRH agonist luteal support (0.1 mg subcutaneously every other day, starting on day 3 after embryo transfer) or to a control group supported by 80 µg of recombinant human chorionic gonadotrophin (HCG) on day 3 after embryo transfer. All patients underwent a day 5 blastocyst transfer. Randomization to the HCG luteal support was stopped owing to two cases of ovarian hyperstimulation syndrome (OHSS) and the study was continued solely with GnRH agonist luteal support. RESULTS: The study included 39 women in the repeated GnRH agonist luteal support group and seven in the HCG micro dose group. There were no cases of OHSS among patients supported by a GnRH agonist, and no other adverse events were recorded. There were no cases of bleeding before the pregnancy test, and hence no cases of an insufficient luteal phase. A clinical pregnancy rate of 43.6% was achieved with GnRH agonist luteal support. Hormone dynamics during the stimulation cycle reflected rising LH and progesterone concentrations after the introduction of GnRH agonist support. CONCLUSIONS: Repeated doses of GnRH agonist every other day as a method of luteal support provided safe and effective luteal support for women who underwent GnRH agonist triggering in a GnRH antagonist IVF cycle.

Does stress affect IVF outcomes? A prospective study of physiological and psychological stress in women undergoing IVF.

RESEARCH QUESTION: What are the effects of physiological and psychological stress on fertility outcomes for women undergoing IVF? DESIGN: A prospective cohort study of 72 patients undergoing IVF in 2017 and 2018. Physiological stress was assessed by salivary cortisol measurements: (i) pretreatment, when the patient received the IVF protocol; (ii) before oocyte retrieval (follicular cortisol was also measured); and (iii) before embryo transfer. Emotional stress was evaluated at each assessment with the State-Trait Anxiety Inventory and a 1-10 Visual Analogue Scale (VAS, referred to as the 'Stress Scale'. Correlations between cortisol concentrations, psychological stress and IVF outcome were assessed. RESULTS: Salivary cortisol concentrations increased by 28% from pretreatment phase (0.46 ± 0.28 µg/dl) to maximum concentration on oocyte retrieval day (0.59 ± 0.29 µg/dl, P = 0.029) and then decreased by 29% on embryo transfer day (0.42 ± 0.23 µg/dl, P = 0.0162). On embryo transfer day, cortisol among women in their first cycle was higher than women who underwent more than one treatment (P = 0.024). Stress Scale score increased by 39% from pretreatment to a maximum score on oocyte retrieval day and then decreased by 12% on embryo transfer day. Salivary cortisol and Stress Scale were not related to subsequent embryo transfer, fertilization rate, embryo quality or clinical pregnancy rate. Follicular cortisol concentration was positively correlated with fertilization rate (r = 0.4, P = 0.004). CONCLUSION: It can be cautiously concluded that physiological and psychological stress do not negatively affect IVF outcomes. Moreover, high follicular cortisol concentrations might have positive effects on pregnancy rates.

Number of Oocytes Retrieved as a Criterion for "Freeze-All" Strategy versus a Single "Rescue" Bolus of Low-Dose Human Chorionic Gonadotropin Following GnRH Agonist for Ovulation Triggering: A Pilot Study.

AIM: To evaluate the number of oocytes retrieved as a criterion - when to use a "freeze-all" or low-dose "rescue human chorionic gonadotropin (hCG)" strategy. METHODS: A retrospective study. Instead of the classic hCG trigger, an E2 level of ≥3,000 pg/mL was used to trigger ovulation with GnRH agonist. The decision whether to "freeze all" or perform fresh embryo transfer (ET) with a bolus of hCG was made based on a maximum number of 20 oocytes retrieved. Beyond this cut off, a "freeze-all" strategy was implemented. Below this cut-off value, a fresh ET using a single bolus of 62.5 µg hCG on day 3 following oocyte pick-up was performed. The main outcome measures were clinical pregnancy rates and ovarian hyperstimulation syndrome (OHSS). RESULTS: E2 and progesterone levels increased after the rescue hCG bolus administration (E2 from 643.4 ± 311.1 to 1,086.1 ± 574.7 pg/mL, p = 0.003 and progesterone from 13.1 ± 4.8 to 39.2 ± 28.7 ng/mL, p < 0.0001). The clinical pregnancy rates were 25% in the freeze-all group and 32% in the rescue hCG group (p = 0.57). OHSS was not reported in either group. CONCLUSIONS: Both strategies seem to be efficacious and safe. An upper limit of 20 retrieved oocytes appears to be safe for applying a rescue hCG strategy.

hCG Triggering in ART: An Evolutionary Concept.

Human chorionic gonadotropin (hCG) is no longer a single, omnipotent ovulation triggering option. Gonadotropin releasing hormone (GnRH) agonist, initially presented as a substitute for hCG, has led to a new era of administering GnRH agonist followed by hCG triggering. According to this new concept, GnRH agonist enables successful ovum maturation, while hCG supports the luteal phase and pregnancy until placental shift.

Outcome of early versus late multifetal pregnancy reduction.

Multifetal pregnancy reduction (MPR) is an accepted method of reducing complications of triplet pregnancies and higher-order multifetal pregnancies. Eighty-three pregnancies that underwent early (68 weeks) transvaginal MPR were compared with 125 pregnancies that underwent late (11-14 weeks) transabdominal MPR. Rates of pregnancy loss, preterm delivery, gestational diabetes and hypertensive disorders were similar among both groups. Early MPR was associated with a lower risk for small for gestational age newborns (6.5% versus 19.2%; P = 0.034; OR 0.32; 95% CI 0.11 to 0.92) and a higher risk for single-fetus loss (6% versus 0.8%; P = 0.041; OR 10.58; 95% CI 1.1 to 101.94). Preterm delivery rates seemed to be similar between the two groups. In MPR from triplets, an apparent benefit was observed for early MPR in preterm deliveries before 37 weeks, whereas, in MPR from high-order pregnancies, a benefit was observed for late MPR in deliveries before 32 weeks. Perinatal outcomes of twin pregnancies after early and late MPR seem to be grossly similar. Optimal timing for multifetal reduction depends on other factors, namely, the selectivity of the procedure and patient's preference.

Cigarette smoking and hormones.

PURPOSE OF REVIEW: The purpose is to provide a summary of the effects of cigarette smoking on steroid hormone metabolism and how it affects female fertility. RECENT FINDINGS: Components of tobacco smoke such as polycyclic aromatic hydrocarbons lead to transcriptional upregulation of a number of genes, including members of the cytochrome P450 (CYP) family, in particular CYP1B1 and CYP1A1. In humans, CYP1A1 and CYP1A2 are the primary enzymes catalyzing the 2-hydroxylation of estradiol. This pathway shunts available estrogen away from the more estrogenically potent 16α-hydroxylation to the production of catechol estrogens, mainly 2 and 4 hydroxyestradiol. SUMMARY: Smoking has multiple effects on hormone secretion and metabolism. These effects are mainly mediated by the pharmacological action of tobacco alkaloids (nicotine and its metabolite cotinine). A strong body of evidence indicates that the negative effects of cigarette smoking on fertility compromises nearly every system involved in the reproductive process.

Time lapse microscopy is useful for elective single-embryo transfer.

The aim of our study was to evaluate time lapse microscopy (TLM) as a selection tool for single-embryo transfer (SET) on day 5, blastocyst stage. An observational cohort study was conducted. Patients who had SET were compared to patients who had double embryo transfer (DET). A total of 108 patients were included in analysis, 83 had SET, and 25 underwent DET. Embryos were incubated and evaluated using TLM. The pregnancy rates were similar between the groups (42.2% in SET and 48.0% in DET). However, the multiple pregnancy rate was significantly higher in the DET group compared to the SET group (41.7% versus 2.9%, respectively; p < 0.001). This study concludes that SET with TLM do not decrease pregnancy rates compared to DET. However, transfers of two embryos increase the rate of multiple pregnancies.

The effect of medical versus surgical treatment of spontaneous miscarriage on subsequent in vitro fertilization cycles.

OBJECTIVE: To evaluate the effect of dilation and curettage (D&C) and misoprostol as treatments for spontaneous miscarriage (SM) on in vitro fertilization (IVF) parameters in the subsequent IVF cycle. DESIGN: Multicenter, retrospective, cohort study. Women treated for SM after IVF treatment with D&C or misoprostol and underwent a subsequent IVF cycle was included. The main outcome measures were ovarian response, endometrial thickness and pregnancy rate in the subsequent IVF cycle after MA. RESULTS: Among 73 patients with miscarriage, 41 had D&C and 32 were given misoprostol. Baseline serum follicle stimulating hormone (FSH) levels and ovarian responses before and after treatment of miscarriage were comparable. No significant differences were observed between the D&C and the misoprostol groups in basal FSH levels, endometrial thickness and parameters of ovarian response in the subsequent IVF cycle. CONCLUSION: D&C and misoprostol are both effective treatments for IVF patients with miscarriage, without an adverse effect on subsequent IVF treatment outcome.

What are the best predictors for successful GnRH antagonist protocol in in vitro fertilization (IVF) treatment?

OBJECTIVE: To determine factors that affect the success rate of GnRH antagonist protocol in in vitro fertilization (IVF) treatment. DESIGN: Retrospective cohort study. PATIENTS: Patients who underwent IVF cycle with their first GnRH antagonist protocol. INTERVENTION: Antagonist protocol during IVF treatment. The main outcome measurements were; Number of retrieved oocytes, embryo quality and pregnancy rate. RESULTS: Gravidity was negatively correlated with number of eggs (p = 0.017), while total follicle number ≥15 (p = 0.044) and E(2) on day of human chorionic gonadotropin (HCG) (p = 0.000) had a positive correlation with number of eggs. Maximum follicle size at HCG administration showed a trend toward an inverse correlation (p = 0.053). Addition of LH to drug stimulation was negatively correlated with number of eggs in comparison to rFSH only (p = 0.013 and 0.0000, respectively). Age and number of frozen eggs were negatively correlated with successful pregnancy (p = 0.025 and 0.004, respectively), while embryo quality, gravidity and number of embryos were positive (p = 0.011 and 0.014, respectively). CONCLUSION: Controlled parameters like timing of antagonist start, duration of antagonist and the optimal leading follicle diameter for HCG triggering had no effect on treatment outcomes.

Pregnancy outcome of early multifetal pregnancy reduction: triplets to twins versus triplets to singletons.

Multifetal pregnancy reduction (MPR) of triplets to twins results in improved pregnancy outcomes compared with triplet gestations managed expectantly. Perinatal outcomes of early transvaginal MPR from triplets to twins were compared with reduction from triplets to singletons. Seventy-four trichorionic triplet pregnancies that underwent early transvaginal MPR at 6-8 weeks gestation were included. Cases were divided into two groups according to the initial procedure: reduction to twin (n = 55) or to singleton (n = 19) gestations. Infants from triplet pregnancies reduced to twins were delivered earlier (36.6 versus 37.9 weeks; P = 0.04) and had lower mean birth weights (2364 g versus 2748 g; P = 0.02) compared with those from triplets reduced to singleton gestations. The rates of pregnancy loss before 24 weeks (3.6% versus 5.3%), as well as of preterm delivery before 32 and 34 weeks of gestation (0% versus 5.3% and 7.3% versus 5.3%, respectively) were similar between the twin and singleton pregnancies. No significant difference was found in the prevalence of gestational diabetes (15.1% versus 5.6%) or gestational hypertension (24.5% versus 16.7%) between the groups. Selective reduction of triplet pregnancies to singleton rather than twin gestations is associated with improved outcomes.

Effects of treatment of ectopic pregnancy with methotrexate or salpingectomy in the subsequent IVF cycle.

Ectopic pregnancy is a known risk for patients treated with IVF. The objective of this study was to evaluate the effect of methotrexate (MTX) and laparoscopic salpingectomy as treatments of ectopic pregnancy on ovarian response during IVF cycles. Data of all women treated for ectopic pregnancy as a result of IVF treatment were evaluated; the study included women who had an unruptured ectopic pregnancy after IVF treatment that was treated with either MTX or laparoscopic salpingectomy and underwent a subsequent IVF cycle. The main outcome measures were baseline serum FSH concentrations and ovarian response in the subsequent IVF cycle after treatment of ectopic pregnancy. Of a total of 58 patients, 36 were previously treated with MTX and 22 others by salpingectomy. No significant differences were observed between the MTX and the salpingectomy groups in the parameters of ovarian response in the subsequent IVF cycle.

Monitoring stimulated cycles during in vitro fertilization treatment with ultrasound only--preliminary results.

OBJECTIVE: To evaluate if monitoring patients by ultrasound (US) only during in vitro fertilization (IVF) treatment is safe. DESIGN: Randomized prospective study. INTERVENTION: Patients undergoing their first IVF treatment were randomized into two groups. The ultrasound only group (study group) was monitored by US for follicle size and endometrial thickness without blood tests. In this group, only one blood test was taken before human chorionic gonadotropin (hCG) injection, to ensure a safe level of estradiol (E(2)) regarding ovarian hyperstimulation syndrome (OHSS) risk. The control group was monitored by ultrasound plus serum estradiol and progesterone concentration at each visit. MAIN OUTCOME MEASURE: Clinical pregnancy rate. RESULTS: No differences were found between the groups in the parameters of IVF treatment, induction days, number of ampoules, E(2) level of hCG, as well as embryo quality. The clinical pregnancy rate was not statistically different between the groups, 57.5% vs. 40.0%, respectively (p = 0.25). No OHSS cases were found among the study or control groups. CONCLUSION: Ultrasound as a single monitoring tool for IVF cycles is reliable, safe, patient friendly, and reduces treatment expenses. In an era of cost effectiveness awareness, this regimen should be considered for routine management in IVF programs.

Gonadotropin releasing hormone agonist triggering for in vitro maturation cycles.

The objective was to evaluate the outcomes of in vitro maturation (IVM) cycles using gonadotropin releasing hormone agonist (GnRH-ag) triggering. A retrospective cohort of IVM cycles from January 2015 to December 2019 in a single university-affiliated centre was examined. Main outcome measures were: (i) IVM maturation rate; and (ii) IVM maturation result. Secondary outcome measures were: (i) metaphase II (MII) rate on the day of egg retrieval; (ii) final MII maturation rate; and (iii) pregnancy rates. A total of 98 IVM cycles were performed during the study period: 50 (51%) were triggered with GnRH-ag (17 received FSH priming and 33 did not) and 48 cycles (49%) were triggered by hCG (37 with FSH priming and 11 without). A significant (p = 0.01) difference was noticed in maturation rate on egg retrieval day, in favour of the GnRH-ag group, although not in the final maturation rate achieved. Pregnancy rates were comparable between treatment sub-groups. GnRH-ag triggering in IVM cycles is an optional triggering mode and can be considered an acceptable option, especially when fertility preservation is a concern. GnRH agonists resulted in higher maturation rate on day of oocyte retrieval, but no difference in the total maturation rate.

Standardization of Post-Vitrification Human Blastocyst Expansion as a Tool for Implantation Prediction.

The increased use of vitrified blastocysts has encouraged the development of various criteria for selecting the embryo most likely to implant. Post-thaw assessment methods and timetables vary among investigators. We investigated the predictive value of well-defined measurements of human blastocyst re-expansion, following a fixed incubation period. Post-thaw measurements were taken exactly at 0 and 120 ± 15 min. Minimum and maximum cross-sectional axes were measured. Three groups were defined: Group 1: embryos that continued to shrink by 10 µm or more; group 2: embryos that ranged from -9 to +9 µm; and group 3: re-expansion of 10 µm or more. Patient and morphokinetic data were collected and integrated into the analysis. A total of 115 cases were included. The clinical pregnancy rate for group 1 was 18.9%; group 2, 27%; and group 3, 51.2% (p = 0.007). Pre-thaw morphologic grading and morphokinetic scores of the study groups did not reveal differences. p-values were 0.17 for the pre-thaw morphologic score, 0.54 for KID3, and 0.37 for KID5. The patients' demographic and clinical data were similar. The clinical pregnancy rate correlated with the degree of thawed blastocyst re-expansion measured 2 h after incubation. This standardized measure is suggested as a tool to predict the potential of treatment success before embryo transfer.

A prospective study of C-reactive protein in patients with obesity during IVF.

This prospective cohort pilot study investigated the physiology of C-reactive protein (CRP) during in vitro fertilization (IVF) cycles and its effect on outcomes in women with and without obesity. The study was conducted from April to August 2014, in the IVF Unit of a university-affiliated hospital. Women aged 18-42 years were enrolled. Those with chronic inflammatory diseases or acute illness were excluded. A total of 31 patients were included: 17 with BMI < 30 kg/m2 and 14 with BMI ≥ 30 kg/m2. Serum CRP levels were measured: (i) before starting ovarian stimulation; (ii) on the day of ß-HCG administration; and (iii) on day of ovum pick-up (OPU), in both serum and follicular fluid. Serum CRP levels were significantly higher in women with obesity at all time points. For the entire cohort, a positive correlation was found between basal oestradiol (E2) and basal CRP (r = 0.71, p < 0.05). A specific pattern of CRP levels was not detected during the IVF cycle. High serum CRP levels on OPU day had a negative effect on embryo quality (p = 0.056). CRP ≥ 0.5 mg/dL was associated with lower quality embryos (2.6 ± 0.3 vs. 3.3 ± 0.3; p = 0.04). High serum CRP level on OPU day negatively affects embryo quality.

The effect of maternal body mass index (BMI) and telomere function on in vitro fertilization (IVF) outcome: a preliminary cohort study.

Telomeres are a specific base sequence of DNA, responsible for chromosome stability and DNA protection. We aimed to investigate the association between telomere systems and IVF outcomes according to patients' BMI. For all telomere characteristics, there was a distinct trend towards shorter telomeres and activation of telomere shortening compensatory mechanisms in the BMI group >25 kg/m2, reaching statistical significance for senescence only (r = 0.7, p value <0.01). There was a trend towards a relationship between telomere length and number of oocytes between telomere length and fertilization rate, but these did not reach a statistical significance. For pregnancy outcome, all telomere characteristics were better for the patients who achieved a pregnancy. While there is paucity of data in the literature concerning the association between telomere characteristics and infertility, telomeres might contribute to the association between obesity and sub-optimal IVF results.