Delayed pulmonary embolism following oocyte retrieval in invitro fertilization: A neglected risk factor for thromboembolic events?

Diagnosis of Acute Pulmonary Embolism: Always Be Vigilant

After completing this article, readers should be able to: 1. Describe the outcomes of assisted reproductive technologies (ART) for singleton, twin, and other multiple births. 2. Describe the role of fertility in adverse outcomes seen with ART births. 3. Review the association of birth defects with ART. 4. Delineate the association of disease of genomic imprinting with ART. 5. Describe the relationship between ART and the subsequent incidence of neurodevelopmental sequelae. In the 1977 ruling “Carey v. Population Services International,” the United States Supreme Court ruled that the decision to bear children is constitutionally protected. (1) Significant interest already had been shown in the development and improvements of in vitro fertilization (IVF) for infertile couples. The first human pregnancy and human birth using IVF were reported by Steptoe and Edwards in the United Kingdom. (2) Their work resulted in the first baby born via reproductive technologies, Louise Brown, born on July 25, 1978, at Oldham General Hospital in Oldham, United Kingdom. (3) She was born via a planned cesarean section, and her birthweight was 2.61 kg. The first successful viable IVF in the United States was performed by Jones and Seager-Jones in 1981 in Norfolk, Virginia. (4) Assisted reproductive technologies (ART) have seen a recent surge in popularity. The Centers for Disease Control and Prevention (CDC) reported that 122,872 cycles of ART were initiated in 2003, resulting in the delivery of 48,756 neonates, (5) accounting for approximately 1% of all neonates delivered in the United States. The percentage is higher in many countries, including Denmark, where it is estimated that 5% of all deliveries are with the assistance of ART. (6) Couples pursue ART for myriad reasons, including tubal transport factors, ovulatory dysfunction, uterine factors, endometriosis, male- and female-specific factors, and when a cause of infertility is unknown. (5) It would be very …

Thromboembolic events are serious but rare complications following ovarian stimulation for in-vitro fertilization (IVF). We report a case of severe ovarian hyperstimulation syndrome (OHSS), presenting in a second IVF cycle with a late complication of right internal jugular vein thrombosis despite mini-dose heparin prophylaxis. Thrombosis and thromboembolism as late complications of OHSS have been reported by others but not after prophylactic heparinization. The patient was successfully treated with heparin and the twin pregnancy is ongoing. In pregnant patients with severe OHSS consideration should be given to treatment with low dose heparin throughout the first trimester to prevent the serious complications of thrombosis and thromboembolism.

For the last few decades urinary human chorionic gonadotrophin (hCG) has been used to induce final oocyte maturation triggering in in vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI) cycles. Recombinant technology has allowed the production of two drugs that can be used for the same purpose, to mimic the endogenous luteinizing hormone (LH) surge. This allows commercial production to be adjusted according to market requirements; the removal of all urinary contaminants; and the safe subcutaneous administration of a compound with less batch-to-batch variation. However, prior to a change in practice the effectiveness of the recombinant drugs should be known compared to the currently used urinary human chorionic gonadotrophin (uhCG). To assess the efficacy and safety of subcutaneous recombinant hCG (rhCG) and high dose recombinant LH (rLH) compared with intramuscular uhCG for inducing final oocyte maturation triggering in IVF and ICSI cycles. We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (January 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010), MEDLINE (1966 to January 2010) and EMBASE (1980 to January 2010). Two review authors independently scanned titles and abstracts and selected those that appeared relevant for collection of the full paper. Only truly randomised controlled trials comparing rhCG and rLH with urinary hCG for final oocyte maturation triggering in IVF and ICSI cycles for treatment of infertility in normo-gonadotropic women were included. Assessment for inclusion or exclusion, quality assessment and data extraction were performed independently by two authors. Discrepancies were discussed in the presence of a third author and consensus reached. Quality assessment included method of randomisation, allocation concealment, blinding of participants and assessors, reporting of a power calculation and intention-to-treat analysis. Fourteen RCTs (n = 2306) were identified; 11 compared rhCG with uhCG and three compared rhLH with uhCG. There was no evidence of a statistically significant difference between rhCG and uhCG regarding the ongoing pregnancy or live birth rate (6 RCTs: OR 1.04, 95% CI 0.79 to 1.37; P = 0.83, I(2) = 0%). There was no significant difference in the incidence of ovarian hyperstimulation syndrome (OHSS) between rhCG and uhCG (3 RCTs: OR 1.5, 95% CI 0.37 to 4.1; P = 0.37, I(2) = 0%). There was no evidence of statistically significant difference between rhLH and uhCG regarding the ongoing pregnancy or live birth rate (OR 0.94, 95% CI 0.50 to 1.76) and incidence of OHSS (OR 0.82, 95% CI 0.39 to 1.69). These results leave open the possibility of strong differences in favour of either treatment for both ongoing pregnancy and OHSS. We conclude that there is no evidence of difference between rhCG or rhLH and uhCG in achieving final follicular maturation in IVF, with equivalent pregnancy rates and OHSS incidence. According to these findings uHCG is still the best choice for final oocyte maturation triggering in IVF and ICSI treatment cycles.

Pulmonary embolism (PE) is a serious and preventable complication after surgery. Blood transfusion is a common event during surgery. The aim of the present study was to identify whether intra-operative blood product transfusions increase the risk of symptomatic post-operative PE. A retrospective, single-center case-control study at Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University between 1 January 2013 and 31 December 2016 was performed. Adult hospitalized patients with confirmed symptomatic PE after surgery were defined as case group. Each patient was matched with two adult patients without symptomatic PE who underwent the same procedure on the same day or within one week. Perioperative data especially detailed blood transfusion was collected. Forward stepwise logistic regression analysis was performed. During the study period, altogether 188,512 procedures were included, and postoperative PE were confirmed in 40 (0.02%) patients. Twelve (30.0%) case patients and 16 (20.0%) control patients received intra-operative blood transfusion. Intra-operative blood transfusion was revealed as a significant predictor for symptomatic post-operative PE (OR 80.669, 95% CI: 3.312-1,964.641, P=0.007), along with female sex (OR 86.921, 95% CI: 4.242-1,781.124, P=0.004), older age (OR 1.078, 95% CI: 1.005-1.156, P=0.035), longer length of stay before surgery (OR 1.124, 95% CI: 1.040-1.214, P=0.003) and longer operation time (OR 1.013, 95% CI: 1.002-1.025, P=0.024). Intra-operative blood transfusion was associated with an increased risk of symptomatic post-operative PE. PE prophylaxis and selective screening should be considered in patients who had received intra-operative blood transfusion, especially in female patients.

Caval-Iliac Vein Angle and Risk of Pulmonary Embolism in Patients with Right-Sided Deep Vein Thrombosis.

Study question Is progesterone receptor (PGR) downregulation disrupted within endometrial epithelial compartment, during embryo receptivity phase in assisted reproductive technology (ART) cycles? Summary answer PGR is not downregulated in endometrial epithelial cells from ART cycles during embryo receptivity phase. What is known already Progesterone (P4) promotes the downregulation of its own progesterone receptor (PGR). During the mid-luteal phase, PGR is downregulated in endometrial epithelial cells (EEC), a critical process for embryo implantation. Embryos are unable to attach to the maternal surface when PGR expression is sustained in EEC. Non-physiologic ovarian steroid produced or employed in ART cycles may alter endometrial development compromising its receptivity. Scarce information is available whether PGR is downregulated in EEC from ARTs including ovarian stimulation for in vitro fertilization (IVF) cycles or hormonal endometrial preparation for frozen thawed embryo transfer (HEP-FET). Study design, size, duration Cross sectional study including endometrial samples from fertile women during natural cycle (FNC, n = 23), from infertile women submitted to IVF (n = 19) and from infertile women who underwent mock HEP-FET (n = 35). Samples were obtained between 2018–2019. Sample size was calculated considering a power of 90%, alpha error=0.05, an expected PGR expression of 2 and 0.5 in ART and FNC groups, respectively, having a standard deviation=0.9. At least 9 patients would be necessary in each group. Participants/materials, setting, methods Endometrial samples were obtained during mid-luteal phase scheduled 7 days after ovulation in FNC, 5 days after oocyte retrieval in IVF without embryo transfer or 5 days after P4 supplementation in HEP-FET. Immunohistochemistry was employed to quantify PGR using histologic score (Hscore). PGR mRNA levels were determined by qRT-PCR from EEC dissected by laser capture microdissection. Anova test was used for comparing means of Hscore and mRNA among groups. Statistical significance was established as P < 0.05. Main results and the role of chance No statistical differences were found in demographic characteristics including age, body mass index or endometrial thickness. The PGR expression was reduced in FNC compared to IVF and HP-FET endometria (0.6 ± 0.1, 1.9 ± 0.9 and 2.2 ± 0.9 respectively; P < 0.0001). The PGR mRNA levels from ECC dissected by laser capture microdissection were higher in IVF and HP-ET cycles compared to FNC (10.6 ± 3.1, 13.6 ± 2.3 and 0.8 ± 0.1 respectively; P < 0.0001) corroborating the elevated PGR Hscore in EEC from ART cycles. Limitations, reasons for caution This is a descriptive study reporting failure of PGR downregulation in endometria from ART cycles with vaginal P4 supplementation during the luteal-phase. Whether interference or resistance to P4 signal is the mechanism involved in the failure of PGR down regulation in ART cycles needs to be determined Wider implications of the findings: PGR downregulation within EEC was shown in FNC. The retained PGR expression detected in most ART cycles may interfere with embryo implantation and might explain the restricted pregnancy success. Future studies might reveal whether PGR evaluation in EEC can predict embryo implantation. Trial registration number Not Aplicable

• Several cardiovascular/hemostatic disturbances haves been reported in patients with COVID-19, but the real frequency and their potential association with the pathogenic mechanisms of SARS-CoV-19 still remain to be defined. • We investigated the relative frequency of acute coronary syndrome, deep venous thrombosis, pulmonary embolism, stroke and upper gastrointestinal bleeding in COVID patents attending emergency departments (EDs), before hospitalization and compared them with frequencies in the general ED population attending 50 Spanish EDs. • We found that the risk of pulmonary embolism is clearly increased in COVID patients, with an OR of 4.53 with respect to non-COVID patients (95% confidence interval 4.03- 5.10). Additionally, the diagnosis of pulmonary embolism was 2 fold more frequent among ED comers in 2020 compared to 2019, suggesting a SARS-CoV-2 role in such increment of cases.. The remaining entities studied were not found to be unequivocally increased in the present study and need further investigation.

<h3>Background</h3> The suspicion of PE is a common reason for both hospital admission and hospital stays. Being able to prevent admission in low risk PE patients has previously shown to be safe and cost effective with an established ambulatory service running in our hospital since 2010. In this study we describe the findings from an 8 year retrospective analysis of this service, building on a previous 2 year study. <h3>Method</h3> An 8 year retrospective analysis from June 2010 to January 2018 was carried out using the PE database. Patients with suspected PE referred to the service using acceptance criteria (appendix a). PE risk was then stratified using the PE severity index (PESI) (3). D-dimers were performed in the low and intermediate probability groups. Those with negative d-dimers were discharged, those with high risk or positive d-dimer underwent imaging in the form of CT pulmonary angiography (CTPA) or ventilation-perfusion (VQ) scanning. This was generally a same day service. For a subset of 418 patients (admitted April-December 2017) 30-day mortality was determined. <h3>Results</h3> 3767 patients were referred to the service. Out of these patients 2651 (70%) were female and 1116 (30%) were male. 1474 (40%) referrals came from general practice, 898 (24%) from bed bureau, 621 (17%) came from the clinical decisions unit and 562 (15%) came from the emergency department. 106 (3%) of referrals came from other sources. 269 (7%) had a confirmed PE out of which 265 (99%) were managed as outpatients. 1438 CTPAs were performed, 226 (18%) were positive. 416 VQ scans were performed, 27 (6%) were positive. 30-day mortality was zero. <h3>Conclusions</h3> The analysis shows ambulatory PE care to be effective with 99% of those with confirmed PE being managed without admission. This is an improvement of 27% from the previous study. The service is safe with zero 30-day mortality in a recent subgroup. Summarizing, this is the largest ambulatory PE study which demonstrates the effectiveness and safety of an outpatient ambulatory pulmonary embolism (PE) pathway. Similar services such as this should be implemented in other centres. <h3>Reference</h3> https://www.ncbi.nlm.nih.gov/pubmed/16020800

ObjectiveThe aim of this retrospective cohort study was to evaluate the clinical and neonatal outcomes between day 4 and day 5 embryo transfer across different fertilization methods.MethodsThis retrospective cohort study was conducted between January 2018 and March 2023, enrolling a total of 1,245 fresh embryo transfer cycles, including 1,023 in vitro fertilization (IVF) cycles and 222 intracytoplasmic sperm injection (ICSI) cycles. Among these, IVF cycles included 793 day 4 transfers and 230 day 5 transfers; ICSI cycles included 179 day 4 transfers and 43 day 5 transfers. The study conducted a comparative analysis of clinical pregnancy outcomes between day 4 and day 5 transfers.ResultsIn IVF or ICSI cycles, no significant differences were found in clinical pregnancy rate (CPR), implantation rate (IR), live birth rate (LBR), or other clinical outcomes between transfers of day 4 and day 5 embryos (P > 0.05). In IVF cycles with single high-quality embryo transfer, the CPR (62.72%, P = 0.026), gestational week of delivery (39 weeks, P = 0.026) of day 4 were significantly higher than day 5 (38 weeks). After controlling for potential confounding factors, the CPR of the day 4 group was also higher than day 5 (OR 0.578, 95% CI 0.352-0.949, P = 0.030). In IVF or ICSI cycles with day 4 high-quality embryo transfer, the LBR (63.06%, P = 0.006; 70.37%, P = 0.006) and multiple pregnancy rate (MPR; 53.29%, P < 0.001; 50%, P < 0.001) of transferring double high-quality embryo were significantly higher than transferring single high-quality embryo (LBR: 50.87%, 44.23%; MPR: 0%, 3.23%).ConclusionIn IVF or ICSI cycles, day 4 embryo transfer is considered a viable option or alternative to day 5 blastocyst transfer with no difference in clinical and neonatal outcomes. In IVF cycles with single high embryo transfer, day 4 transfer is recommended due to its significantly higher pregnancy rate compared to day 5 transfer. To reducing MPRs and preterm birth rates (PBRs), day 4 single embryo transfer is recommended if embryos achieve high-quality grade (full compaction) on day 4.

Study question Our objective was to compare the results and costs between conjugal intrauterine insemination (IAC) and in vitro fertilization (IVF) in a third-level public health hospital. Summary answer The direct estimated cost for achieving a clinical pregnancy was € 3808.24 for IAC and € 14,195.88 for IVF. What is known already There is a belief among patients, professionals, and media in favor of the results offered by IVF. Studies on the results, risks, complications and costs are difficult to understand, thus making IVF the most widespread and in demand reproduction technique among fertility clinics. In 2013 the National Institute of Health and Care Excellence conducted a study comparing artificial insemination using 25 mg of clomiphene citrate vs. expectant management of sterility, without finding significant differences. After this, in their guide they recommended the elimination of insemination from the couples’ treatment protocols, proposing to replace it with three cycles of IVF. Study design, size, duration This is a retrospective observational study of a total of 1384 conjugal insemination cycles carried out in our center between 2007–2019 and 646 cycles of in vitro fertilization, intracytoplasmic injection (ICSI) or mixed. Participants/materials, setting, methods All IAC were included. IVF cycles analyzed were those made under the diagnose of tubal factor, to homogenize the samples. The calculation of the direct costs of each technique has been carried out by the collection of the costs of these procedures from the registry of public costs of the Andalusian public health system. The pharmacy spending in an average cycle has been obtained from the public prices of prescriptions made in our service. Main results and the role of chance The direct estimated cost for achieving a clinical pregnancy with the cumulative clinical pregnancy rate found in our sample was € 3808.24 for IAC and € 14,195.88 for IVF. The additional cost of a pregnancy achieved by IVF compared to one achieved by IAC was € 10,387.64. The mean age of the patients was higher in the group undergoing in vitro fertilization treatment (34.41 years) compared to those undergoing artificial insemination treatment (32.18 years), the differences between both being statistically significant ( p &amp;lt; 0.005). We also found statistically significant differences between the clinical pregnancy rate (12.2% in the group that underwent an AI and the 25.8% in which an IVF was performed) and the live newborn rate between both groups (8.7% in the group that underwent AI and 16% in which IVF was performed), both being higher for the group subjected to in vitro fertilization. In the twin pregnancy rate, we also found significant differences (p 0.005) between both groups, being 6.8% in the patients undergoing IVF compared to 0.8% in the inseminations. Limitations, reasons for caution Regarding the costs per cycle, indirect costs of these have not been taken into account, such as values in the cost of pregnancy and delivery of single or multiple pregnancies, or costs of complications derived from the techniques (ovarian hyperstimulation syndrome, fetal reductions, terminations for other reasons, etc.) Wider implications of the findings: The recommendations made by the NICE promote IVF treatment to couples with infertility of unknown origin. In our opinion, this recommendation should be subjected to a more extensive cost-effectiveness analysis of both techniques, given that IVF requires a considerably higher investment of resources, finding results not so different as expected. Trial registration number Not applicable

Extremes of body mass index reduce in vitro fertilization pregnancy rates

Objective To evaluate the ability of cabergoline administration in patients with polycystic ovarian syndrome undergoing treatment with gonadotropins in artificial reproductive technique cycles to reduce the risk of ovarian hyperstimulation syndrome (OHSS), as well as to compare its effect with prednisolone. Patients and methods Women with polycystic ovarian syndrome undergoing stimulation by gonadotropins (200–300 U of Puregon) in a long protocol were divided into three groups. Group I comprised 50 patients and this was considered as the control group. Group II included 75 women taking prednisolone 10 mg twice a day from the day of human chorionic gonadotropin (HCG) injection till the date of a pregnancy test. The third group included 75 women taking cabergoline 0.5 mg, one tablet, on 2 successive days, repeated 1 week later, starting from the day of HCG injection. All patients were reviewed by vaginal ultrasound 5 days after the HCG injection for clinical and sonographic signs of OHSS. Results OHSS developed in six of the 48 patients (12.5%) from the control group (two patients), who were excluded from the study, in seven of the 72 patients (9.7%) from the prednisolone group, and in two patients of the 73 patients (2.7%) who completed the study from the cabergoline group. Conclusion Cabergoline plays a significant role in the prevention of OHSS in patients with polycystic ovarian syndrome undergoing ovarian stimulation by gonadotropins.

IntroductionAge, polycystic ovary syndrome (PCOS), low body mass index (BMI), high antral follicle count (AFC), increased anti-Muller hormone (AMH) levels, and elevated serum estradiol (E2) concentrations are risk factors for ovarian hyperstimulation syndrome (OHSS). However, data on the relationship between risk factors and OHSS severity in patients with PCOS are rare.ObjectiveThis retrospective study examined the risk factors for OHSS and their effect on OHSS severity in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).MethodThe records of 2,699 women were reviewed and included in this study. These women were diagnosed with PCOS during their first IVF/ICSI cycle between January 2010 and December 2017. We analyzed the association between each of the interrogated risk factors (including female age, BMI, AFC, basal serum E2, and the number of oocytes retrieved) and OHSS. The effects of each risk factor on OHSS severity were further explored. Logistic regression was performed as part of the above analysis.ResultsOf the 2,699 women with PCOS who underwent assisted reproductive technology (ART), 75.2% had a normal response to controlled ovarian hyperstimulation (COH), while 24.8% developed OHSS. All OHSS patients were younger and had lower BMIs and basal serum follicle-stimulating hormone (FSH) and E2 levels but higher AFCs than those in the normal group. AFC demonstrated a strong correlation with OHSS, with a cutoff value of 24 in patients with PCOS. A total of 19.5% of the patients had mild OHSS, while 80.5% had moderate OHSS. Compared with those in the moderate OHSS group, those in the mild OHSS group were older and had higher basal serum FSH levels and lower serum E2 and T levels. However, BMI and AFC were not different between the mild and moderate OHSS groups. Basal serum E2 showed a strong correlation with OHSS severity, with a cutoff value of 37.94 pg/ml.ConclusionsAFC is a strong marker of OHSS, and basal serum E2 is the best predictor of OHSS severity in women with PCOS undergoing IVF treatment.

Study question Does the live birth rate differ between the two regimens for luteal phase supplementation in IVF cycles in women with a history of IVF failure? Summary answer The live birth rate did not differ with dydrogesterone + progesterone gel vs. subcutaneous aqueous progesterone + progesterone gel. What is known already Supplementation of the luteal phase in in vitro fertilization (IVF) cycles is crucial to increase the chance of a live birth. Progesterone is the treatment of choice due to a lower risk of complications compared to human chorionic gonadotropin (hCG) and gonadotropin-releasing hormone (GnRH) analogues. There is no preferred progestogen for use in the general population of women undergoing IVF. The optimal progesterone treatment regimen in the event of previous IVF failure is unknown. Study design, size, duration A prospective randomized tertiary single-center study was conducted. The study included 161 women, aged 25-43 years, with FSH on cycle day 2-4 ≤10 IU/L, with at least one failed IVF cycle, undergoing government-funded IVF in the years 2015-2016. Participants/materials, setting, methods 161 included women were randomized after oocytes retrieval to 2 groups of luteal IVF cycle phase supplementation: dydrogesterone (Duphaston®) + progesterone in vaginal gel (Crinone®) or aqueous progesterone solution in subcutaneous injection (Prolutex®) + progesterone in vaginal gel (Crinone®). At least one blastocyst was obtained in the enrolled women. All women underwent fresh embryo transfer. After viable pregnancy confirmation, treatment was continued until the 12th week of gestation. Main results and the role of chance The indications for IVF were: male factor (51%), tubal factor (27%), endometriosis (24%), decreased ovarian reserve (17%), idiopathic infertility (14%), ovulation disorders (6%), occurring in various combinations. Out of 161 women enrolled in the study, 94 had a history of 1 failed IVF cycle, and 67 had at least 2 failed IVF cycles. Among 94 women with 1 failed IVF, 62 received dydrogesterone + progesterone gel vs. 32 aqueous progesterone + progesterone gel, and the percentages of live births, clinical pregnancies and biochemical pregnancies were: 29 vs. 21% (p = 0.37), 10 vs. 6% (p = 0.53), 5 vs. 12% (p = 0.21). Among 67 women with at least 2 failed IVFs, 24 received dydrogesterone + progesterone gel vs. 43 aqueous progesterone + progesterone gel, and the percentages of live births, clinical pregnancies and biochemical pregnancies were: 17 vs. 32% (p = 0.19), 4 vs. 0% (p = 0.14), 9 vs. 9% (p = 0.95). The results were comparable with both treatment regimens. There were no significant adverse events reported for both treatment regimens. Limitations, reasons for caution The limitations of the study are the small sample size, its single-center character and heterogeneity of indications for IVF. Wider implications of the findings In light of the lack of evidence of greater efficacy of either of the two luteal phase supplementation regimens of the IVF cycle in women with a history of IVF failure, the choice of treatment should be guided by other considerations, i.e. potential side effects, dosing convenience and patient preference. Trial registration number 1072.6120.47.2021