Postpartum hemorrhage among twin pregnancies - Medically assisted versus spontaneously conceived.

INTRODUCTION: In singleton pregnancies, an increased risk of Postpartum hemorrhage (PPH) have been linked with assisted reproductive technology (ART) and abnormal placentation. It is unknown wheather such association exists in twin pregnancies conceived by Medically assisted reproduction (MAR). The aim of the current study was to compare maternal blood loss among twin pregnancies conceived by different types of MAR treatments to spontaneously conceived twins and to identify the cycle characteristics if an association exits. METHODS: Retrospective study conducted on data collected between 2011 and 2020. The study cohort included all twin pregnancies conceived by MAR and born at our institution. Controls were spontaneously conceived twins matched for maternal age on a 1:2 (study: controls) ratio. RESULTS: Overall 113 MAR twin births categorized into three groups; 25 ovulation induction, 59 fresh ART, 29 frozen-thawed ART cycles, and 226 controls were included. The incidence of PPH was higher among MAR twin pregnancies (5.3%) compared to the controls (4%). The highest incidence was observed among women in the frozen-thawed group (13.8%) which differed significantly compared with the controls (p = 0.024). A significant difference was also observed in the mean decrease of postpartum hemoglobin levels between these two groups (2.13 g/dL versus 1.3 g/dL respectively, p = 0.002). Blood transfusion was nearly 2.5 times more common in the frozen-thawed group (3.4%) compared to the control group (1.3%). DISCUSSION: The present study demonstrates that frozen embryo transfer (FET) ART-conceived twin pregnancies are associated with a markedly increased rate of PPH compared to spontaneously conceived twins.

Perimortem and postmortem sperm acquisition: review of clinical data.

PURPOSE: To provide the clinicians with the most comprehensive medical information about sperm acquisition peri/postmortem. METHODS: The review was conducted according to the PRISMA statement. MEDLINE and Cochrane databases were searched up to January 2021. All studies reporting post or perimortem harvesting of sperm with any indication of an outcome, recognition and viability of sperm, and its utilization and treatment outcome were included. Studies that recorded cases but discussed only the ethical or legal issues without any information about the medical details were excluded. RESULTS: Twenty-four studies were included in this review. One hundred forty-eight cases were described; in 113 of them, sperm was retrieved. A variety of techniques for sperm acquisition were used. The data collected are limited and comparing the efficacy of the different approaches is not feasible. The longest time interval described between the death and viable sperm acquisition was 3 days. The sperm quality varies between the studies. One hundred thirty-six mature oocytes were injected with the retrieved sperm; the fertilization rate was 41%. Transfer cycles of 25 embryos and 8 live births are reported in the medical literature. CONCLUSION: The overall low quality and high heterogeneity of the available data impair the ability to draw definitive conclusions. However, it can be stated that sperm acquisition up to at least 3 days postmortem can result in the live birth of healthy offspring. Further studies are needed to clarify the medical questions regarding the best techniques, success rates, and wellbeing of the parties involved.

Progesterone and estrogen levels are associated with live birth rates following artificial cycle frozen embryo transfers.

PURPOSE: Does an association exist between serum progesterone and estradiol levels and live birth rates in artificial cycle frozen embryo transfer (AC-FET)? METHODS: Retrospective cohort study was based on prospectively collected data at a university-affiliated fertility center. Included were all cycles using an artificial endometrial preparation with estradiol hemihydrate (Estrofem, 2 mg/8 h) and vaginal progesterone (Endometrin 100 mg/8 h), autologous oocytes, and cleavage stage embryo transfers. Serum progesterone and estradiol levels were measured 14 days after FET. A total of 921 cycles in 568 patients from to December 2010 to June 2019 were investigated. Live birth was the primary outcome measure. RESULTS: Significant association was found between live birth and progesterone as well as estradiol levels (progesterone 14.65 vs 11.62 ng/ml, p = 0.001; estradiol 355.12 vs 287.67 pg/ml, p = 0.001). A significant difference in live birth rate was found below and above the median progesterone level (10.9 ng/ml, p = 0.007). Lower estradiol level was significantly associated with lower live birth rate (< 188.2 pg/ml 8.3%, > 263.1 pg/ml 16%, p = 0.02). CONCLUSIONS: Serum progesterone and estradiol levels impact live birth rate in AC-FET.

Ideal lag time from ovulation to oocyte aspiration using a GnRH agonist trigger.

BACKGROUND: In ART, oocyte maturation (M2) and ovulation is stimulated by a hormonal trigger. For maturation to occur, sufficient "lag time" must elapse between the trigger and aspiration, ranging from 32 to 38 hours. Premature aspiration can result in poor yields; late aspiration risks spontaneous ovulation. AIM: Our study examines optimal lag time using a GnRH antagonist protocol and GnRH agonist trigger for ICSI. METHODS AND MATERIALS: We analyzed data from 220 women undergoing GnRH antagonist protocol using a GnRH agonist trigger for ICSI at our clinic between 02/2012-03/2018. Patients were divided into 4 groups based on lag time: 34.00-34.99 hours (n = 32), 35.00-35.99 hours (n = 113), 36.00-36.99 hours (n = 57) and 37.00 h or more (n = 18). Analyses were performed with the Kruskal-Wallis test, Chi-Square, and Spearman's rho correlation. RESULTS: A positive correlation was found for the number of M2 oocytes aspirated and lag time (ρ = 0.138, p = 0.04) and for the total number of oocytes aspirated and lag time, (ρ = 0.174, p = 0.01). No correlation was found between the proportion of M2 oocytes aspirated and lag time (p = 0.217). The third group (36 h) had significantly more M2 oocytes aspirated than the second group (35 h) (12.4 ± 7.1 vs 9.4 ± 6.2; p = 0.039). The four groups did not differ for the proportion of mature M2 oocytes (H = 2.453, p = 0.484). The four groups differed in the frequency of live births per fresh embryos transferred (χ2 = 9.364, p = 0.025). CONCLUSION: Our study identified a positive correlation between lag time and both the number of M2 oocytes and the total number of oocytes aspirated-factors which lead to an increased rate of successful pregnancies. Further research is necessary.

The Importance of Mid-Follicular Phase Luteinizing Hormone Rise in GnRH Antagonist-Based Ovarian Stimulation for IVF.

INTRODUCTION: Previous publications examined the endocrinology of follicular stimulation, focusing on luteinizing hormone (LH) levels changes. In selected, good prognosis IVF patients, a sharp drop in LH serum level was demonstrated between cycle days 2 and 6. OBJECTIVE: The purpose of this study was to examine if this finding holds true for unselected patients. METHODS: We retrospectively included 165 consecutive patients treated with a GnRH antagonist-based ovarian stimulation protocol during the year 2015. RESULTS AND CONCLUSIONS: In 33% of the patients an increase in LH, rather than the expected decrease, was demonstrated after 5 stimulation days. There was no difference in pregnancy outcome. Our results suggest that an increase in LH levels during ovarian stimulation occurs mainly in "high responders", or "low responders". LH rise in mid follicular phase may result in a sharp LH drop once a GnRH antagonist is given, and the possible need for LH supplementation.

Gonadotropin Releasing Hormone Agonist Final Oocyte Maturation and Human Chorionic Gonadotropin as Exclusive Luteal Support in Normal Responders.

BACKGROUND/AIMS: Gonadotropin releasing hormone (GnRH) agonist triggering results in an endogenous gonadotropin flare. Although it effectively stimulates ovulation, GnRH agonist triggers results in an early luteolysis and requires modification of the luteal support. The current study aims to evaluate GnRH agonist triggering with exclusive human chorionic gonadotropin (hCG) luteal support. METHODS: In this prospective observational study, 56 normogonadotropic-assisted reproductive technology patients, stimulated using a GnRH-antagonist protocol, were studied. Final oocyte maturation was achieved with 0.2 mg triptorelin acetate followed by progesterone free luteal support with human choriogonadotropin (1,500 IU * 2). A control group was selected from a pool of 1,023 normogonadotropic patients who received Choriogonadotropin alfa for final oocyte maturation and progesterone suppositories for luteal support. RESULTS: No significant difference was found for the number of oocytes, oocyte maturation rate, fertilization and implantation rate, clinical pregnancy rate (25 vs. 26.7%) and live birth rate (25 vs. 21.4%). Progesterone levels in conception cycles were significantly higher in the study group than corresponding levels in the control group. CONCLUSION: GnRH agonist triggering with exclusive hCG support may be a valid alternative to hCG triggering with progesterone support. This protocol combines the potential advantages of a physiological trigger with a simple, patient-friendly, luteal support.

Increased coagulation index as measured by Thromboelastography during ovarian stimulation for in vitro fertilization: Influence of the final oocyte maturation triggering agent.

OBJECTIVE: Thromboelastography (TEG) is a viscoelastic test of hemostasis which allows measurement of the processes of clot initiation, propagation, stabilization, and dissolution in real time. In this study we aimed to evaluate the alterations in coagulation as measured by TEG during In Vitro Fertilization (IVF) stimulation cycles and to investigate whether final oocyte maturation with recombinant hCG (rhCG) versus GnRH agonist results in a different coagulation state. STUDY DESIGN: This is a prospective observational study which included fifty-three normogonadotrophic women. All the patients received an antagonist IVF treatment protocol. Final oocyte maturation was triggered with either rhCG (n = 25) or GnRH agonist (n = 26). Two patients did not complete the study due to poor response. Venous blood was drawn in the early and late follicular phase and on the day of ovum pickup. The TEG parameters assessed were R (time to first clot formation), K (time until the clot reaches a fixed strength), alpha angle (the rate of clot formation), MA (reflects maximum strength of the platelet-fibrin clot), LY30 (percent of clot lysis at 30 min after MA is reached) and the CI (the overall coagulability). RESULTS: The overall coagulation index of the entire study population was significantly increased on the day of ovum pickup as compared to the early follicular phase. This increase in the coagulation index was also significant in a subanalysis of patients triggered with rhCG. Contrarily, there was no significant increase in the coagulation index in the subgroup of patients triggered with GnRH agonist. CONCLUSION: Our results demonstrate a procoagulable state in patients after ovulation induction. Final triggering with GnRH agonist rather than rhCG, might lower this hypercoagulability pattern.

Health and functioning of adolescents conceived by assisted reproductive technology.

OBJECTIVE: To evaluate the general health, mental health, and cognitive ability of assisted reproductive technology (ART)-conceived adolescents. DESIGN: A nested case-control study within a historic cohort. SETTING: Not applicable. PATIENT(S): A total of 253 ART-conceived adolescents born between 1982 and 1993 and 253 matched references according to birth year, gender, and the high-school they attended. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Medical and psychiatric diagnoses, and cognitive ability recorded at the military preinduction screening (ages 16-17 years) and doctor's appointments throughout the military service. RESULT(S): No differences were detected in general and mental health of ART adolescents or cognitive ability, compared with the reference group. Similar results were obtained after stratification for gender and singleton births. The ART adolescents had fewer cases of discharge from military service due to health reasons (4% vs. 8.3%). Follow-up during the military service revealed that male ART adolescents had significantly more doctor's appointments compared with the reference group (23.80 ± 15.59 vs. 19.95 ± 13.79). CONCLUSION(S): Our preliminary results provide reassurance that in the long-run health and functioning of ART-conceived adolescents is not compromised. Further studies with larger cohorts are needed to confirm these results.

Clinical benefit using sperm hyaluronic acid binding technique in ICSI cycles: a systematic review and meta-analysis.

The human oocyte is surrounded by hyaluronic acid, which acts as a natural selector of spermatozoa. Human sperm that express hyaluronic acid receptors and bind to hyaluronic acid have normal shape, minimal DNA fragmentation and low frequency of chromosomal aneuploidies. Use of hyaluronic acid binding assays in intracytoplasmic sperm injection (ICSI) cycles to improve clinical outcomes has been studied, although none of these studies had sufficient statistical power. In this systematic review and meta-analysis, electronic databases were searched up to June 2015 to identify studies of ICSI cycles in which spermatozoa able to bind hyaluronic acid was selected. The main outcomes were fertilization rate and clinical pregnancy rate. Secondary outcomes included cleavage rate, embryo quality, implantation rate, spontaneous abortion and live birth rate. Seven studies and 1437 cycles were included. Use of hyaluronic acid binding sperm selection technique yielded no improvement in fertilization and pregnancy rates. A meta-analysis of all available studies showed an improvement in embryo quality and implantation rate; an analysis of prospective studies only showed an improvement in embryo quality. Evidence does not support routine use of hyaluronic acid binding assays in all ICSI cycles. Identification of patients that might benefit from this technique needs further study.

A randomized trial comparing time intervals from HCG trigger to intrauterine insemination for cycles utilizing GnRH antagonists.

Intrauterine insemination (IUI) during ovarian stimulation cycles is typically performed 36 hours after human chorionic gonadotropin (hCG) injection. We hypothesized that adjusting the time interval to IUI to better coincide with ovulation may increase pregnancy rates. Patients undergoing induction of ovulation utilizing gonadotropins and gonadotropin releasing hormone (GnRH) antagonists and IUI were divided to three groups based on the time from hCG injection to IUI: 36, 42, and 48 hours. Primary outcome was defined as the clinical pregnancy rate. Secondary outcomes comprised additional parameters including multifetal pregnancy rate. A total of 92 patients completed the study. Baseline parameters were similar between the groups. The clinical pregnancy rate in the three groups was 20%, 38%, and 24%, respectively. While the 42 hour time interval had a higher numerical pregnancy rate, the pregnancy rates did not differ statistically among the study groups. The multifetal pregnancy rate did not differ among the three groups as well. A larger study is necessary to ascertain if a 42 hour time interval can indeed improve pregnancy rates.

Lag time from ovulation trigger to oocyte aspiration and oocyte maturity in assisted reproductive technology cycles: a retrospective study.

OBJECTIVE: To study the correlation between the lag time from ovulation trigger to oocyte aspiration and the proportion of metaphase II (MII) mature oocytes aspirated. DESIGN: Retrospective study. SETTING: Fertility and IVF center in an academic regional hospital. PATIENT(S): A total of 511 women undergoing IVF-intracytoplasmic sperm injection at our center, with at least one oocyte available for maturity determination. INTERVENTION(S): Data were retrieved from patient electronic databases and files. Demographic data, hormone treatments and ovarian response, and the time of ovulation trigger and oocyte aspiration were recorded. MAIN OUTCOME MEASURE(S): The primary outcome was the proportion of MII mature oocytes relative to the total number of oocytes aspirated and allocated to intracytoplasmic sperm injection. Pregnancy rates and clinical pregnancy rates were secondary outcomes. RESULT(S): There were fewer MII mature oocytes when the lag time between oocyte trigger and aspiration was between 33.45 hours and 34.45 hours. The proportion of MII oocytes seems to increase up to a 35-hour lag time and then stabilizes up to 38 hours. Pregnancy and clinical pregnancy rates did not differ among the different time groups studied. CONCLUSION(S): Oocyte aspiration should be scheduled at least 35 hours after ovulation trigger. Oocytes can be aspirated in a 3-hour window of time between 35 and 38 hours without compromising results. Further research should elucidate whether even longer lag times will improve the proportion of MII mature oocytes.

Rescue intracytoplasmic sperm injection: a systematic review.

OBJECTIVE: To assess the feasibility, efficacy, and safety of rescue intracytoplasmic sperm injection (ICSI) in cases of fertilization failure, using a scientific literature search. DESIGN: Systematic review. SETTING: Centers for reproductive care. PATIENT(S): Infertility patients with total or partial fertilization failure during an IVF cycle. INTERVENTION(S): An electronic literature search was performed in PubMed from 1992 through May 2013. The search was then expanded by using listed references from selected articles. MAIN OUTCOME MEASURE(S): Pregnancy rate. The secondary outcome measures were fertilization rate, normal fertilization rate, cleavage rate, birth rate, and malformation rate. RESULT(S): Thirty-eight studies including 1,863 patients were included. The pooled pregnancy rate was 14.4%; 194 babies were delivered. CONCLUSION(S): Rescue ICSI can result in the delivery of a healthy newborn, although the pregnancy rates are low. The clinical evidence did not indicate an elevated rate of malformations, although the data are limited and incomplete.

Haptoglobin phenotypes and in vitro fertilization treatment outcomes.

The haptoglobin (Hp) protein has been implicated in various aspects of reproduction. One possible mechanism is through its effect on angiogenesis. Angiogenesis plays a major role in follicle production. The Hp insertion polymorphism results in the production of Hp proteins denoted Hp 1-1, 2-1, and 2-2, with markedly different angiogenic activities. We sought to determine if the number of oocytes aspirated during in vitro fertilization is related to the Hp type and to compare clinical data and treatment outcomes. We conducted a prospective non-interventional study in an academic in vitro fertilization center serving northern Israel. All patients undergoing in vitro fertilization who agreed to have their haptoglobin phenotype and clinical data evaluated anonymously were included. The main outcome measure was the number of oocytes harvested from each aspiration. The groups did not differ regarding ethnicity or BMI, though women with the Hp1-1 phenotype had a longer duration of infertility (p = 0.037) and a higher gonadotropin requirement (p = 0.024) to achieve the same treatment outcome. Women with mechanical factor infertility were more likely (p = 0.042) to have the Hp 1-1/2-1 phenotypes than the Hp2-2 phenotype. There were no differences in the number of oocytes aspirated or the pregnancy rate. In summary, we could not establish a correlation between Hp phenotype and oocyte number or IVF outcomes though the Hp2-2 phenotype may be protective against mechanical factor infertility. Further studies with a larger sample size, particularly concerning the Hp1-1 phenotype, are required in order to extend these results.

Thrombophilia and stillbirth: possible connection by intrauterine growth restriction.

OBJECTIVE: To define the association between thrombophilia and unexplained stillbirth. DESIGN: A case-control study. SETTING: Obstetric department in a university affiliated hospital (Ha'Emek Medical Center, Afula). POPULATION: A total of 53 women who delivered stillborns between March 1998 and June 2002 and 59 women with unremarkable obstetric history who delivered at the same period. METHODS: Presence of genetic and acquired markers of thrombophilia was investigated. MAIN OUTCOME MEASURE: Presence or absence of thrombophilia. RESULTS: Thrombophilia was found in 34% of the women who delivered stillborns and in 20% of the 59 women with normal pregnancies (non-significant). However, significantly higher prevalence of thrombophilia (73%) was found in women who delivered small for gestational age stillborns compared with women who delivered normal birthweight stillborns (73%vs 18.4%, P < 0.0001). CONCLUSIONS: There is no association between thrombophilia and stillbirth, overall. However, there is a clear association between thrombophilia and stillbirth of extremely growth restricted infants.

Clinical and ultrasonographic weight estimation in large for gestational age fetus.

OBJECTIVE: To examine prospectively the effect on pregnancy outcome of a management protocol, that adds ultrasonographic weight estimation in fetuses suspected clinically as large. STUDY DESIGN: Prospective follow up study of all singleton deliveries during a 1 year period. All patients underwent routine clinical estimation of fetal weight. When clinical estimation of fetal weight was > or = 3700 g, patients were referred for ultrasonographic estimation of fetal weight. When the latter was > or = 4000 g the patient was informed about the risks of birth trauma. Cesarean section was recommended only when > or = 4500 g. Ultrasonography was repeated every 4 days when possible. Predictive values of clinical and ultrasonographic estimations of fetal weight for diagnosing macrosomia, defined for the purpose of this study as 4000 g or more, and their effect on the rate of cesarean sections. RESULTS: Five hundred fifty-five (14.4%) out of 3844 singletons were estimated as 3700 g or more. Only 315 fetuses had ultrasonographic estimation of weight within 3 days of delivery. The sensitivity of clinical and ultrasonographic prediction of macrosomia was 68 and 58%, respectively. Cesarean section rate in newborns weighing 4000 g or more was 22% when macrosomia was clinically suspected compared to 11% when it was not (P<0.05). In fetuses estimated ultrasonographically as 4000 g or larger the cesarean section rate was doubled (50.7% versus 24.9%, P<0.05) compared to those estimated as smaller than 4000 g, although actual weight of 4500 g or more was recorded in 10.6 and 8.5% of these groups, respectively. There were no cases of shoulder dystocia in macrosomic babies when macrosomia was not detected by ultrasound compared to two cases of shoulder dystocia (2.7%) when macrosomia was detected by ultrasound. CONCLUSION: Antenatal suspicion of macrosomia increased the cesarean section rate while the associated improvement in pregnancy outcome remains questionable. The contribution of ultrasound, added to routine clinical estimation of fetal weight, was clinically insignificant apart from a further increase in cesarean section rate.