Congenital anomaly and perinatal outcome following blastocyst- vs cleavage-stage embryo transfer: systematic review and network meta-analysis.

OBJECTIVES: To compare the reported rate of any congenital anomaly and perinatal outcome of pregnancy following blastocyst- vs cleavage-stage embryo transfer using a pairwise meta-analysis and to evaluate the same outcomes following fresh-blastocyst, frozen-blastocyst, fresh-cleavage or frozen-cleavage embryo transfer using a network meta-analysis. METHODS: A literature search was performed in PubMed, Scopus and CENTRAL and registers for ongoing studies, from inception to February 2022, for randomized controlled trials (RCTs) with any sample size and observational studies including at least 100 live births per group, comparing the rates of any congenital anomaly and perinatal outcome of pregnancy following fresh/frozen embryo transfer at cleavage (day 2-3) vs blastocyst (day 5-7) stage. Risk ratios (RRs) along with their 95% CIs were pooled via a random-effects model meta-analysis. Within a frequentist network meta-analysis framework, outcomes of all four treatment modalities (i.e. fresh-blastocyst, fresh-cleavage, frozen-blastocyst, frozen-cleavage) were compared further. Any congenital anomaly constituted the primary outcome, whereas preterm delivery (delivery < 37 weeks), low birth weight (LBW; < 2500 g), gender of the neonate (male), perinatal death and healthy neonate (defined as liveborn neonate, delivered at term, weighing ≥ 2500 g, surviving for at least 28 days postbirth and without any congenital anomaly) were considered as secondary outcomes. Subgroup analyses by plurality (liveborn singleton vs multiple pregnancy) were conducted in the pairwise and network meta-analyses. The risk of bias was assessed using the RoB2 tool for RCTs and the ROBINS-I tool for non-randomized studies. Certainty of evidence was assessed using GRADE. RESULTS: Through the literature search, 550 studies were retrieved and 33 were included in the systematic review. We found no significant difference in the risk for any congenital anomaly between blastocyst- and cleavage-stage transfer (RR, 0.80 (95% CI, 0.63-1.03); 10 studies; n = 192 442; I2 = 85.5%). An increased probability of a male neonate was observed following blastocyst- vs cleavage-stage transfer (RR, 1.07 (95% CI, 1.06-1.09); 18 studies; n = 227 530; I2 = 32.7%). No significant differences in other secondary outcomes or significant subgroup differences between liveborn singletons and multiple pregnancies were observed. The network meta-analysis showed a significantly lower risk for LBW following frozen-blastocyst vs fresh-blastocyst (RR, 0.76 (95% CI, 0.60-0.95)) or fresh-cleavage (RR, 0.74 (95% CI, 0.59-0.93)) transfer. Frozen-blastocyst transfer was associated with an increased risk for perinatal death compared with the fresh-cleavage method (RR, 2.06 (95% CI, 1.10-3.88)). The higher probability of a male neonate following blastocyst transfer remained evident in the network comparisons. All outcomes were assessed to be of very-low certainty of evidence. CONCLUSIONS: Current very-low certainty of evidence shows that there may be little-to-no difference in the risk for congenital anomaly or adverse perinatal outcome of pregnancy following blastocyst- vs cleavage-stage embryo transfer, although there was a slightly increased probability of a male neonate following blastocyst transfer. When considering cryopreservation, frozen-blastocyst transfer was associated with a reduction in the risk for LBW compared with both fresh-transfer modalities, and fresh-cleavage transfer may be associated with a reduction in the risk for perinatal death compared with frozen-blastocyst transfer. High-quality RCTs with separate data on fresh and frozen cycles and consistent reporting of culture conditions and freezing methods are mandatory. Individual participant data meta-analyses are required to address the substantial inconsistency resulting from current aggregate data approaches. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Effect of human papilloma virus infection on in-vitro fertilization outcome: systematic review and meta-analysis.

OBJECTIVES: To identify, appraise and summarize the available data concerning the impact of human papilloma virus (HPV) infection on reproductive outcome following in-vitro fertilization (IVF). METHODS: We searched for studies in PubMed, EMBASE, Scopus, Lilacs and the Cochrane Central Register of Controlled Trials from inception to March 2017. Any type of HPV infection assessed through polymerase chain reaction, subfertility factors and IVF indications and protocols were considered. Our primary outcomes were live birth/ongoing pregnancy and miscarriage, while secondary outcomes included clinical and laboratory parameters. We planned subgroup analyses according to the status of cervical cytology and presence of infection in the male partner. We assessed the relative risk (RR), using a random-effects model; heterogeneity was assessed using the I2 statistic. Quality of the evidence was evaluated using the recommendations of the GRADE Working Group. RESULTS: From the 14 studies eligible for inclusion, quantitative data from 10, evaluating 299 women with HPV infection and 2049 women without HPV infection, were included in the analysis. The pooled results showed no significant difference between HPV-infected and non-infected women in rates of live birth/ongoing pregnancy (RR, 1.16 (95% CI, 0.88-1.53); I2 = 0%; six studies, 983 women), clinical pregnancy (RR, 1.06 (95% CI, 0.74-1.54); I2 = 61%; eight studies, 1173 women) or miscarriage (RR, 1.58 (95% CI, 0.93-2.69); I2 = 8%; six studies, 290 clinical pregnancies). The overall quality of the evidence was very low, downgraded two levels because of serious limitations of the included studies (observational studies) and imprecision. In contrast, pooled results in the subgroup analysis based on the presence of infection in the male partner showed significant differences in rates of live birth/ongoing pregnancy (RR, 0.43 (95% CI, 0.23-0.82); I2 = 0%; three studies, 429 participants; P = 0.01) and miscarriage (RR, 3.70 (95% CI, 1.94-7.05); I2 = 0%; two studies, 90 participants; P < 0.0001). CONCLUSIONS: The available evidence is still inadequate to enable us to draw firm conclusions regarding the effect of HPV infection in women on the most important reproductive outcomes following IVF; however, it suggests that the effect is not large for rates of live birth/ongoing pregnancy and clinical pregnancy. When infection is present in the male partner, it seems that there is a negative effect on live birth/ongoing pregnancy rate and an increase in miscarriage rate, a finding that should be interpreted with caution, owing to the very low quality of evidence supporting it. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Interleukin 15 concentrations in follicular fluid and their effect on oocyte maturation in subfertile women undergoing intracytoplasmic sperm injection.

PURPOSE: To calculate the concentrations of interleukin 15 (IL-15) in follicular fluid (FF) and evaluate their relation with oocyte maturation, follicle size, and patients' body mass index (BMI) and age. METHODS: Follicular fluid specimens were obtained from 56 subfertile women undergoing intracytoplasmic sperm injection (ICSI) during oocyte retrieval for measurement of IL-15 concentrations with ELISA. Wilcoxon's test and Pearson's correlation coefficient were used to correlate FF concentrations of IL-15 with follicular size and stage of oocyte maturation, along with patients' BMI and age. RESULTS: IL-15 concentrations in FF of follicles with immature oocytes were significantly greater than those from follicles with mature ones (median 5.333 vs. 3.250 pg/ml, respectively, p < 0.001). There was a significant negative correlation between IL-15 concentrations and follicle size (r = - 0.333, p = 0.003). No significant correlation was observed between IL-15 concentrations and patients' BMI and age (p > 0.05). CONCLUSIONS: IL-15 concentrations in FF are adversely related with the size of the follicles and the maturity of the corresponding retrieved oocytes in a cohort of expected normal responders undergoing intracytoplasmic sperm injection (ICSI). Follicular fluid concentrations of IL-15 should be investigated as a possible predictive factor for oocyte maturity.

Preeclampsia: What Does the Father Have to Do with It?

Preeclampsia (PE) is one of the leading causes of maternal and fetal morbidity and mortality, with incidence rates ranging between 2 and 5 % in the Western World. The exact causes of the disease remain largely unknown, because of the complex pathophysiologic mechanisms involved in the process. Genetic, environmental, and epigenetic parameters have been implicated by various authors as culprits for the pathogenesis of PE. Recent reports in the literature highlight the paternal role. Still, the exact extent and mechanism remain elusive. In this systematic review, we attempt to present data regarding the paternal role in a concise and comprehensive manner.

Reactive oxygen species in the follicular fluid of subfertile women undergoing In Vitro Fertilization: a short narrative review.

Reactive Oxygen Species (ROS) are produced as a normal product of aerobic metabolism. Naturally, there is an array of protective mechanisms that neutralize ROS, while any potential imbalance between ROS and antioxidants results in oxidative stress. In an In Vitro Fertilization (IVF) setting, existing literature suggests a favorable outcome in terms of oocyte quality/maturation and fertilization rate with increased ROS levels, while other study groups have presented significant data on the detrimental effect of increased ROS concentration in the quality of embryos exposed and their potential to advance. In this study, we examine the conflicting views of the role of ROS in fertilization and embryo quality, especially through their concentration in the follicular fluid of subfertile women undergoing IVF. The current debate could possibly be attributed to the different assay methods and end-point outcomes employed by each research group, along with the noted limited number of the relevant studies published on the subject. Properly conducted studies can further validate and elicit the exact role of ROS as well as their association to female reproduction, and especially to women undergoing IVF.

Clinical complications after transvaginal oocyte retrieval: a retrospective analysis.

There are little systematic data reported in the literature on complications observed after transvaginal oocyte retrieval (OR) guided by ultrasound. We report our experience in 542 in vitro fertilisation cycles. The frequency of severe complications in our patients was 0.72%; of these, two cases were bronchospasm during anaesthesia (0.36%) and two were cases of intraperitoneal bleeding (0.36%); minor vaginal bleeding was the most frequent complication (18.08%), which was treated easily. Through this retrospective analysis, it is evident that clinical suspicion is of particular importance in detecting post-OR complications on one hand, but on the other these complications are rare and most are treated conservatively.

The practical role of anti-Müllerian hormone in assisted reproduction.

The objective of this study was to offer a brief critical summary of the literature on the role of AMH in the subfertility work up and during ART, while exploring its role in predicting ART success.

Mediators of chronic inflammation in polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is an endocrine disorder affecting 5-10% of reproductive-age women. Hyperandrogenemia, which characterizes the syndrome, stimulates the maturation of adipocytes and favors central obesity. The linking hub between obesity and other metabolic manifestations of the syndrome seems to be chronic low-grade inflammation. We discuss the most reliable current data regarding the role of inflammatory mediators in PCOS, with particular focus on the genetic mechanisms implicated. C-reactive protein levels are 96% higher in PCOS patients than in healthy controls. Patients with the -308A polymorphism of the tumor necrosis factor-α gene have elevated androgens in comparison with carriers of the -308G. Interleukin 18 (IL-18) is elevated in lean patients, with a further rise in the presence of obesity and insulin resistance. Polymorphisms of the IL-1a, IL-1b and IL-6 genes have also been associated with PCOS. Plasminogen activator inhibitor-1 levels are positively associated with the syndrome, and carriers of the 4G allele of the 4G/5G polymorphism are at risk of developing PCOS. Other mediators discussed include adhesion molecules, osteoprotegerin, asymmetric dimethylarginine, homocysteine and advanced glycation end-products. The elucidation of the pathogenetic mechanisms implicated in PCOS and their connection with low-grade inflammation may in the future offer the opportunity for the formulation of novel therapeutic strategies and individualized therapy for these patients.

Ovarian carcinosarcoma: a case report, diagnosis, treatment and literature review.

BACKGROUND/AIM: This report aims to present a rare case of ovarian carcinosarcoma and its current, optimal diagnosis and therapy strategy. DESCRIPTION OF CASE: We report the case of a 70-year-old patient, who presented at the Obstetrics and Gynecology Department of the University Hospital of Mainz, with a short history of increased abdominal circumference. CONCLUSION: The symptoms, diagnosis, and therapy of carcinosarcoma follow the pattern of a high grade epithelial ovarian cancer, fallopian cancer and primary peritoneal cancer. The rarity of this disease is a barrier to conducting prospective trials and establishing guidelines for high-quality evidence data. Hippokratia 2015; 19 (3): 256-259.

Three cases of diabetes insipidus complicating pregnancy.

Diabetes insipidus (DI) is a rare complication of pregnancy. In cases related to pregnancy, the condition is thought to result from enhanced placental clearance of arginine vasopressin secondary to placental vasopressinase production. In such cases careful monitoring of the patient's fluid balance during and after pregnancy is essential. If treatment is necessary, desmopressin is the drug of choice. In the present article, we present three cases of pregnancy complicated by DI.

Spinal and epidural versus general anesthesia for elective cesarean section at term: effect on the acid-base status of the mother and newborn.

OBJECTIVE: To compare general, epidural and combined spinal-epidural anesthesia with respect to short-term outcome of newborns delivered by elective Cesarean section of healthy parturients with normal pregnancies. STUDY DESIGN: A total of 238 eight pregnant women admitted to our institution between January 1998 and July 2002, for whom elective Cesarean section was planned after 38 weeks' gestation, were grouped according to the kind of anesthesia used for the procedure. Maternal characteristics, birth weight, Apgar scores, and maternal and umbilical artery (UA) acid-base parameters were analyzed. RESULTS: Maternal pH was significantly lower and pCO2: and pO2 were significantly higher in the general anesthetic group, compared to the other two groups (7.38 +/- 0.03 vs. 7.43 +/- 0.02 and 7.43 +/- 0.05, respectively; 35.03 +/- 3.88 mmHg vs. 29.25 +/- 5.05 mmHg and 29.64 +/- 4.16 mmHg, respectively; and 224.56 +/- 86.77 mmHg vs. 151.28 +/- 38 mmHg and 157.36 +/- 53.51 mmHg, respectively, p < 0.05). The pH of the UA was higher in the general anesthetic group, compared to the spinal-epidural group (7.29 +/- 0.02 vs. 7.26 +/- 0.06, p < 0.05). The pO2 as well as O2 saturation of the UA were higher when general anesthetic was administered, compared to the two regional modalities (15.60 +/- 5.48 mmHg vs. 9.29 +/- 4.41 mmHg and 9.20 +/- 4.06 mmHg, respectively; and 17.37 +/- 9.79% vs. 7.87 +/- 4.98% and 6.90 +/- 5.22%, respectively, p < 0.05). UA O2 saturation fell to zero in some cases in the combined spinal-epidural group, without an evident effect on fetal well-being. No fetal acidemia was noted in any group. Neonatal outcomes were similar in the three groups studied. CONCLUSIONS: Type of anesthesia does not influence short-term outcomes in infants born via elective Cesarean section, although differences in acid-base status of both the mother and especially the newborn recommend careful use of spinal anesthesia.

Soluble Fas and Fas-ligand levels in mid-trimester amniotic fluid and their associations with severe small for gestational age fetuses: a prospective observational study.

We aimed to determine the second-trimester amniotic fluid (AF) levels of soluble Fas (sFas) and Fas-ligand (FasL) and investigate their association with fetal growth. Therefore, sFas and FasL levels were measured by enzyme immunoassay in the AF of 21 small for gestational age (SGA), 13 large for gestational age (LGA), and 44 appropriate for gestational age (AGA) fetuses of pregnant women who underwent amniocentesis at between 15 and 22 weeks gestation. Our study results showed that sFas and FasL levels were detectable in AF. sFAS median (25th-75th centile) levels were 3.8 (2.8-4.6) ng/ml in SGA, 3.6 (3.1-4.5) ng/ml in AGA, and 4.0 (3.1-4.4) ng/ml in LGA. FasL median (25th-75th centile) levels were 26.0 (20.3-32.7) pg/ml in SGA, 22.7 (18.4-28.5) pg/ml in AGA, and 21.5 (15.8-30.9) pg/ml in LGA. The differences were not statistically significant. Nevertheless, statistically significant differentiation of FasL levels existed when SGA fetuses in the extremes of distribution (≤5th, ≤2.5th centile) were considered. This is the first study presenting sFas and FasL concentrations in early second-trimester amniotic fluid in AGA, SGA, and LGA fetuses. We found indications that severe and very severe SGA fetuses (≤5th and ≤2.5th centile) have high levels of FasL in the amniotic fluid. This finding probably reflects the increased rate of apoptosis that is assumed to exist in cases of extreme growth restriction.

Progress in evidence based reproductive surgery.

The Consolidated Standards of Reporting Trials (CONSORT) was introduced in 1996 to improve the methodological quality of published reports of randomised controlled trials. By doing a systematic review of randomised controlled trials on reproductive surgery, our group can demonstrate that the overall quality of the published reports of randomised studies on reproductive surgical interventions has improved after CONSORT. Nevertheless, some problems still -remain. By discussing the benefits and pitfalls of randomised trials in reproductive surgery, our opinion paper aims to stimulate the reader's further interest in evidence-based practice in reproductive surgery.

What should be the maximum FSH dose in IVF/ICSI in poor responders?

Various protocols of ovarian stimulation have been proposed for optimising IVF/ICSI results in women presenting with a poor response to controlled ovarian stimulation; however, achieving a good response to stimulation for this category of patients still remains a challenge. The most extensively employed strategy to improve follicular response in these so-called 'poor responders' involves the use of high doses of gonadotrophins. A small number of randomised controlled trials and retrospective studies have evaluated the effectiveness of the high-dose FSH regimes over a 300 IU threshold. The results of these studies have shown these approaches to be of little or no clinical benefit, although both the costs of treatment and side-effects were higher. There are other studies that have examined 450 IU FSH regimens or even more. This paper presents an overview in all these clinical trials, trying to evaluate the safest and most effective upper limit of FSH that may be used for controlled ovarian hyperstimulation.