Does gonadotropin-releasing hormone agonist cause luteolysis by inducing apoptosis of the human granulosa-luteal cells?

OBJECTIVES: To evaluates the effect of different modes of final follicular maturation triggering on the degree of apoptosis of granulosa cells (GCs) and the potential effect on progesterone secretion. METHODS: Thirty patients undergoing controlled ovarian hyperstimulation for IVF who received hCG, GnRH agonist, or dual trigger for final follicular maturation were included in the study. Granulosa cells were obtained at the time of oocyte retrieval. The proportion of apoptotic cells was evaluated via TUNEL and immunohistochemistry. RESULTS: The proportion of apoptotic cells was significantly higher in the GnRH agonist-alone group compared to hCG-alone and the dual trigger groups (13.5 ± 1.5% vs. 7.8% ± 1.8 vs. 10.1% ± 2, respectively, P < 0.01). Moreover, the expression of active-caspase-3 was also significantly increased in the GnRH agonist-alone group compared with the hCG-alone and the dual trigger groups (15.5% ± 2.9 vs. 8.4% ± 1.6 vs. 12.7% ± 2.6, respectively, P < 0.01). The progesterone levels measured in the granulosa-luteal cell culture medium after 24 h of incubation were similar between the three groups. CONCLUSIONS: The levels of apoptosis are increased after GnRH agonist/dual trigger. The increased apoptosis might be one of the culprit of the subsequent premature demise of the corpus luteum post GnRH agonist trigger.

Does macroscopic estimation of the extent of placental abruption correlate with pregnancy outcomes?

INTRODUCTION: We aimed to study the correlation between the extent of placental abruption (PA), as grossly estimated immediately after delivery, and pregnancy outcomes, in correlation with placental histopathology. MATERIALS AND METHODS: Pregnancy and placental reports of all pregnancies complicated by PA (clinically diagnosed) between 11/2008-12/2018 were reviewed. We compared maternal background, pregnancy outcomes, and placental histopathology between cases of PA divided into three groups according to the extent of abruption: Group 1-<30 %, Group 2-30-49 %, and Group 3->50 % of placental surface. Placental lesions were classified according to the current "Amsterdam" criteria. The primary outcome was defined as a composite of severe neonatal morbidity and included ≥ 1 of the following complications: seizures, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, periventricular leukomalacia, blood transfusion, necrotizing enterocolitis, intrauterine fetal demise, or neonatal death. RESULTS: A total of 260 PA cases were included: 111 (42.7 %) in Group 1, 94 (36.2 %) in Group 2, and 55 (21.1 %) in Group 3. The rate of the primary outcome (7.2 % vs. 11.7 % vs. 27.3 %, p = 0.02) was associated with the degree of PA as well as maternal heavy smoking (p = 0.04), DIC (p = 0.03), umbilical artery Ph <7.1 (p = 0.02), 5-minute Apgar scores <7 (p = 0.03), NICU admissions, placental maternal vascular malperfusion lesions (p = 0.04), and neonatal weights <5th percentile (0.04). In multivariable analysis severe adverse neonatal outcome was independently associated with the percentage of PA (aOR = 1.4, 95 % CI = 1.3-3.9). CONCLUSION: The extent of placental abruption, as estimated by the examiner, correlated with DIC and severe neonatal outcomes and may serve as an early alarming sign in deliveries complicated by PA.

Enhancing patient mobility following cesarean-delivery - the efficacy of an improved postpartum protocol assessed with pedometers.

BACKGROUND: The incidence of thromboembolic complications is highest in the immediate postpartum period, especially following caesarean delivery (CD). Ambulation following CD is important in their prevention. We examined the effect of an educational protocol on patients' mobility following CD, with the use of digital step counters (pedometers). METHODS: Starting February 2018, we implemented an educational protocol at the maternity ward, which included nurses' tutoring and subsequent patients' education, regarding the importance of early ambulation. Following CD, ambulation was initiated 4 h following surgery (as compared to 6 h prior). Scheduled IV acetaminophen was administered at six-hour intervals for 48 h (as compared to only 24 h prior), while additional analgesics were given upon patient request. We compared maternal demographics, delivery and postpartum course between the pre-protocol group (n = 101) and the post-protocol group (n = 100). All patients were asked to wear pedometers for 48 h following the delivery to assess ambulation. RESULTS: Patients' demographics, surgical and post-partum course were non-significant between the groups, except for surgical length (48.5 ± 14.6 vs. 53.5 ± 15.3 min in the pre and post protocol groups, respectively, p = 0.02). The pre-protocol group was treated with more additional analgesics (p = 0.02). A higher number of steps was taken in the post-protocol group as compared to the pre-protocol group (4394 ± 2985 vs.3551 ± 2931, respectively p = 0.04). In a linear regression analysis in which the number of steps served as the dependent variable, this educational protocol was independently associated with a higher number of steps [coefficient 988 steps, 95% CI 137-1838, p = 0.02], as was smoking, after adjustment for surgical length, emergent surgery, maternal age and body mass index. CONCLUSION: An educational protocol which included earlier ambulation and regular interval pain control was associated with improved ambulation following CD.

Effect of Digital Step Counter Feedback on Mobility After Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of a personalized repeated feedback approach using digital step counters (pedometers) on mobility after cesarean delivery in high-risk patients. METHODS: This was a randomized controlled trial at a tertiary university hospital. Patients who underwent cesarean delivery and were defined as high risk for thromboembolic events were asked to wear a pedometer around their wrists postpartum for 48 hours. Patients were randomized to the feedback group, which received personalized feedback by the research staff regarding their mobility at three set timepoints, or the control group, which received standard care. The number of steps taken by patients was compared between the groups and served as the primary outcome. Secondary outcomes included patient reported pain, physical and mental recovery, and overall satisfaction. Sample size was predetermined to detect a 25% between-group difference in the primary outcome. RESULTS: From December 2018 to July 2019, 215 patients were recruited, randomized and completed follow-up-108 in the feedback group and 107 in the control group. Patients' demographics and intrapartum course were similar between the groups. The number of steps taken was significantly higher in the feedback group compared with the control group: 5,918±3,116 vs 4,161±2,532 steps, P<.001. Pain scores were similar between the groups, as was analgesic consumption. Patients in the feedback group reported a significantly easier physical and mental postpartum recovery and were significantly more satisfied with their delivery experience. Postpartum complications did not differ between the groups. CONCLUSION: In high-risk patients after cesarean delivery, mobility was improved by using a personalized feedback approach. Enhanced mobility was not associated with a higher rate of complications or pain and was positively associated with patient satisfaction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03724760.

The role of umbilical cord gas studies in the prediction of adverse neonatal outcomes in scheduled nonlaboring term singleton cesarean deliveries.

BACKGROUND: Most major societies do not state a specific recommendation against or in favor of routine umbilical cord gas studies sampling. OBJECTIVE: We aimed to study the correlation between abnormal umbilical cord gas studies (using 5 different definitions) and adverse neonatal outcomes in scheduled nonlaboring term singleton cesarean deliveries. STUDY DESIGN: The medical charts, surgical records, and neonatal charts of all singleton cesarean deliveries at 370/7-416/7 weeks of gestation between January 2009 and May 2018 from a single tertiary center were reviewed. The cohort of singleton cesarean deliveries was divided into those with "normal" vs "abnormal" umbilical cord gas studies with the 5 different definitions: (1) definition A: pH ≤7.15; (2) definition B: pH ≤7.15 and base excess ≤-12 mmol/L; (3) definition C: pH ≤7.1l (4) definition D: pH ≤7.1 and base excess ≤-12 mmol/L, and (5) definition E: pH <7.0 and base excess ≤-12 mmol/L. Adverse neonatal outcomes included Apgar scores at 5 minutes ≤7, neonatal sepsis, blood transfusion, phototherapy, respiratory morbidity (presence of respiratory distress syndrome, transient tachypnea of the newborn infant, mechanical ventilation, need for respiratory support, or meconium aspiration), cerebral morbidity (presence of intraventricular hemorrhage, seizures, or hypoxic-ischemic encephalopathy), necrotizing enterocolitis, or death. Composite adverse outcome was ≥1 of the aforementioned complications. RESULTS: Overall, 3001 singleton cesarean deliveries were included. The rate of abnormal umbilical cord gas studies with the use of definitions A-E was 2.6%, 0.3%, 1.2%, 0.3%, and 0.1%, respectively. The overall rate of adverse neonatal outcome for the entire cohort was 14.43% (433/3001). There was no correlation between abnormal umbilical cord gas studies and composite adverse neonatal outcome with the use of any of the definitions A-E (P=.2, P=.3, P=.2, P=.3, P=.1, respectively). The sensitivity and specificity of abnormal umbilical cord gas studies as a predictor of composite adverse neonatal outcome were calculated for each of the abnormal umbilical cord gas studies definitions; although the sensitivity was extremely low (0-2.07%), the specificity was high (97.2-99.9%) CONCLUSION: Abnormal umbilical cord gas studies are an uncommon finding in cases of singleton term singleton cesarean deliveries and do not correlate with adverse neonatal outcomes. Therefore, the clinical usefulness and cost-effectiveness of obtaining these studies routinely should be questioned.

The VEGF and PEDF levels in the follicular fluid of patients co- treated with LETROZOLE and gonadotropins during the stimulation cycle.

BACKGROUND: Previous studies have shown that androgens, in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. Recent studies have shown that aromatase inhibitor, letrozole, improves ovarian response to FSH in normal and poor responder patients, possibly by increasing intraovarian androgen levels. Studies in mice also showed an effect of letrozole to increase pigment epithelium-derived factor (PEDF) and to lower vascular epithelial growth factor (VEGF), which might be expected to reduce the risk of ovarian hyperstimulation syndrome (OHSS) with stimulation. The aim of this study was to compare the VEGF and PEDF levels in the follicular fluids of normal responders treated with letrozole and gonadotropins during the ovarian stimulation with patients treated with gonadotropins only. METHODS: A single center, prospective clinical trial. We collected follicular fluid from 26 patients, on a GnRH antagonist protocol, dual triggered with hCG and GnRH agonist. The patients in one group were co-treated with letrozole and gonadotropins during the ovarian stimulation and the patients in the other group were treated with gonadotropins only. VEGF, PEDF, estrogen, progesterone and testosterone levels were measured by ELISA kits. RESULTS: The age of the patients, the total dose of gonadotropins and the number of oocytes were comparable between the two groups. In the follicular fluid, the estrogen levels (2209 nmol/l vs. 3280 nmol/l, p = 0.02) were significantly decreased, and the testosterone levels (246.5 nmol/l vs. 40.7 nmol/l, p < 0.001) were significantly increased in the letrozole group compared to the gonadotropin only group. The progesterone levels (21.4 µmol/l vs. 17.5 p = NS) were comparable between the two groups. The VEGF levels (2992 pg/ml vs. 1812 pg/ml p = 0.02) were significantly increased and the PEDF levels (9.7 ng/ml vs 17.3 ng/ml p < 0.001) were significantly decreased in the letrozole group. CONCLUSIONS: Opposite to observations in the mouse, we found that VEGF levels were increased and PEDF levels were decreased in the follicular fluid in patients treated with letrozole during the stimulation cycles. Further investigation is required to determine if patients treated with letrozole during the IVF stimulation protocol are at increased risk for developing OHSS as a result of these findings.