New Insights on the Biomechanics of the Fetal Membrane.

During pregnancy, the Fetal Membrane (FM) is subjected to mechanical stretching that may result in preterm labor. The structural integrity of the FM is maintained by its collagenous layer. Disconnection and reconnection of molecular bonds between collagen fibrils is the fundamental process that governs the irreversible mechanical and supramolecular changes in the FM. At a critical threshold strain, bundling and alignment of collagen fibrils alter the super-molecular structure of the collagenous layer. Recent studies indicate that these changes are associated with inflammation and/or expression of specific proteins that are known to be related to uterine contractions and labor. The potential healing of stretching-induced damages in the FM by mediators involved in mechano-transduction is discussed.

Association between betamethasone levels and respiratory distress syndrome in preterm births: A prospective cohort study.

The recommended fixed dosage of betamethasone for pregnancies at risk of preterm birth was determined in the 1970s, regardless of gestational age (GA), number of fetuses, and maternal weight. We aimed to examine the association between maternal and neonatal betamethasone serum levels and neonatal respiratory distress syndrome (RDS) and to examine whether levels correlate with maternal weight, GA, or number of fetuses. A prospective study was conducted at a single academic medical center between August 2016 and February 2019. Women received betamethasone and delivered between 28+0 and 34+6 weeks were included. Maternal serum levels (MSLs), and neonatal serum levels (NSLs) of betamethasone at delivery were analyzed using Corticosteroid enzyme-linked immunosorbent assay kit. RDS was diagnosed according to clinical and radiographic findings. We assumed that the sensitivity of NSLs to detect RDS is 95%; hence, 150 neonates were needed (power 80%, alpha 0.05). Overall, 124 women were included; including 96 (77.4%) singletons, 26 (21.0%) twins, and 2 (1.6%) triplets, corresponding to 154 neonates. RDS was diagnosed in 35 neonates (22.7%). After adjusting for GA, time elapsed from the last dose, and number of doses, NSLs were associated with RDS (relative risk: 0.97, 95% confidence interval: 0.94-0.99, p = 0.011). A level of 6.00 ng/ml predicted RDS with a sensitivity of 80.0% and specificity of 64.7%. Adjusted MSLs were not associated with RDS. Both maternal and neonatal serum levels were not associated with the number of fetuses and maternal weight. In conclusion, NSLs are associated with RDS whereas MSLs are not.

Fetal Biometry in the Israeli Population: New Reference Charts.

BACKGROUND: Selection of appropriate reference charts for fetal biometry is mandatory to ensure an accurate diagnosis. Most hospitals and clinics in Israel use growth curves from the United States. Charts developed in different populations do not perform well in the Israeli population. OBJECTIVES: To construct new reference charts for fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), using a large sample of fetuses examined at 14-42 weeks gestational age in a medical center and a community ultrasound unit located in two different regions of Israel. METHODS: Data from the medical center and the community clinic were pooled. The mean and standard error of each measure for each week was calculated. Based on these, reference charts were calculated using quantiles of the normal distribution. The performance of the reference charts was assessed by comparing the new values to empiric quantiles. RESULTS: Biometric measurements were obtained for 79,328 fetuses. Growth charts were established based on these measurements. The overall performance of the curves was very good, with only a few exceptions among the higher quantiles in the third trimester in the medical center subsample. CONCLUSIONS: We present new local reference charts for fetal biometry, derived from a large and minimally selected Israeli population. We suggest using these new charts in routine daily obstetric practice.

Measurement of betamethasone concentration in maternal serum treated for fetal lung maturity; Is it feasible?

BACKGROUND: The association between maternal serum concentration of betamethasone given for fetal lung maturity and perinatal outcome has not been investigated. This may be due to an absence of a reliable method for measuring serum betamethasone concentrations. We aimed in the current study to assess the feasibility of a specific ELISA kit to measure the concentrations of betamethasone in maternal serum and to examine the trend of sequential measurements after a course of betamethasone for fetal lung maturity. METHODS: Pregnant women at risk for preterm birth who received betamethasone between 24 and 34 weeks of gestation were prospectively included. Serum concentrations were determined before administering betamethasone (baseline), and 36 hours, 48 hours, 72 hours, and 5 to 7 days after the 1(st) dose. Betamethasone concentration in samples was determined using Corticosteroid ELISA kit. The Friedman test was used to test whether there were significant differences between the measurements. RESULTS: Five singleton pregnancies were included. Using the ELISA kit, betamethasone concentration in maternal serum samples was obtained for all women. Among the five measurements performed, the concentration was highest at 36 hours after the 1(st) dose and close to baseline at the 5(th) measurement performed after 5 to 7 days (p < 0.05). Serum concentration varied at each time point between the five women but similar trend was observed. CONCLUSION: Betamethasone concentration is measurable in the serum of pregnant women with this ELISA kit.

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.

Characterization of irreversible physio-mechanical processes in stretched fetal membranes.

We perform bulge tests on live fetal membrane (FM) tissues that simulate the mechanical conditions prior to contractions. Experimental results reveal an irreversible mechanical behavior that appears during loading and is significantly different than the mechanical behavior that appears during unloading or in subsequent loading cycles. The irreversible behavior results in a residual strain that does not recover upon unloading and remains the same for at least 1h after the FM is unloaded. Surprisingly, the irreversible behavior demonstrates a linear stress-strain relation. We introduce a new model for the mechanical response of collagen tissues, which accounts for the irreversible deformation and provides predictions in agreement with our experimental results. The basic assumption of the model is that the constitutive stress-strain relationship of individual elements that compose the collagen fibers has a plateau segment during which an irreversible transformation/deformation occurs. Fittings of calculated and measured stress-strain curves reveal a well-defined single-value property of collagenous tissues, which is related to the threshold strain εth for irreversible transformation. Further discussion of several physio-mechanical processes that can induce irreversible behavior indicate that the most probable process, which is in agreement with our results for εth, is a phase transformation of collagen molecules from an α-helix to a ß-sheet structure. A phase transformation is a manifestation of a significant change in the molecular structure of the collagen tissues that can alter connections with surrounding molecules and may lead to critical biological changes, e.g., an initiation of labor. STATEMENT OF SIGNIFICANCE: This study is driven by the hypothesis that pre-contraction mechanical stretch of the fetal membrane (FM) can lead to a change in the microstructure of the FM, which in turn induces a critical biological (hormonal) change that leads to the initiation of labor. We present mechanical characterizations of live FM tissues that reveal a significant irreversible process and a new model for the mechanical response of collagen tissues, which accounts for this process. Fittings of calculated and measured results reveal a well-defined single-value property of collagenous tissues, which is related to the threshold strain for irreversible transformation. Further discussion indicates that the irreversible deformation is induced by a phase transformation of collagen molecules that can lead to critical biological changes.

Precesarean Prophylactic Balloon Catheters for Suspected Placenta Accreta: A Randomized Controlled Trial.

OBJECTIVE: To examine the effect of prophylactic balloon catheters on bleeding morbidity among women with a prenatal diagnosis of placenta accreta. METHODS: In a randomized trial, women with a prenatal diagnosis of placenta accreta were randomized to either preoperative prophylactic balloon catheters (intervention group) or to a control group. Other than placement of the prophylactic balloon catheters in the anterior division of the internal iliac arteries, the same multidisciplinary approach was used in both groups. The primary study outcome was the number of packed red blood cell (RBC) units transfused. To detect a mean reduction of three packed RBC units with the prophylactic balloon catheters, 12 women in each group were needed. RESULTS: Between January 2009 and March 2015, 27 women were randomized: 13 in the intervention group and 14 in the control group. Demographic and obstetric characteristics were similar between the groups. Six (46.2%) women in the intervention and seven (50.0%) in the control group underwent cesarean hysterectomy (P=.84). There were no significant differences between the intervention and control groups in the mean number of packed RBC units transfused, 5.2 (±6.2) and 4.1 (±3.8), respectively (P=.90), or in the calculated blood loss, 4,950 (±5,051) and 4,709 (±3,434) mL (P=.72). The number of women with blood loss greater than 2,500 mL, number of plasma products transfused, duration of surgery, peripartum complications, and hospitalization length did not differ significantly between the groups. Reversible adverse effects related probably to prophylactic balloon catheter insertion were noted in 2 of 13 (15.4%) women. CONCLUSION: In women with preoperative suspicion of placenta accreta, preoperative placement of prophylactic balloon catheters did not affect the number of packed RBC units transfused. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01373255. LEVEL OF EVIDENCE: I.

Trend in major neonatal and maternal morbidities accompanying the rise in the cesarean delivery rate.

The aim of the study was to explore a cesarean delivery rate (CDR) beyond which major neonatal and maternal morbidities may outweigh the benefits of the procedure itself. A retrospective population-based cohort study was conducted at a single university teaching hospital between 1993 and 2012. Pregnant women who delivered at a gestational age of 23 weeks or more were included. Data including delivery mode, brachial plexus injury (BPI), neonatal encephalopathy (NE), placenta accreta (PA), blood transfusion (BT), and cesarean hysterectomy (CH) for each year were extracted, plotted, and trends analyzed. The Cochran-Armitage Trend Test was used to identify trends and correlations. Overall, 83,806 deliveries took place during this period. CDR increased from 10.9% to 21.7% (p < 0.001). Significant decreases in the incidence of BPI (p < 0.001) and NE (p = 0.006) were observed. At CDRs of 13.6% and 20%, there was no further significant decrease in the incidence of BPI and NE, respectively. The incidence of BT increased significantly (p < 0.001) while the increase in the incidence of PA was not significant (p = 0.06) nor the change in the incidence of CH (p = 0.4). A CDR of 20% may still confirm additional beneficial effect on major perinatal morbidities without a significant increase in the incidence of PA.

[ABANDONED EMBRYOS OR SURPLUS FERTILIZED OOCYTES--SEEKING THE SOLUTION FOR A FROZEN BURNING PROBLEM].

Israel is a world leader in the utilization rate of in vitro fertilization (IVF). During many IVF cycles, spare fertilized oocytes are cryopreserved. Today, thousands of fertilized oocytes, cryopreserved long ago, are stored in Israeli IVF units. The effort to contact the individuals who own the fertilized oocytes, so that they will approve thawing or finance continued storage, have mostly fAed. In this article we discuss the moral status of the fertilized oocyte and the ethical principles which should govern the way in which we deal with abandoned embryos. We present the different accounts for moral status and the diverse opinions regarding the status of the fertilized oocyte. At the end of the discussion we state our position regarding the ethical way to deal with the abandoned fertilized oocytes.

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.

Long-term outcome of obstetric anal sphincter injury repaired by experienced obstetricians.

OBJECTIVE: To examine the long-term outcomes of women with obstetric anal sphincter injury (OASI) repaired by obstetricians without the involvement of colorectal surgeons. METHODS: A retrospective cohort study was undertaken of women who had been admitted for delivery between 2004 and 2012. All OASIs had been repaired by experienced obstetricians using the end-to-end technique. An unexposed group (no OASI) was matched at a ratio of 1:1. Fecal incontinence was graded using a modified Wexner questionnaire. RESULTS: Overall, 113 OASIs were recorded. Sixty-seven (59.3%) and 71 (62.8%) women from the exposed and unexposed groups, respectively, agreed to participate in the study (P=0.9). Continence to both stool and gas was reported by 48 (71.6%) and 64 (90.1%) women in the exposed and unexposed groups, respectively (P=0.03). The incidence of urgency, dyspareunia, and use of a pad or constipating agents was the same in both groups. CONCLUSION: The long-term outcome of OASI repair performed by experienced obstetricians is comparable to that reported in the literature. Some women who did not sustain an OASI reported fecal incontinence, which suggests that only a proportion of fecal incontinence can be attributed to OASI.

Distribution of estrogen and progesterone receptors isoforms in endometrial cancer.

BACKGROUND: 70-80% of sporadic endometrial carcinomas are defined as endometrioid carcinoma (EC). Early-stage, well differentiated endometrial carcinomas usually retain expression of estrogen and progesterone receptors (ER and PR, respectively), as advanced stage, poorly differentiated tumors often lack one or both of these receptors. Well-described EC prognosis includes tumor characteristics, such as depth of myometrial invasion. Therefore, in the current study, we evaluated the expression profile of ER and PR isoforms, including ER-α, PR-A and PR-B, in correlation to EC tumor histological depth. METHODS: Using immunohistochemistry and image analysis software, the expression of ER-α, PR-A, PR-B and Ki67 was assessed in endometrial stroma and epithelial glands of superficial, deep and extra-tumoral sections of 15 paraffin embedded EC specimens, and compared to 5 biopsies of non-malignant endometrium. RESULTS: Expression of PR-A and ER-α was found to be lower in EC compared to nonmalignant tissue, as the stromal expression was dramatically reduced compared to epithelial cells. Expression ratios of both receptors were significantly high in superficial and deep portions of EC; in non-tumoral portion of EC were close to the ratios of nonmalignant endometrium. PR-B expression was low in epithelial glands of EC superficial and deep portions, and high in the extra-tumoral region. Elevated PR-B expression was found in stroma of EC, as well. CONCLUSIONS: The ratio of ER-α and PR-A expression in the epithelial glands and the stroma of EC biopsies may serve as an additional parameter in the histological evaluation of EC tumor. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1155060506119016.

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.

Establishment of fetal biometric charts using quantile regression analysis.

OBJECTIVES: Fetal growth evaluation is an essential component of pregnancy surveillance. There have been several methods used to construct growth charts. The conventional charts used in current daily practice are based on small numbers and traditional statistical methods. The purpose of this study was to improve fetal biometric charts based on a much larger number of observations with an alternative statistical method: quantile regression analysis. A comparison between the charts is presented. METHODS: During the 12 years of study, 17,708 sonographic examinations of pregnant women from the north of Israel, between 12 and 42 weeks of pregnancy, were performed. Fetal measurements were obtained by several operators using various equipment and included head circumference, abdominal circumference, and femur length. RESULTS: Growth charts were established based on these measurements. CONCLUSIONS: In this study, we constructed biometric growth charts using a large cohort of pregnant women. These charts offer the advantages of specific estimated regression parameters for each specified percentile, thus better defining the normal range. We suggest using these new charts in routine daily obstetric practice.

Human amniotic epithelial cells differentiate into cells expressing germ cell specific markers when cultured in medium containing serum substitute supplement.

BACKGROUND: Human amniotic epithelial cells (hAECs) maintain the plasticity of pregastrulation embryonic cells, having the potential to differentiate into all three germ layers. The potential of these cells to differentiate into cells expressing germ cell specific markers has never been described before. METHODS: In the present study, hAECs were cultured in medium containing serum substitute supplement (SSS). Gene and protein expression of germ cell and oocyte specific markers was assessed by reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence staining and flow activated cell sorter analysis (FACS) in hAECs at different time points during the differentiation into cells expressing germ cell specific markers. RESULTS: When cultured with SSS, already at passage 1, hAECs start to express the germ cell specific genes C-KIT, DAZL, VASA and ZP3 and at passage 5 large round cells, resembling oocytes, appeared. The cells express the germ cell specific marker DAZL, the oocyte specific markers GDF9 and ZP3 and the meiosis specific markers DMC1 and SCP3 at the protein level. CONCLUSIONS: From our preliminary results we can conclude that hAECs have the potential to differentiate into cells expressing germ cell specific markers.

Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial.

OBJECTIVE: To compare the tocolytic efficacy and tolerability of nifedipine with that of atosiban among pregnant women with preterm labor. METHODS: Pregnant women admitted with preterm labor and intact membranes between 24 and 33 weeks 6 days of gestation, between January 2008 and December 2011, were randomly assigned to either atosiban or nifedipine treatment. Assigned treatment was planned for up to 48 hours. If progress was determined after 1 hour or more, a crossover of the study drugs was performed. The primary outcome was to estimate the tocolytic efficacy and tolerability profile that was assessed in terms of the proportion of women who were not delivered and did not require an alternate tocolytic agent within 48 hours. Secondary outcomes were gestational age at delivery and neonatal morbidity. RESULTS: Seventy-five women in the nifedipine group and 70 in the atosiban group were included and analyzed. Baseline demographic and obstetric characteristics were comparable. Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours respectively (P=.03). At 7 days from enrollment, 55 (78.6%) women allocated to atosiban and 67 (89.3%) to nifedipine remained undelivered with or without a rescue agent (P=.02). Mean gestational age at delivery was 35.2 (±3.0) and 36.4 (±2.8) weeks among the atosiban and nifedipine groups, respectively (P=.01). Mean birth weight and neonatal morbidity were comparable. CONCLUSIONS: Atosiban has fewer failures within 48 hours. Nifedipine may be associated with a longer postponement of delivery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00599898.

Risk factors for infection following cesarean delivery: an interventional study.

OBJECTIVE: To identify risk factors for infection following cesarean delivery (CD) and to investigate the effect of intervention on modifiable risk factors (MRF). METHODS: A prospective, two-period cohort intervention study. All CD performed between September 2006 and August 2007 (era 1) and between July 2009 and June 2010 (era 2) were included. Infection control program was implemented before era 2 and included a refresher course in aseptic and scrub techniques to all surgical teams. Infectious morbidity was recognized up to 30 days from the operation. Risk factors were identified by multiple logistic regressions. RESULTS: A total of 1616 women included and analyzed during both eras. Logistic regression revealed that residency (rural as compared to urban), obesity and urgency of the CD were significant risk factors for infection. Prior to intervention, senior obstetricians had a lower infection rate than senior gynecologists (p = 0.02). Within both groups, the incidence in era 2 decreased and was comparable (obstetricians: 5.7 vs. 1.6%; p = 0.005; gynecologists: 12.7 vs. 1.1%; p = 0.003). Among the group of scrub nurses who took part in less than 20 CD during era 1, the intervention reduced significantly the infection rate during era 2 (p = 0.0002). CONCLUSION: Surgical team is a MRF for infection following CD. Intervention decreased this unintended clinical effect attributed to surgical teams.

Comparison of intrapartum outcome among immigrant women from Ethiopia and the general obstetric population in Israel.

OBJECTIVE: To compare intrapartum outcome between ethnic Ethiopian women and the general obstetric population in Israel. METHODS: In a retrospective study, computerized data from all Ethiopian women who delivered between January 2004 and August 2011 at a university teaching hospital in Afula, Israel, were assessed. The control group comprised non-Ethiopian Israeli women, who were matched at a ratio of 1:2 on the basis of deliveries that took place immediately before and after delivery by an Ethiopian woman. The primary outcome was incidence of operative delivery. RESULTS: During the study period, 576 Ethiopian women delivered along with 1152 matched control women. Ethiopian women had a higher incidence of pre-eclampsia (6.8% versus 4.0%, P=0.01) and early postpartum hemorrhage (4.3% versus 1.6%, P=0.003) than control women. After adjustment for potential confounders, the incidence of vacuum or cesarean delivery was significantly higher among Ethiopian than among control women (odds ratio, 1.68; 95% confidence interval, 1.28-2.20; P=0.002). The incidence of composite major perinatal morbidity, including Erb palsy and cord pH less than 7.1, tended to be higher among Ethiopian women than among control women (2.3% versus 1.1%; P=0.053). CONCLUSION: Although prepartum and intrapartum care are standardized, Ethiopian women had a less favorable intrapartum outcome.