Delivery outcomes in the subsequent pregnancy following the conservative management of placenta accreta spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: Cesarean hysterectomy is generally presumed to decrease maternal morbidity and mortality secondary to placenta accreta spectrum disorder. Recently, uterine-sparing techniques have been introduced in conservative management of placenta accreta spectrum disorder to preserve fertility and potentially reduce surgical complications. However, despite patients often expressing the intention for future conception, few data are available regarding the subsequent pregnancy outcomes after conservative management of placenta accreta spectrum disorder. Thus, we aimed to perform a systematic review and meta-analysis to assess these outcomes. DATA SOURCES: PubMed, Scopus, and Web of Science databases were searched from inception to September 2022. STUDY ELIGIBILITY CRITERIA: We included all studies, with the exception of case studies, that reported the first subsequent pregnancy outcomes in individuals with a history of placenta accreta spectrum disorder who underwent any type of conservative management. METHODS: The R programming language with the "meta" package was used. The random-effects model and inverse variance method were used to pool the proportion of pregnancy outcomes. RESULTS: We identified 5 studies involving 1458 participants that were eligible for quantitative synthesis. The type of conservative management included placenta left in situ (n=1) and resection surgery (n=1), and was not reported in 3 studies. The rate of placenta accreta spectrum disorder recurrence in the subsequent pregnancy was 11.8% (95% confidence interval, 1.1-60.3; I2=86.4%), and 1.9% (95% confidence interval, 0.0-34.1; I2=82.4%) of participants underwent cesarean hysterectomy. Postpartum hemorrhage occurred in 10.3% (95% confidence interval, 0.3-81.4; I2=96.7%). A composite adverse maternal outcome was reported in 22.7% of participants (95% confidence interval, 0.0-99.4; I2=56.3%). CONCLUSION: Favorable pregnancy outcome is possible following successful conservation of the uterus in a placenta accreta spectrum disorder pregnancy. Approximately 1 out of 4 subsequent pregnancies following conservative management of placenta accreta spectrum disorder had considerable adverse maternal outcomes. Given such high incidence of adverse outcomes and morbidity, patient and provider preparation is vital when managing this population.

Drug use associated tricuspid valve infective endocarditis in pregnancy.

BACKGROUND AND AIM: We report a case of intravenous drug use associated tricuspid valve endocarditis in a 28-year-old pregnant female at 26-week gestation. METHODS: Patient management required a multidisciplinary collaboration between cardiac surgery, obstetrics and gynecology, and neonatal critical care. RESULTS: Despite appropriate intravenous antibiotics, the patient developed life-threatening complications and underwent planned cesarean delivery at 28 weeks 6 days gestation followed by interval tricuspid valve replacement 1 week later. CONCLUSIONS: Both the patient and her infant were successfully managed through the perioperative period.

Limiting the Exposure of Select Fetuses to Intrauterine Infection/Inflammation Improves Short-Term Neonatal Outcomes in Preterm Premature Rupture of Membranes.

BACKGROUND: To improve neonatal outcomes in pregnancies at heightened risk for early-onset neonatal sepsis (EONS), there is a need to identify fetuses that benefit from expectant management as opposed to early delivery. Detectable haptoglobin and haptoglobin-related protein (Hp&HpRP switch-on status) in cord blood has been proposed as a biomarker of antenatal exposure to intra-amniotic infection and/or inflammation (IAI), an important determinant of EONS. SUBJECTS AND METHODS: We analyzed 185 singleton newborns delivered secondary to preterm premature rupture of membranes (PPROM). In 123 cases, amniocentesis was performed to exclude amniotic fluid (AF) infection. Delivery was indicated for 61 cases with confirmed infection. Women without AF infection (n = 62) and those without amniocentesis (n = 62) were managed expectantly. Interleukin 6 and Hp&HpRP switch-on status were evaluated by ELISA and Western blot. Newborns were followed prospectively for short-term outcomes until hospital discharge or death. RESULTS: Newborns exposed antenatally to IAI had an increased risk of adverse neonatal outcome [OR: 3.0 (95% CI: 1.15-7.59)]. Increasing gestational age [OR: 0.61 (95% CI: 0.52-0.70)] and management with amniocentesis [OR: 0.37 (95% CI: 0.14-0.95)] lowered the newborn's risk of developing adverse outcomes. DISCUSSION: In the setting of PPROM and IAI, early delivery benefits a select subgroup of fetuses that have not yet progressed to Hp&HpRP switch-on status.

IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes.

Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL-6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130.

The management of the critically ill obstetric patient.

Hypertensive disorders, postpartum hemorrhage, and sepsis are the most common indications for intensive care unit admission among obstetric patients. In general, ICU mortality is low, and better than would be predicted using available mortality prediction tools. Provision of care to this special population requires an intimate understanding of physiologic changes that occur during pregnancy. Clinicians must be aware of the way various diagnostic and treatment choices can affect the mother and fetus. Most clinically necessary radiographic tests can be safely performed and fall under the maternal radiation exposure limit of less than 0.05 Gray (Gy). Careful attention must be paid to acid-base status, oxygenation, and ventilation when faced with respiratory failure necessitating intubation. Cesarean delivery can be justified after 4 minutes of cardiac arrest and may improve fetal and maternal outcomes. The treatment of obstetric patients in the ICU introduces complexities and challenges that may be unfamiliar to many critical care physicians; teamwork and communication with obstetricians is crucial.

Heparin elevates circulating soluble fms-like tyrosine kinase-1 immunoreactivity in pregnant women receiving anticoagulation therapy.

BACKGROUND: Alterations in circulating levels of pro- and antiangiogenic factors have been associated with adverse pregnancy outcomes. Heparin is routinely administered to pregnant women, but without clear knowledge of its impact on these factors. METHODS AND RESULTS: We conducted a longitudinal study of 42 pregnant women. Twenty-one women received prophylactic heparin anticoagulation, and 21 healthy pregnant women served as controls. Compared with gestational age-matched controls, heparin treatment was associated with increased circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1) in the third trimester (P<0.05), in the absence of preeclampsia, placental abruption, or fetal growth restriction. Heparin had no effect on circulating levels of vascular endothelial growth factor, placenta growth factor, or soluble endoglin as assessed by ELISA. In vitro, low-molecular weight and unfractionated heparins stimulated sFlt-1 release from placental villous explants, in a dose- and time-dependent manner. This effect was not due to placental apoptosis, necrosis, alteration in protein secretion, or increased transcription. Western blot analysis demonstrated that heparin induced shedding of the N-terminus of Flt-1 both in vivo and in vitro as indicated by a predominant band of 100-112 kDa. By using an in vitro angiogenesis assay, we demonstrated that serum of heparin-treated cases inhibited both basal and vascular endothelial growth factor-induced capillary-like tube formation. CONCLUSIONS: Heparin likely increases the maternal sFlt-1 through shedding of the extracellular domain of Flt-1 receptor. Our results imply that upregulation of circulating sFlt-1 immunoreactivity in pregnancy is not always associated with adverse outcomes, and that heparin's protective effects, if any, cannot be explained by promotion of angiogenesis.

Maternal Outcomes in Subsequent Pregnancies After Classical Cesarean Delivery.

OBJECTIVE: To compare maternal outcomes in subsequent pregnancies of patients who had a prior classical cesarean delivery with those with a prior low transverse cesarean delivery. METHODS: We conducted a cross-sectional analysis of patients with live singleton births at or after 24 weeks of gestation who had a prior classical cesarean delivery or a low transverse cesarean delivery in the 2016-2019 National Inpatient Sample database. Outcome measures included mode of delivery, uterine rupture, and severe maternal morbidity (SMM), as defined by the Centers for Disease Control and Prevention. Maternal outcomes were compared using the χ2 test and the propensity score method, accounting for differences in patients' clinical risk factors. Multivariable regressions further assessed how patients' sociodemographic and hospital characteristics might influence the differences in maternal outcomes between the two groups. RESULTS: The sample included 1,671,249 patients: 25,540 with prior classical cesarean delivery and 1,645,709 with prior low transverse cesarean delivery. Cesarean delivery occurred in 95.5% of patients with prior classical cesarean compared with 91.3% of those with prior low transverse delivery (P<.001; propensity score method: odds ratio [OR] 0.99, 95% CI 0.85-1.16) and uterine rupture occurred in 1.1% and 0.3%, respectively (P<.001; propensity score method: OR 2.17, 95% CI 1.40-3.36). Among patients with prior classical cesarean delivery, uterine rupture occurred in 10.6% of those who underwent labor compared with 0.3% of those who did not (P<.001). Rates of SMM were 5.9% and 2.0% in the two groups, respectively (P<.001; propensity score method: OR 1.87, 95% CI 1.53-2.29). After adjustment of maternal sociodemographic and hospital characteristics, differences in the risk of uterine rupture and SMM between the two groups were attenuated but remained significant. CONCLUSION: Prior classical cesarean delivery was associated with a higher risk of uterine rupture and SMM in subsequent pregnancies, compared with prior low transverse cesarean delivery, even after accounting for patients' clinical, sociodemographic, and hospital characteristics.

Ultrasound Image Quality Comparison Between a Handheld Ultrasound Transducer and Mid-Range Ultrasound Machine.

Objectives: Not all labor and delivery floors are equipped with ultrasound machines which can serve the needs of both obstetricians and anesthesiologists. This cross-sectional, blinded, randomized observational study compares the image resolution (RES), detail (DET), and quality (IQ) acquired by a handheld ultrasound, the Butterfly iQ, and a mid-range mobile device, the Sonosite M-turbo US (SU), to evaluate their use as a shared resource. Methods: Seventy-four pairs of ultrasound images were obtained for different imaging purposes: 29 for spine (Sp), 15 for transversus abdominis plane (TAP) and 30 for diagnostic obstetrics (OB) purposes. Each location was scanned by both the handheld and mid-range machine, resulting in 148 images. The images were graded by three blinded experienced sonographers on a 10-point Likert scale. Results: The mean difference for Sp imaging favored the handheld device (RES: -0.6 [(95% CI -1.1, -0.1), p = 0.017], DET: -0.8 [(95% CI -1.2, -0.3), p = 0.001] and IQ: -0.9 [95% CI-1.3, -0.4, p = 0.001]). For the TAP images, there was no statistical difference in RES or IQ, but DET was favored in the handheld device (-0.8 [(95% CI-1.2, -0.5), p < 0.001]). For OB images, the SU was favored over the handheld device with RES, DET and IQ with mean differences of 1.7 [(95% CI 1.2, 2.1), p < 0.001], 1.6 [(95% CI 1.2, 2.0], p < 0.001] and 1.1 [(95% CI 0.7, 1.5]), p < 0.001), respectively. Conclusions: Where resources are limited, a handheld ultrasound may be considered as a potential low-cost alternative to a more expensive ultrasound machine for point of care ultrasonography, better suited to anesthetic vs. diagnostic obstetrical indications.

Influence of b2 adrenergic receptor polymorphism (rs1042713 and rs1042714) on anthropometric, hormonal and lipid profiles in polycystic ovarian syndrome.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a frequently encountered disorder. This study aimed to identify polymorphisms in ADRB2 in Saudi PCOS development and to study its influence on lipids, hormones, and anthropometric parameters. METHODS: Saudi females (100) suffering from PCOS and healthy controls (100) were investigated. The estimation of cholesterol, triglycerides, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), plasma glucose, leptin Insulin, and ghrelin were carried out. The DNA was extracted, and ADRB2 fragment carrying the exon 1 was amplified and sequenced. RESULTS: The waist, W/H ratio, lipids, glucose, and insulin were significantly higher in the obese PCOS compared to the normal weight group. The leptin and ghrelin were not different. Two single nucleotide polymorphisms (SNPs): rs1042713 (Arg16Gly; A>G) and rs1042714 (Gln27Glu; C>G) were identified. The genotype and allele frequency of rs1042713 did not differ in the total PCOS and normal weight, and obese PCOS compare to the controls. However, rs1042714 was significantly associated with PCOS development, where the minor G allele was protective against PCOS development. CONCLUSIONS: The rs1042714 polymorphism of the ADRB associates with PCOS development in Saudis, while rs1042713 does not. However, the GG genotype of rs1042713 associates significantly with elevated BMI, waist, hip, W/H, and leptin, and decreased ghrelin. On the other hand, rs1042714 genotypes do not associate with any abnormality except the homozygous GG have higher triglycerides and lower HDL-C. Interestingly, glucose showed different correlation patterns in individuals carrying different genotypes of the two studied SNP, indicating clearly that the metabolic responses to a normal nutrient are significantly influenced by the genotypes of the SNPs in ADRB2.

Normative postpartum intraabdominal pressure: potential implications in the diagnosis of abdominal compartment syndrome.

OBJECTIVE: We sought to establish normative values of intraabdominal pressure (IAP) in postpartum women with and without arterial hypertension. STUDY DESIGN: Bladder pressure was measured via a Foley catheter 1 hour following completion of cesarean section in supine and semirecumbent positions in 21 patients. RESULTS: Mean supine IAP (6.4 +/- 5.2 mm Hg) was significantly lower than semirecumbent IAP (11.6 +/- 7.2 mm Hg) (P < .05). Body mass index (BMI) was significantly correlated to IAP regardless of the gestational age (r(2) supine = 0.46, semirecumbent = 0.37; P = .004 for either). Increasing gravidity was associated with decreasing IAP. Patients with arterial hypertension had higher BMI, were delivered earlier, and had higher IAP than patients with normal arterial pressure, either in supine or semirecumbent position. However, these relationships were not significant when results were controlled for BMI. CONCLUSION: Postcesarean section IAP is higher than in the general surgical population. Patients with hypertensive disorders have IAPs approaching to intraabdominal hypertension range.

Fetal renal artery impedance as assessed by Doppler ultrasound in pregnancies complicated by intraamniotic inflammation and preterm birth.

OBJECTIVE: The objective of the study was to evaluate the fetal renal artery impedance in the context of inflammation-associated preterm birth. STUDY DESIGN: We conducted a prospective Doppler assessment of the fetal renal artery impedance in 70 singleton fetuses. The study group consisted of 56 premature fetuses (median, 28.1 [interquartile range, 25.3-30.6] weeks at enrollment). Gestational age (GA) reference ranges were generated based on fetuses with uncomplicated pregnancies (n = 14). Doppler studies included renal artery pulsatility index (PI), resistance index (RI), systolic/diastolic (S/D) ratio, and presence or absence of end-diastolic blood flow. Proteomic profiling (surface-enhanced laser desorption ionization time-of-flight) was used for assessment of intraamniotic inflammation and biomarker peak corresponding to beta2-microglubin. Data were interpreted in relationship to amniotic fluid index (AFI), cord blood interleukin (IL)-6 and erythropoietin (EPO) levels. The cardiovascular and metabolic profiles of the neonates were investigated in the first 24 hours of life. RESULTS: Fetuses delivered by mothers with intraamniotic inflammation had higher cord blood IL-6 but not EPO levels. Fetal inflammation did not affect either renal artery PI, RI, S/D ratio, or end-diastolic blood flow. Neonates delivered in the context of intraamniotic inflammation had higher serum blood urea nitrogen levels, which correlated significantly with AF IL-6 levels. The renal artery RI and SD ratio were inversely correlated with the AFI independent of GA, cord blood IL-6, and status of the membranes. CONCLUSION: The fetus is capable of sustaining normal renal artery impedance despite inflammation. Resistance in the renal vascular bed affects urine output independent of inflammation.

Nucleated red blood cells are a direct response to mediators of inflammation in newborns with early-onset neonatal sepsis.

OBJECTIVE: The objective of the study was to test the hypothesis that inflammation modulates fetal erythroblastosis and/or the release of nucleated red blood cells (NRBCs) independent of hypoxia or fetal stress. We sought to determine whether fetal inflammation is associated with an elevation in neonatal NRBC count in the setting of inflammation-associated preterm birth. STUDY DESIGN: The relationships between peripheral NRBC count, histological chorioamnionitis, umbilical cord interleukin (IL)-6, erythropoietin (EPO), cortisol, and acid-base status were analyzed in 68 preterm singletons, born to mothers who had an amniocentesis to rule out infection. Proteomic profiling of amniotic fluid identified presence of intraamniotic inflammation according to established parameters. NRBC counts were assessed within 1 hour of birth. Early-onset neonatal sepsis (EONS) was established based on hematological and microbiological indices. IL-6, EPO, and cortisol levels were measured by immunoassays. Fetal acid-base status was determined within 10 minutes of delivery. Parametric or nonparametric statistics were used. RESULTS: Fetuses with EONS (n = 19) were delivered at earlier gestational ages (mean +/- SD: 27.1 +/- 2.8 weeks, P = .001) and more often by mothers with intraamniotic inflammation (P = .022) and histological chorioamnionitis (P < .001). Neonates with EONS had higher absolute NRBC counts (P = .011). NRBC counts were directly correlated with cord blood IL-6 levels (P < .001) but not with EPO, cortisol or parameters of acid-base status levels regardless of EONS status. These relationships remained following correction for gestational age, diabetes, intrauterine growth restriction, and steroid exposure. CONCLUSION: In the setting of inflammation-associated preterm birth and in the absence of hypoxia, elevations in NRBCs in the early neonatal period may be a direct response of exposure to inflammatory mediators in utero.

A Novel Approach to Serial Amnioinfusion in a Case of Premature Rupture of Membranes Near the Limit of Viability.

Prelabor rupture of the membranes (PROM) near the limit of viability is associated with significant risks for both mother and fetus. Preterm labor, intra-amniotic infection, and placental abruption are the immediate risks to the pregnancy; however, the fetus incurs additional risks related to the sequela of persistent oligohydramnios. Transabdominal intra-amniotic infusions have been studied. Results, suggesting that this intervention may prolong the latency period, and potentially, decrease pulmonary hypoplasia in surviving neonates without evidence of increasing risk of intra-amniotic infection. To our knowledge, the use of antibiotic-infused fluid has not been reported in this clinical scenario. Therefore, we present a case of a patient with PROM before the limit of viability who underwent serial transabdominal amnioinfusions with oxacillin-containing normal saline, which resulted in membrane resealing and neonatal survival with no additional maternal morbidity.

Cesarean Scar Pregnancy, Incidence, and Recurrence: Five-Year Experience at a Single Tertiary Care Referral Center.

OBJECTIVE: To describe the treatment and subsequent pregnancy outcomes in patients with cesarean scar pregnancies at a single institution over 5 years. METHODS: This is a case series of all cesarean scar pregnancies diagnosed from May 2013 to March 2018 at Yale-New Haven Hospital. Data were collected on each patient using electronic medical record review and included patient demographics; medical, surgical, and obstetric history; pregnancy characteristics; treatment modalities used; response to therapy; complications; and subsequent pregnancy outcomes. RESULTS: Thirty cases of cesarean scar pregnancies were diagnosed in 26 patients, including one recurrence in one patient and three recurrences in another. Forty-six percent of cesarean scar pregnancies were in Hispanic women. The median number of prior cesarean deliveries was two. Mean gestational age at the time of diagnosis was 46 days (SD±10). Fetal cardiac activity was detected in 18 cases. Three patients initially were erroneously diagnosed with a viable intrauterine pregnancy and failed medical termination. Others opted for termination through systemic methotrexate alone (n=4), systemic and local methotrexate (n=12), systemic and local methotrexate with potassium chloride injected into the gestational sac (n=3), potassium chloride injection with laparotomy and wedge resection (n=1), methotrexate with bilateral uterine artery embolization (n=2), or intrauterine balloon (n=4). Five patients who underwent expectant management or methotrexate therapy had retained products of conception and required hysteroscopy and curettage. One patient opted for hysterectomy after failed curettage. After complete resolution of cesarean scar pregnancies, there were 10 subsequent spontaneous conceptions in eight patients, including four recurrent cesarean scar pregnancies, four term pregnancies, and one spontaneous abortion. One viable normally located pregnancy is ongoing. CONCLUSION: There is a wide array of treatment modalities available for cesarean scar pregnancies. Women with a cesarean scar pregnancy are at risk for its recurrence in the future, although normal pregnancy after a cesarean scar pregnancy is also possible. Safe outcomes depend on timely diagnosis and multidisciplinary care by skilled clinicians.

Ultrasound evaluation of the uterine scar after cesarean delivery: a randomized controlled trial of one- and two-layer closure.

OBJECTIVE: To survey the uterine scar thickness by ultrasonography in women randomly assigned to one- or two-layer hysterotomy closure after primary cesarean delivery. METHODS: This was a randomized, blinded trial of uterine scar closure with ultrasonographic follow-up. Thirty consecutive patients undergoing primary cesarean delivery were enrolled and randomly assigned to one- or two-layer closure of the hysterotomy. Ultrasound surveillance of the uterine scar thickness was performed at baseline (before surgery) and 48 hours, 2 weeks, and 6 weeks post partum. RESULTS: Patient compliance with the postpartum surveillance protocol was 90%, and the uterine scar was visualized in 99% of attempted ultrasonographic examinations. There were no differences between groups at baseline or at any of the follow-up evaluations. An initial 5- to 6-fold increase in uterine scar thickness was observed, followed by a gradual decrease with the 6-week measurements still thicker than baseline. Repeated measures analysis of variance showed significant variation across time points starting either at baseline (P<.001) or at 48 hour postoperatively (P<.001), but this variation did not depend on closure type (P=.79 for all visits and P=.81 beginning with 48-hour postoperative time point). CONCLUSION: The process of uterine scar remodeling can be successfully monitored by ultrasonography. Uterine scar thickness diminishes progressively after both one- or two-layer closure but does not vary with mode of hysterotomy closure. The uterine scar thickness remains increased even at 6 weeks post partum, suggesting that the process of uterine scar remodeling extends beyond the traditional postpartum period. CLINCAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00224250

Amniotic Fluid Soluble Myeloid Differentiation-2 (sMD-2) as Regulator of Intra-amniotic Inflammation in Infection-induced Preterm Birth.

PROBLEM: TLR4 mediates host responses to pathogens through a mechanism that involves protein myeloid differentiation-2 (MD-2) and its soluble form sMD-2. The role of sMD2 in intra-amniotic inflammation-induced preterm birth has not been previously explored. METHOD OF STUDY: Human amniotic fluid (AF) sMD-2 was studied by Western blotting in 152 AF samples of patients who had an amniocentesis to rule-out infection (yes infection, n = 50; no infection, n = 50) or women with normal pregnancy outcome (second trimester genetic karyotyping, n = 26; third trimester lung maturity testing, n = 26). Histological localization and mRNA expression of MD2 in fetal membranes were studied by immunohistochemistry and RT-PCR. The ability of fetal membrane to release sMD-2 and inflammatory cytokines was studied in vitro. RESULTS: Human AF contains three sMD-2 proteoforms whose levels of expression were lower at term. Intra-amniotic infection upregulated sMD-2. MD-2 mRNA and immunohistochemistry findings concurred. In vitro, LPS and monensin increased, while cycloheximide decreased sMD-2 production. Recombinant sMD-2 modulated TNF-α and IL-6 levels in a dose- and time-dependent fashion. CONCLUSION: sMD2 proteoforms are constitutively present in human AF. The intensity of the intra-amniotic inflammatory response to bacteria or perhaps to other TLR4 ligands may be facilitated through synthesis and release of sMD2 by the amniochorion.

Human chorionic gonadotropin administration is associated with high pregnancy rates during ovarian stimulation and timed intercourse or intrauterine insemination.

BACKGROUND: There are different factors that influence treatment outcome after ovarian stimulation and timed-intercourse or intrauterine insemination (IUI). After patient age, it has been suggested that timing of insemination in relation to ovulation is probably the most important variable affecting the success of treatment. The objective of this study is to study the value of human chorionic gonadotropin (hCG) administration and occurrence of luteinizing hormone (LH) surge in timing insemination on the treatment outcome after follicular monitoring with timed-intercourse or intrauterine insemination, with or without ovarian stimulation. METHODS: Retrospective analysis of 2000 consecutive completed treatment cycles (637 timed-intercourse and 1363 intrauterine insemination cycles). Stimulation protocols included clomiphene alone or with FSH injection, letrozole (an aromatase inhibitor) alone or with FSH, and FSH alone. LH-surge was defined as an increase in LH level > or =200% over mean of preceding two days. When given, hCG was administered at a dose of 10,000 IU. The main outcome was clinical pregnancy rate per cycle. RESULTS: Higher pregnancy rates occurred in cycles in which hCG was given. Occurrence of an LH-surge was associated with a higher pregnancy rate with clomiphene treatment, but a lower pregnancy rate with FSH treatment. CONCLUSIONS: hCG administration is associated with a favorable outcome during ovarian stimulation. Awaiting occurrence of LH-surge is associated with a better outcome with CC but not with FSH treatment.

Modulation of amniotic fluid activin-a and inhibin-a in women with preterm premature rupture of the membranes and infection-induced preterm birth.

PROBLEM: Activins and inhibins are important modulators of inflammatory processes. We explored activation of amniotic fluid (AF) activin-A and inhibin-A system in women with intra-amniotic infection and preterm premature rupture of the membranes (PPROM). METHOD OF STUDY: We analyzed 78 AF samples: '2nd trimester-control' (n=12), '3rd trimester-control' (n=14), preterm labor with intact membranes [positive-AF-cultures (n=13), negative-AF-cultures (n=13)], and PPROM [positive-AF-cultures (n=13), negative-AF-cultures (n=13)]. Activin-A levels were evaluated ex-vivo following incubation of amniochorion and placental villous explants with Gram-negative lipopolysaccharide (LPS) or Gram-positive (Pam3Cys) bacterial mimics. Ability of recombinant activin-A and inhibin-A to modulate inflammatory reactions in fetal membranes was explored through explants' IL-8 release. RESULTS: Activin-A and inhibin-A were present in human AF and were gestational age-regulated. Activin-A was significantly upregulated by infection. Lower inhibin-A levels were seen in PPROM. LPS elicited release of activin-A from amniochorion, but not from villous explants. Recombinant activin-A stimulated IL-8 release from amniochorion, an effect that was not reversed by inhibin-A. CONCLUSION: Human AF activin-A and inhibin-A are involved in biological processes linked to intra-amniotic infection/inflammation-induced preterm birth.

Activation of the receptor for advanced glycation end products system in women with severe preeclampsia.

CONTEXT: Activation of the receptor for advanced glycation end products (RAGE) mediates cellular injury. Soluble forms of RAGE [soluble RAGE (sRAGE), endogenous secretory (esRAGE)] bind RAGE ligands, thereby preventing downstream signaling and damage. OBJECTIVES: The objective of the study was to characterize the changes in maternal serum, amniotic fluid, and cord blood soluble receptor for advanced glycation end products (sRAGE) during physiological gestation and to provide insight into mechanisms responsible for RAGE activation in preeclampsia. DESIGN AND SETTINGS: This was a cross-sectional study at a tertiary university hospital. PATIENTS: We studied 135 women in the following groups: nonpregnant controls (n = 16), healthy pregnant controls (n = 68), pregnant women with chronic hypertension (n = 13), or pregnant women with severe preeclampsia (sPE; n = 38). INTERVENTIONS AND MAIN OUTCOME MEASURES: sRAGE and esRAGE levels were evaluated in vivo by ELISA in maternal serum, amniotic fluid, and cord blood and in vitro after stimulation of the amniochorion and placental explants with lipopolysaccharide or xanthine/xanthine oxidase. Placenta and amniochorion were immunostained for RAGE. Real-time quantitative PCR measured RAGE mRNA. RESULTS: Pregnant women had significantly decreased serum sRAGE compared with nonpregnant subjects (P < 0.001). sPE women had higher serum and amniotic fluid sRAGE and esRAGE relative to those expected for gestational age (P < 0.001). Cord blood sRAGE remained unaffected by sPE. RAGE immunoreactivity and mRNA expression appeared elevated in the amniochorion of sPE women. Xanthine/xanthine oxidase (but not lipopolysaccharide) significantly up-regulated the release of sRAGE (P < 0.001) in the amniochorion explant system. CONCLUSIONS: Fetal membranes are a rich source of sRAGE. Elevated maternal serum and amniotic fluid sRAGE and esRAGE, paralleled by increased RAGE expression in the amniochorion, suggest activation of this system in sPE.

Proteomics mapping of cord blood identifies haptoglobin "switch-on" pattern as biomarker of early-onset neonatal sepsis in preterm newborns.

BACKGROUND: Intra-amniotic infection and/or inflammation (IAI) are important causes of preterm birth and early-onset neonatal sepsis (EONS). A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns. METHODOLOGY/PRINCIPAL FINDINGS: We studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3) versus GA-matched controls (n = 3). Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1(st)-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP) in newborns with EONS (presumed and culture-confirmed) independent of GA at birth and birthweight (P<0.001). Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood ("switch-on pattern") as opposed to non-EONS newborns who had near-absent "switch-off pattern" (P<0.001). Fetal Hp phenotype independently impacted Hp&HpRP. A bayesian latent-class analysis (LCA) was further used for unbiased classification of all 180 cases based on probability of "antenatal IAI exposure" as latent variable. This was then subjected to 2(nd)-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input), interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20%) versus high (≥70%) probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses lowering the number needed to harm and increasing the odds ratios for several adverse outcomes including intra-ventricular hemorrhage. CONCLUSIONS/SIGNIFICANCE: Antenatal exposure to IAI results in precocious switch-on of Hp&HpRP expression. As EONS biomarker, cord blood Hp&HpRP has potential to improve the selection of newborns for prompt and targeted treatment at birth.