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.

Conception and viable twin pregnancy in a patient with metastatic melanoma while treated with CTLA-4 and PD-1 checkpoint inhibition.

The treatment of cancer during pregnancy presents a unique challenge. Optimal treatments are often altered or even delayed to protect fetal growth and organogenesis. The landscape of cancer treatment has shifted dramatically over the past several years and treatment with checkpoint inhibitors, including anti-PD1 and anti-CTLA-4 agents has revolutionized treatment outcomes for patients across numerous tumor types. Until recently, little is known about the use of checkpoint inhibitor therapy during pregnancy; however, in animal studies, exposure to checkpoint inhibitors at the time of or after conception led to high incidences of spontaneous abortion, stillbirth, and premature delivery. In this report, we describe the successful pregnancy and clinical course of a patient diagnosed with metastatic melanoma who conceived twins while undergoing dual checkpoint blockade with ipilumumab and nivolumab. While there are case reports of patients receiving checkpoint inhibitors during pregnancy, our case is the first to describe a successful pregnancy that was conceived during treatment with combination anti-CTLA-4 and PD-1, with therapy continuing throughout pregnancy. This case adds to the growing evidence that favorable pregnancy outcomes may be possible while receiving checkpoint inhibition, which will hopefully allow for more optimal treatment of young pregnant patients with cancer.

Identification of haptoglobin switch-on status in archived placental specimens indicates antenatal exposure to inflammation and potential participation of the fetus in triggering preterm birth.

OBJECTIVE: Haptoglobin (Hp) has key immunoregulatory roles that vary with phenotype (Hp1-1, Hp2-1, Hp2-2). Cord blood Hp expression is switched-off in the normal fetus. We hypothesized that in the setting of fetal inflammation placenta becomes inundated with Hp of fetal origin that in turn modulates the output of PGE2 and MMP-9 in a phenotype dependent manner. METHODS: Placentas from 40 pregnancies complicated by preterm birth (PTB) (<37 weeks), without (n = 15) or with (n = 25) intra-amniotic infection and histological chorioamnionitis (HCA) were scored for intensity of Hp immunostaining. Hp mRNA levels were evaluated by PCR. Cord blood Hp levels, switch-on status and phenotypes were determined by ELISA and Western blotting. Using a villous trophoblast explant system we investigated if Hp can modulate the release of PGE2 and MMP-9 in the presence or absence of lipopolysaccharide (LPS). RESULTS: All cases with HCA had positive Hp immunoreactivity within fetal vascular spaces. Hp staining intensity correlated with cord blood Hp levels and IL-6. Placentas with and without HCA had similar Hp mRNA levels suggesting Hp immunostaining in the fetal spaces is of fetal rather than placental origin. Both Hp1-1 and Hp2-2 up-regulated PGE2 release in the presence of LPS (2-fold over the LPS level, P < .05), without affecting MMP-9 concentrations. CONCLUSIONS: Fetal Hp switch-on status, a marker of antenatal exposure to intra-amniotic infection/inflammation, can be reliably established through evaluation of archived placental specimens. In the setting of infection/inflammation, Hp enhances placental PGE2 output thereby supporting the role of the fetus in triggering parturition.

Effect of pain and analgesia on compensatory reserve.

BACKGROUND: The measurement of the body's capacity to compensate for reduced blood volume can be assessed with a compensatory reserve measurement (CRM). The CRM, which is calculated from changes in features of the arterial waveform, represents the integration of compensatory mechanisms during states of low tissue perfusion and oxygenation, such as hemorrhage. This study was designed to test the hypothesis that pain which activates compensatory mechanisms and analgesia that result in reduced blood pressure are associated with lower compensatory reserve. This study evaluated CRM in obstetric patients during labor as pain intensity increased from no pain to severe pain and compared CRM before and after epidural anesthesia. METHODS: CRM was calculated from a finger pulse oximeter placed on the patient's index finger and connected to the DataOx monitor in healthy pregnant women (n = 20) before and during the active labor phase of childbirth. RESULTS: As pain intensity, based on an 11-point scale (0, no pain; 10, worst pain), increased from 0 to 8.4 ± 0.9 (mean ± SD), CRM was not affected (81 ± 10% to 82 ± 13%). Before analgesia, CRM was 84 ± 10%. CRM at 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after analgesia was 82 ± 11%, 83 ± 14%, 83 ± 15%, 86 ± 12%, 89 ± 9%, and 87 ± 10%, respectively. There was a transient 2% reduction followed by a 5% increase in CRM from before to after epidural anesthesia (p = 0.048). Pain scores before and after analgesia were 7 ± 2 and 1 ± 1, respectively (p < 0.001). CONCLUSION: These results indicate that pain and analgesia contribute minimally, but independently to the reduction in compensatory reserve associated with trauma and hemorrhage. As such, our findings suggest that analgesia can be safely administered on the battlefield while maintaining the maximal capacity of mechanisms to compensate for blood loss. LEVEL OF EVIDENCE: Diagnostic study, level II.

Imbalance of Amniotic Fluid Activin-A and Follistatin in Intraamniotic Infection, Inflammation, and Preterm Birth.

CONTEXT: Microbial invasion of the amniotic fluid (AF) cavity stimulates an inflammatory response that involves activin-A, a pleiotropic mediator member of the TGFß superfamily involved in connective tissue remodeling. The role of AF follistatin, a natural inhibitor of activin-A, in inflammation-induced preterm birth (PTB), has yet to be determined. OBJECTIVE: The objective of the study was to investigate the relationships between AF activin-A and follistatin in physiological gestation and in pregnancies complicated by PTB and to evaluate a possible role played by the activin-A-follistatin balance in processes leading to PTB and preterm premature rupture of membranes (PPROM). STUDY DESIGN: The AF levels of total activin-A and follistatin were immunoassayed in 168 women with a normal pregnancy outcome or PTB with and without intraamniotic inflammation or PPROM. The impact of the activin-A-follistatin imbalance on PTB terminal effector pathways (prostaglandins [prostaglandin E2, prostaglandin F2α] and matrix metalloproteinases [MMP-1, MMP-2, MMP-3, and MMP-9]) was investigated in an amniochorion explant system challenged with lipopolysaccharide (LPS) to mimic inflammation. RESULTS: AF follistatin and the activin-A to follistatin ratio varied with gestational age, both decreasing toward term (P < .001). Activin-A was up-regulated in AF infection (>2-fold elevation in activin-A to follistatin ratio) correlating directly with severity of inflammation (both P < .001). Activin-A increased prostaglandins, MMP-1, and MMP-9 released by amniochorion (P < .05) to LPS-equivalent levels. Follistatin effectively blunted the prostaglandin response to activin-A and LPS and that of MMPs after activin-A but not after LPS challenge. CONCLUSION: Activin-A and follistatin are part of the complex inflammatory response of the gestational sac to infection and modulate effector pathways leading to PTB. The activin-A to follistatin ratio may play a role in determining the clinical phenotype of PTB as preterm labor or PPROM.

Calciprotein particles as potential etiologic agents of idiopathic preterm birth.

Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality and is often preceded by preterm premature rupture of the membranes (PPROM) without an identifiable cause. Pathological calcification, the deposition of hydroxyapatite (HA) in nonskeletal tissues, has been implicated in degenerative diseases including atherosclerosis and aneurism rupture. Among pathogenic mechanisms, the aberrant aggregation of HA into calciprotein particles (CPPs) and the HA-induced differentiation of mesenchymal cells into osteoblasts (ectopic osteogenesis) have been implicated. We explored the hypothesis that CPPs form in human amniotic fluid (AF), deposit in fetal membranes, and are linked mechanistically to pathogenic pathways favoring PTB. We demonstrated that fetal membranes from women with idiopathic PPROM frequently show evidence of ectopic calcification and expression of osteoblastic differentiation markers. Concentrations of fetuin-A, an endogenous inhibitor of ectopic calcification, were decreased in AF of idiopathic PPROM cases, which reflected their reduced functional capacity to inhibit calcification. Using long-term cultures of sterile AF, we demonstrated coaggregation of HA with endogenous proteins, including fetuin-A. The fetuin-HA aggregates exhibited progressive growth in vitro in a pattern similar to CPPs. When applied to amniochorion explants, AF-derived CPPs induced structural and functional pathological effects recapitulating those noted for PPROM. Our results demonstrate that disruption of protein-mineral homeostasis in AF stimulates the formation and deposition of CPPs, which may represent etiologic agents of idiopathic PPROM. Therapeutic or dietary interventions aimed at maintaining the balance between endogenous HA formation and fetuin reserve in pregnant women may therefore have a role in preventing PTB.

Remote sensing of coral reefs and their physical environment.

There has been a vast improvement in access to remotely sensed data in just a few recent years. This revolution of information is the result of heavy investment in new technology by governments and industry, rapid developments in computing power and storage, and easy dissemination of data over the internet. Today, remotely sensed data are available to virtually anyone with a desktop computer. Here, we review the status of one of the most popular areas of marine remote sensing research: coral reefs. Previous reviews have focused on the ability of remote sensing to map the structure and habitat composition of coral reefs, but have neglected to consider the physical environment in which reefs occur. We provide a holistic review of what can, might, and cannot be mapped using remote sensing at this time. We cover aspects of reef structure and health but also discuss the diversity of physical environmental data such as temperature, winds, solar radiation and water quality. There have been numerous recent advances in the remote sensing of reefs and we hope that this paper enhances awareness of the diverse data sources available, and helps practitioners identify realistic objectives for remote sensing in coral reef areas.