This statement summarizes evidence that adverse pregnancy outcomes (APOs) such as hypertensive disorders of pregnancy, preterm delivery, gestational diabetes, small-for-gestational-age delivery, placental abruption, and pregnancy loss increase a woman’s risk of developing cardiovascular disease (CVD) risk factors and of developing subsequent CVD (including fatal and nonfatal coronary heart disease, stroke, peripheral vascular disease, and heart failure). This statement highlights the importance of recognizing APOs when CVD risk is evaluated in women, although their value in reclassifying risk may not be established. A history of APOs is a prompt for more vigorous primordial prevention of CVD risk factors and primary prevention of CVD. Adopting a heart-healthy diet and increasing physical activity among women with APOs, starting in the postpartum setting and continuing across the life span, are important lifestyle interventions to decrease CVD risk. Lactation and breastfeeding may lower a woman’s later cardiometabolic risk. Black and Asian women experience a higher proportion APOs, with more severe clinical presentation and worse outcomes, than White women. More studies on APOs and CVD in non-White women are needed to better understand and address these health disparities. Future studies of aspirin, statins, and metformin may better inform our recommendations for pharmacotherapy in primary CVD prevention among women who have had an APO. Several opportunities exist for health care systems to improve transitions of care for women with APOs and to implement strategies to reduce their long-term CVD risk. One proposed strategy includes incorporation of the concept of a fourth trimester into clinical recommendations and health care policy.

Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication. Premature birth/delivery (PTD) is one of the most significant causes of perinatal mortality and morbidity in developed countries. Preterm infants suffer morbidities including respiratory distress, intraventricular hemorrhage, and cerebral palsy, among other serious diseases.1 These outcomes can have a life-long impact and more than $25 billion is spent each year to take care of these infants. Investigations to define the causes of PTD remain a challenge in the obstetrical field. Preterm labor is a multistage biochemical and biophysical process, during which changes in the myometrium and the cervix occur.The uterine cervix is a complex organ that undergoes extensive changes through gestation and parturition. These changes are a common first step in preterm parturition.2 As a gatekeeper for pregnancy, the cervix is a structural barrier that keeps the fetus inside the uterus until the end of gestation. Collagens, elastin, proteoglycans, and hyaluronate are responsible for the full tensile strength of the cervix.2 Ripening of the cervix is an important biological and clinical event required for a normal parturition. The process is gradual during pregnancy, with a fast final remodeling of the cervix before parturition. Increased collagen degradation and synthesis, and high activity of collagenases have been observed in the human cervix during final ripening.

Adverse neurological outcome is a major cause of long-term morbidity in ex-preterm children. To investigate the effect of parturition and inflammation on the fetal brain, we utilized two in vivo mouse models of preterm birth. To mimic the most common human scenario of preterm birth, we used a mouse model of intrauterine inflammation by intrauterine infusion of lipopolysaccharide (LPS). To investigate the effect of parturition on the immature fetal brain, in the absence of inflammation, we used a non-infectious model of preterm birth by administering RU486. Pro-inflammatory cytokines (IL-10, IL-1β, IL-6 and TNF-α) in amniotic fluid and inflammatory biomarkers in maternal serum and amniotic fluid were compared between the two models using ELISA. Pro-inflammatory cytokine expression was evaluated in the whole fetal brains from the two models. Primary neuronal cultures from the fetal cortex were established from the different models and controls in order to compare the neuronal morphology. Only the intrauterine inflammation model resulted in an elevation of inflammatory biomarkers in the maternal serum and amniotic fluid. Exposure to inflammationinduced preterm birth, but not non-infectious preterm birth, also resulted in an increase in cytokine mRNA in whole fetal brain and in disrupted fetal neuronal morphology. In particular, Microtubuleassociated protein 2 (MAP2) staining was decreased and the number of dendrites was reduced (P < 0.001, ANOVA between groups). These results suggest that inflammation-induced preterm birth and not the process of preterm birth may result in neuroinflammation and alter fetal neuronal morphology. Keywords mouse model of preterm birth; neuroinflammation; neuronal injuryIn the United States, approximately 12% of all live births are delivered preterm (Green et al., 2005). Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity in the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptUnited States. Specifically, PTB is a risk factor for adverse neurological outcome for expreterm children (Anderson and Doyle, 2003;Hack et al., 2005).It has long been believed that cerebral palsy is the primary neurological outcome of clinical interest. However, it is now known that ex-preterm children also are at a significant risk for a spectrum of cognitive and neurobehavioral disorders Wood et al., 2005;Costeloe, 2006;Limperopoulos et al., 2007;Lindstrom et al., 2009) including autism spectrum disorders (Brimacombe et al., 2007;Limperopoulos et al., 2008;Schendel and Bhasin, 2008). Current understanding of the pathogenesis of fetal brain injury in a PTB focuses mainly on specific structural findings of white matter damage (WMD) (Cai et al., 2000;Paintlia et al., 2004;Rousset et al., 2006). This current paradigm may be insufficient to explain the increasing prevalence of adverse cognitive and neurobehavioral outcomes in ex-preterm infants.While adverse neurological outcomes are increasingly prevalent in ex-preterm children, it remains unknown whether th...

Aims: To characterize the transcriptome of human myometrium during spontaneous labor at term. Methods: Myometrium was obtained from women with (ns19) and without labor (ns20). Illumina ᭨ HumanHT-12 microarrays were utilized. Moderated t-tests and false discovery rate adjustment of P-values were applied. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for a select set of differentially expressed genes in a separate set of samples. Enzyme-linked immunosorbent assay and Western blot were utilized to confirm differential protein production in a third sample set. Results: 1) Four hundred and seventy-one genes were differentially expressed; 2) gene ontology analysis indicated enrichment of 103 biological processes and 18 molecular functions including: a) inflammatory response; b) cytokine activity; and c) chemokine activity; 3) systems biology pathway analysis using signaling pathway impact analysis indicated six significant pathways: a) cytokine-cytokine receptor interaction; b) Jak-STAT signaling; and c) complement and coagulation cascades; d) NOD-like receptor signaling pathway; e) systemic lupus erythematosus; and f) chemokine signaling pathway; 4) qRT-PCR confirmed over-expression of prostaglandin-endoperoxide synthase-2, heparin binding epidermal growth factor (EGF)-like growth factor, chemokine C-C motif ligand 2 (CCL2/MCP1), leukocyte immunoglobulin-like receptor, subfamily A member 5, interleukin (IL)-8, IL-6, chemokine C-X-C motif ligand 6 (CXCL6/GCP2), nuclear factor of kappa light chain gene enhancer in B-cells inhibitor zeta, suppressor of cytokine signaling 3 (SOCS3) and decreased expression of FK506 binding-protein 5 and aldehyde dehydrogenase in labor; 5) IL-6, CXCL6, CCL2 and SOCS3 protein expression was significantly higher in the term labor group compared to the term not in labor group. Conclusions: Myometrium of women in spontaneous labor at term is characterized by a stereotypic gene expression pattern consistent with over-expression of the inflammatory response and leukocyte chemotaxis. Differential gene expression identified with microarray was confirmed with qRT-PCR using an independent set of samples. This study represents an unbiased description of the biological processes involved in spontaneous labor at term based on transcriptomics.

BackgroundPremature cervical remodeling/ripening is believed to contribute to preterm delivery (PTD), the leading cause of perinatal morbidity and mortality. Despite considerable research, the causes of term and PTD remain unclear, and there is no effective treatment for PTD. We previously demonstrated that complement activation plays a causative role in cervical remodeling that leads to PTD in mice.Methodology/Principal FindingsHere we found that complement activation is not required for the physiological process that leads to term delivery in mice. Neither increased C3 cervical deposition nor increased C3a and C5a serum levels were observed at term. In addition, macrophages infiltration was found in PTD in contrast to term delivery were no leukocytes were found. Despite the different role of complement and different cellular effector cells, PTD and term delivery share a common dowsntream pathway characterized by increased metalloproteinases (MMPs) release and increased collagen degradation. However, different sources of MMPs were identified. Macrophages are the source of MMPs in PTD while cervical fibroblasts and columnar epithelial cells synthesize MMPs at term delivery. A dramatic diminution in serum progesterone levels precedes parturition at term but not in PTD, suggesting that progesterone withdrawal initiates cervical remodeling at term. On the other hand, MMPs release in PTD is triggered by C5a.Conclusion and SignificanceIn conclusion, preterm and term cervical remodeling occur through the same mechanism but they are initiated by different mediators and effector cells. That complement activation is required for PTD but not for the physiological process that leads to term delivery, suggests that complement is a potential specific biomarker and selective target to prevent PTD and thus avert neonatal mortality and morbidity.

Objective-To elucidate possible mechanisms of fetal neuronal injury in inflammation-induced preterm birth.Study design-Utilizing mouse model of preterm birth, primary cultures were prepared from fetal brains: 1) control neurons (CN); 2) LPS-exposed neurons (LN); 3) control co-culture (CCC), consisting of neurons and glia; 4) LPS-exposed co-culture (LCC), consisting of LPS-exposed neurons and glia. CN and LN were treated with culture media from CN, LN, CCC and LCC after 24 hours in vitro. Immunocytochemistry was performed for culture characterization and neuronal morphology. Quantitative PCR was performed for neuronal differentiation marker, MAP2, and for cell death mediators, Caspases 1, 3 and 9.Results-LPS exposure in vivo did not influence neuronal or glial content in co-cultures but decreased expression of MAP2 in LN. Media from LN and LCC induced morphological changes in control neurons comparable to LN. The neuronal damage caused by in vivo exposure (LN) could not be reversed by media from control groups.Conclusion-LPS-induced preterm birth may be responsible for irreversible neuronal injury.

As the epidemiology of COVID-19 evolves, obstetric care providers and obstetric anesthesiologists must thoughtfully consider routine aspects of inpatient obstetric management and discuss alterations in practice to optimize the safety of our patients and staff. Hospitals should begin collaborations with others in their health region to optimize testing and clinical management protocols for pregnant and postpartum women in their geographic area. These recommendations are not proscriptive and may not apply in your clinical setting. They are intended to introduce concepts to be considered in each setting and give examples of current practices in place. This guidance will be updated as additional data and information emerge. Systems-Level Responses Level of Care Broader health systems and networks should coordinate to identify each hospital's capacity and plans for transferring care as needed to meet both maternal and fetal needs. Communication should frequently occur, as hospital capacities may change rapidly. Cohorting and Other Strategies for Exposure Mitigation One public health intervention to reduce exposure risk is cohorting-co-locating patients who are persons under investigation (PUI) and women who test positive for SARS-CoV2 into a restricted area of the hospital. While not all facilities are able to create an independent obstetrics COVID-19 unit, attempts should be made to designate specific locations for the purposes of containment, which will limit the exposure of unaffected patients and staff.

TMS appears to be a promising treatment option for pregnant women who do not wish to take antidepressant medications.