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OBJECTIVE: To determine the prevalence of acute kidney injury (AKI), placental abruption and postpartum hemorrhage in patients with preeclampsia or HELLP syndrome. STUDY DESIGN: A retrospective study of patients with preeclampsia or HELLP syndrome treated at the University of Mississippi Medical Center from January 2000 through December 2010. MAIN OUTCOME MEASURES: Relationships among the obstetric complications of placental abruption, postpartum hemorrhage, and AKI (serum creatinine > 107 μmol/L) of women with preeclampsia or HELLP syndrome. Additional analysis was undertaken to explore if there was a correlation between postpartum hemorrhage/placental abruption and the severity of HELLP syndrome according to the Mississippi classification system. RESULTS: Data from 1276 women over 11 years were included in the analysis. 67 of 466 patients (14.4%) with HELLP syndrome and 38 of 810 preeclampsia patients (4.7%) met criteria for AKI. Women with either placental abruption or postpartum hemorrhage had statistically significant increased odds of also having AKI (p < 0.01). Women with HELLP and AKI were also more likely to experience either placental abruption or postpartum hemorrhage. Women with Class 1 HELLP with placental abruption or postpartum hemorrhage were also more likely to have AKI than women with preeclampsia. CONCLUSION: HELLP syndrome, AKI and placental abruption or postpartum hemorrhage appear to be interrelated. AKI occurs more frequently in women with HELLP syndrome with or without associated postpartum hemorrhage and placental abruption.

Preeclampsia (PE) is associated with placental ischemia, hypertension (MAP), increased cytolytic natural killer (cNK) cells, tumor necrosis factor alpha (TNF-α) and mitochondrial Reactive Oxygen Species (mt ROS). The reduced uterine perfusion pressure (RUPP) rat model of PE, exhibits many characteristics of PE. We have shown that blockade of TNF-α, via etanercept (ETAN), decreases MAP, however, the effect of ETAN on cNK cells and mt ROS is unknown. We hypothesized that ETAN would decrease cNK cell and mt ROS in RUPP rats. Rats were divided into 3 groups: normal pregnant (NP) (n=20), RUPP (n=20), RUPP + ETAN (0.4 mg/kg) (n=20). On gestational day 14, RUPP surgery was performed, and ETAN was administered on day 18, MAP, blood and tissue mitochondria were collected on day 19. MAP was elevated in RUPP vs. NP (118 ± 2 vs. 102± 1 mmHg, p

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy associated with chronic inflammation, mitochondrial (mt) dysfunction and fetal demise. Natural Killer cells (NK cells) are critical for the innate immune response against tumors or infection by disrupting cellular mt function and causing cell death. Although NK cells can be stimulated by Tumor necrosis factor alpha (TNF-α), we don't know the role of TNF-α on NK cell mediated mt dysfunction during PE. Our objective was to determine if mechanisms of TNF-α induced hypertension included activation of NK cells and multi-organ mt dysfunction during pregnancy. Pregnant rats were divided into 2 groups: normal pregnant (NP) (n = 18) and NP + TNF-α (n = 18). On gestational day 14, TNF-α (50 ng/ml) was infused via mini-osmotic pump and on day 18, carotid artery catheters were inserted. Blood pressure (MAP) and samples were collected on day 19. TNF-α increased MAP (109 ± 2 vs 100 ± 2, p 0.05), circulating cytolytic NK cells (0.771 ± 0.328 vs.0.008 ± 0.003% gated,0.05) and fetal reabsorptions compared to NP rats. Moreover, TNF-α caused mtROS in the placenta (12976 ± 7038 vs 176.9 ± 68.04% fold, p 0.05) and in the kidney (2191 ± 1027 vs 816 ± 454.7% fold, p 0.05) compared to NP rats. TNF-α induced hypertension is associated fetal demise, activation of NK cells and multi-organ mt dysfunction which could be mechanisms for fetal demise and hypertension. Understanding of the mechanisms by which TNF-α causes pathology is important for the use of anti-TNF-α therapeutic agents in pregnancies complicated by PE.

Background Preterm birth (PTB) and pre-eclampsia independently, and frequently concurrently, adversely affect the pregnancy outcomes of millions of mothers and infants worldwide each year. Objectives To fill the gap between PTB and pre-eclampsia, which continue to constitute the two most important current global challenges to maternal and perinatal health. Methods Pubmed, Embase, and Cochrane databases were searched from inception until December 2019 using the terms spontaneous PTB (SPTB), indicated preterm delivery (IPTD), early-onset pre-eclampsia, and pre-eclampsia. Results History of PTB and pre-eclampsia were the strongest risk factors contributing to the occurrence of SPTB or IPTB. The risk of PTB and pre-eclampsia among non-Hispanic African American women was higher than the rate among all other racial/ethnic groups in the United States. Low-dose aspirin (LDA) has been reported to reduce the risk of pre-eclampsia by at least 10% and PTB by at least 14%. Lastly, women and their fetuses who develop early-onset pre-eclampsia are at higher risk for developing hypertension and cardiovascular disease later in life. Conclusions While better clarity is needed, efforts to coordinate prevention of both PTB and pre-eclampsia, even though imperfect, are critically important as part of any program to make motherhood as safe as possible.

Preeclamptic (PE) women have placental ischemia, hypertension (HTN), mitochondrial (mt) dysfunction, increased mt-reactive oxygen species (ROS), cytolytic natural killer (NK) cells, and pro-inflammatory cytokines, such as tumor necrosis factor (TNFα). The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE, is a well-established model to study mechanisms of hypertension in response to placental ischemia during pregnancy. Previous studies from our lab have shown that TNFα is elevated in RUPP rats and that blockade of TNFα, via etanercept (ETAN) decreases TNFα and HTN. However, the effect of TNFα blockade on NK cell activation, mt protein/function, and mtROS is unknown. We hypothesized that ETAN would decrease blood pressure, NK cell activation, mtROS, and improve mt function in RUPP rats. Rats were divided into 4 groups: normal pregnant (NP) (n=41), RUPP (n=34), RUPP+low dose (LD) ETAN (0.4 mg/kg) (n=11), RUPP+high dose (HD) ETAN (0.8 mg/kg) (n=19). LD was used previously, while HD is clinically used to treat chronic inflammatory diseases. Gestational day 14, RUPP surgery was performed and ETAN administered subcutaneous on day 18. Day 19, conscious blood pressure (MAP), blood and tissues were collected, and mt were isolated. Flow cytometry was used for quantification of NK cells. MAP was elevated in RUPP vs. NP (119 ± 1 vs. 102± 1 mmHg, pSupported: AHA18CDA34110264, HL130456, R01HD067541, & P20GM121334

Preeclampsia (PE) is characterized by new-onset hypertension during pregnancy and is associated with immune activation and placental oxidative stress. Mitochondrial dysfunction is a major source of oxidative stress and may play a role in the pathology of PE. We (Vaka VR, et al. Hypertension 72: 703–711, 2018. doi: 10.1161/HYPERTENSIONAHA.118.11290 .) have previously shown that placental ischemia is associated with mitochondrial oxidative stress in the reduced uterine perfusion pressure (RUPP) model of PE. Furthermore, we have also shown that placental ischemia induces natural killer (NK) cell activation in RUPP. Thus, we hypothesize that NK cell depletion could improve mitochondrial function associated with hypertension in the RUPP rat model of PE. Pregnant Sprague-Dawley rats were divided into three groups: normal pregnant (NP), RUPP, and RUPP+NK cell depletion rats (RUPP+NKD). On gestational day ( GD) 14, RUPP surgery was performed, and NK cells were depleted by administering anti-asialo GM1 antibodies (3.5 µg/100 µl ip) on GD15 and GD17. On GD19, mean arterial pressure (MAP) was measured, and placental mitochondria were isolated and used for mitochondrial assays. MAP was elevated in RUPP versus NP rats (119 ± 1 vs.104 ± 2 mmHg, P = 0.0004) and was normalized in RUPP+NKD rats (107 ± 2 mmHg, P = 0.002). Reduced complex IV activity and state 3 respiration rate were improved in RUPP+NKD rats. Human umbilical vein endothelial cells treated with RUPP+NKD serum restored respiration with reduced mitochondrial reactive oxygen species (ROS). The restored placental or endothelial mitochondrial function along with attenuated endothelial cell mitochondrial ROS with NK cell depletion indicate an important role of NK cells in mediating mitochondrial oxidative stress in the pathology of PE.

OBJECTIVE Maternal immune responses are altered during pregnancy and differ between nulliparous and multiparous women. The influence of a prior gestation on autophagy in peripheral blood mononuclear cells (PBMCs) from pregnant women has not been determined and is the subject of this investigation. METHODS Peripheral blood mononuclear cells were isolated from 212 pregnant women and immediately lysed in the presence of protease inhibitors, and the extent of autophagy was determined by quantitation of the concentration of p62 (sequestosome-1) in the lysates by enzyme-linked immunosorbent assay (ELISA). In PBMCs, the p62 level is inversely related to the extent of autophagy. The level of the stress-inducible 70-kDa heat shock protein (hsp70), an inhibitor of autophagy, was also measured in the lysates by ELISA. Data were analyzed by the Spearman rank correlation, Mann-Whitney U test, or Kruskal-Wallis test, as appropriate. RESULTS The p62 concentration in PBMCs increased (autophagy decreased) with the number of previous live ( P = .0322), preterm ( P = .0143), or term ( P = .0418) deliveries. The p62 level was lower (autophagy higher) in women with a prior spontaneous pregnancy loss but no deliveries as compared to women with their first conception ( P = .0087). The intracellular hsp70 concentration correlated with the p62 level ( P < .0001). CONCLUSION Multiparity is associated with a reduced level of autophagy in PBMCs. Dysregulated autophagy might be one mechanism leading to spontaneous abortion in nulliparous women.

We hypothesize that variations in the frequency of genetic polymorphisms, reflecting ancestral differences in living conditions and exposure to microorganisms, increase susceptibility to adverse pregnancy outcome among present day Black North American women. Striking differences were observed in the frequency of genetic variants between Black and White or Hispanic women in 5 genes (IL1RN, MBL2, PPARA, ATG16L1, CIAS1) associated with inflammation and anti-microbial immunity. The CIAS1 and IL1RN polymorphisms were associated with altered interleukin-1β serum levels; the MBL2 polymorphism resulted in a decreased serum mannose-binding lectin concentration. Gene polymorphisms associated with an alteration in innate immunity were most frequent in Black women. This may reflect an evolutionary selection in response to an ancient environment containing a high multitude of microorganisms, and may increase susceptibility of Black women to infection-associated preterm birth in the current North American environment.

Preclinical Research As a result of exposure to the external environment, the human vagina is home to many diverse bacterial species. The composition of the latter varies according to the life stage of the individual female due to differences in hormone production and lifestyle. Advances in bacterial detection using culture-independent methods have greatly altered our knowledge of the composition of the vaginal microbiome especially in nonpregnant reproductive age women. The vaginae of approximately 80% of healthy women are dominated by one of four species of Lactobacillus: L. crispatus, L. iners, L. gasseri, and L. jensenii. The remaining 20% are dominated by a diverse group of anaerobic and facultative bacteria. A predominant characteristic of all bacterial populations in healthy women is the production of lactic acid. The resulting acidification of the vagina retards or prevents the growth of other potentially pathogenic bacteria. Lactic acid also has specific effects on vaginal epithelial cells and immune cells to further protect against pathogen establishment. The interactions between bacterial species as well as their ability to produce various metabolites also influences the composition of the host vaginal immune and biochemical milieu and influences susceptibility to various lower genital tract infections as well as the capability of bacteria to transcend the cervical barrier and invade the upper genital tract. In pregnant women migration of bacteria from the vagina to the uterus is a major cause of preterm birth. A more complete understanding of the composition of the vaginal microbiome and its influence on host processes will lead to development of new protocols utilizing novel reagents to improve the health of pregnant as well as nonpregnant women.

Objective Mechanisms leading to pre-eclampsia remain incompletely defined. Autophagy is a conserved process necessary for cell survival under adverse conditions. We hypothesised that sera from women with healthy pregnancies and women with pre-eclampsia differed in autophagy induction. Design A case–control study. Setting Weill Cornell Medical College. Population Twenty-four normotensive pregnant women and 20 women with pre-eclampsia. Methods Sera were incubated with peripheral blood mononuclear cells (PBMCs) from female donors. After 48 hours the PBMCs were lysed and the intracellular concentration of p62 was determined by enzyme-linked immunosorbent assay (ELISA). Its concentration is inversely proportional to the extent of autophagy induction. Serum endoglin, interleukin 13 (IL–13), insulin-like growth factor 1 (IGF–1), and transforming growth factor β1 (TGF–β1) levels were quantitated by ELISA. Main outcome measures Differences in autophagy induction and serum mediator levels in the two groups. Results Autophagy induction increased with gestational age in sera from normotensive women (P = 0.0045), but not in women with pre-eclampsia. In the presence of an autophagy inducer, the capacity for autophagy induction decreased with gestational age in sera from women with pre-eclampsia (P = 0.0235), but not from controls. Endoglin concentrations were positively associated with the extent of autophagy induction in controls only (P = 0.0141). There was no association between autophagy and serum IL–13, IGF–1, or TGF–β1 levels. Conclusions Sera from women with pre-eclampsia differ from normotensive women by their inability to induce autophagy as a function of gestational age.

Autophagy is a highly conserved process by which defective organelles, non-functional proteins, and intracellular microorganisms become sequestered within structures called autophagosomes, which fuse with lysosomes and the engulfed components are degraded by lysosomal enzymes. In microbial autophagy degraded peptides are used to induce antigen-specific acquired immunity. Viruses, bacteria, fungi, and protozoa have developed strategies to subvert autophagy and/or to use this process to promote their replication and persistence. This review details the mechanisms by which microorganisms that infect the female genital tract and/or are detrimental to pregnancy interact with this host defence mechanism. Based on an understanding of autophagy-related pathological mechanisms, we propose new avenues for research to more effectively prevent and/or treat these infectious diseases.

We evaluated levels of vaginal extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP-8) in vaginal secretions in relation to the composition of vaginal bacterial communities and d- and l-lactic acid levels. The composition of vaginal bacterial communities in 46 women was determined by pyrosequencing the V1 to V3 region of 16S rRNA genes. Lactobacilli were dominant in 71.3% of the women, followed by Gardnerella (17.4%), Streptococcus (8.7%), and Enterococcus (2.2%). Of the lactobacillus-dominated communities, 51.5% were dominated by Lactobacillus crispatus, 36.4% by Lactobacillus iners, and 6.1% each by Lactobacillus gasseri and Lactobacillus jensenii. Concentrations of l-lactic acid were slightly higher in lactobacillus-dominated vaginal samples, but most differences were not statistically significant. d-Lactic acid levels were higher in samples containing L. crispatus than in those with L. iners (P < 0.0001) or Gardnerella (P = 0.0002). The relative proportion of d-lactic acid in vaginal communities dominated by species of lactobacilli was in concordance with the proportions found in axenic cultures of the various species grown in vitro. Levels of l-lactic acid (P < 0.0001) and the ratio of l-lactic acid to d-lactic acid (P = 0.0060), but not concentrations of d-lactic acid, were also correlated with EMMPRIN concentrations. Moreover, vaginal concentrations of EMMPRIN and MMP-8 levels were highly correlated (P < 0.0001). Taken together, the data suggest the relative proportion of l- to d-lactic acid isomers in the vagina may influence the extent of local EMMPRIN production and subsequent induction of MMP-8. The expression of these proteins may help determine the ability of bacteria to transverse the cervix and initiate upper genital tract infections., IMPORTANCE A large proportion of preterm births (>50%) result from infections caused by bacteria originating in the vagina, which requires that they traverse the cervix. Factors that influence susceptibility to these infections are not well understood; however, there is evidence that matrix metalloproteinase (MMP-8) is known to alter the integrity of the cervix. In this work, we show that concentrations of vaginal extracellular matrix metalloproteinase inducer (EMMPRIN) are influenced by members of the vaginal microbial community and concentrations of d- or l-lactic acid isomers in vaginal secretions. Elevated levels of d-lactic acid and the ratio of d- to l-lactic acid influence EMMPRIN concentrations as well as MMP-8 levels. Thus, isomers of lactic acid may function as signaling molecules that alter host gene expression and influence risk of infection-related preterm birth.

Objective Women with vestibulodynia exhibit increased pain sensitivity to contact with the vaginal vestibule as well as with vaginal penetration. The mechanism(s) responsible for this effect remains incompletely defined. Based on reports of a possible role for proteases in induction of pain, we compared levels of proteases and protease inhibitors in vaginal secretions from women with vestibulodynia and controls. Study Design Vaginal secretions from 76 women with vestibulodynia and from 41 control women were assayed by an enzyme-linked immunosorbent assay for the protease inhibitors, secretory leukocyte protease inhibitor (SLPI) and human epididymis protein-4 (HE-4), and the proteases, kallikrein-5 and cathepsins B and S. Concentrations between subjects and controls were compared and levels related to clinical and demographic variables. Results Concentrations of HE-4 and SLPI were markedly reduced in vaginal samples from women with vestibulodynia compared with controls ( P ≤ .006). All other compounds were similar in both groups. HE-4 ( P = .0195) and SLPI ( P = .0033) were lower in women with secondary, but not primary, vestibulodynia than in controls. Subjects who had constant vulvar pain had lower levels of HE-4 and SLPI than did healthy control women ( P ≤ .006) or women who experienced vulvar pain only during sexual intercourse ( P ≤ .0191). There were no associations between HE-4 or SLPI levels and event associated with symptom onset, duration of symptoms, age, number of lifetime sexual partners, or age at sex initiation. Conclusion Insufficient vaginal protease inhibitor production may contribute to increased pain sensitivity in an undefined subset of women with secondary vestibulodynia who experience constant vulvar pain.