Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology.

BACKGROUND: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. OBJECTIVE: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. STUDY DESIGN: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. RESULTS: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. CONCLUSION: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.

Experience of a telehealth and education program with maternal and perinatal outcomes in a low-resource region in Colombia.

INTRODUCTION: Maternal morbidity and mortality rates associated with perinatal care remain a significant public health concern. Rural populations from low and middle-income countries have multiple barriers to access that contribute to a lack of adherence to prenatal care, and high rates of maternal mortality and morbidity. An intervention model based on telehealth and education was implemented between a tertiary high complex care hospital and a second-level hospital from a limited source region. OBJECTIVES: We sought to identify an association in maternal and perinatal care quality indicators after implementing a model based on telehealth and education for patients with obstetric emergencies between two hospitals in a southwestern region of Colombia. METHODS: We conducted an ecological study between 2017 and 2019 to compare before and after obstetric emergency care through telemedicine from a secondary care center (Hospital Francisco de Paula Santander-HFPS) to the referral center (Fundación Valle del Lili-FVL). The intervention included verification visits to determine the installed capacity of care, a concerted improvement plan, and on-site educational training modules in obstetric and perinatal care. RESULTS: There were 102 and 148 patients treated before and after telemedicine implementation respectively. Clinical indicators after model implementation showed a reduction in perinatal mortality of 29%. In addition, a reduction in the need for transfusion of blood products due to postpartum hemorrhage was observed as well as the rate of eclampsia. CONCLUSIONS: Implementing a model based on telehealth and education between secondary and tertiary care centers allowed the strengthening of the security of care in obstetric emergencies and had a positive effect on perinatal mortality.

Personalized assessment of cervical length improves prediction of spontaneous preterm birth: a standard and a percentile calculator.

BACKGROUND: A sonographic short cervix (length <25 mm during midgestation) is the most powerful predictor of preterm birth. Current clinical practice assumes that the same cervical length cutoff value should apply to all women when screening for spontaneous preterm birth, yet this approach may be suboptimal. OBJECTIVE: This study aimed to (1) create a customized cervical length standard that considers relevant maternal characteristics and gestational age at sonographic examination and (2) assess whether the customization of cervical length evaluation improves the prediction of spontaneous preterm birth. STUDY DESIGN: This retrospective analysis comprises a cohort of 7826 pregnant women enrolled in a longitudinal protocol between January 2006 and April 2017 at the Detroit Medical Center. Study participants met the following inclusion criteria: singleton pregnancy, ≥1 transvaginal sonographic measurements of the cervix, delivery after 20 weeks of gestation, and available relevant demographics and obstetrical history information. Data from women without a history of preterm birth or cervical surgery who delivered at term without progesterone treatment (N=5188) were used to create a customized standard of cervical length. The prediction of the primary outcome, spontaneous preterm birth at <37 weeks of gestation, was assessed in a subset of pregnancies (N=7336) that excluded cases with induced labor before 37 weeks of gestation. Area under the receiver operating characteristic curve and sensitivity at a fixed false-positive rate were calculated for screening at 20 to 23 6/7, 24 to 27 6/7, 28 to 31 6/7, and 32 to 35 6/7 weeks of gestation in asymptomatic patients. Survival analysis was used to determine which method is better at predicting imminent delivery among symptomatic women. RESULTS: The median cervical length remained fundamentally unchanged until 20 weeks of gestation and subsequently decreased nonlinearly with advancing gestational age among women who delivered at term. The effects of parity and maternal weight and height on the cervical length were dependent on the gestational age at ultrasound examination (interaction, P<.05 for all). Parous women had a longer cervix than nulliparous women, and the difference increased with advancing gestation after adjusting for maternal weight and height. Similarly, maternal weight was nonlinearly associated with a longer cervix, and the effect was greater later in gestation. The sensitivity at a 10% false-positive rate for prediction of spontaneous preterm birth at <37 weeks of gestation by a short cervix ranged from 29% to 40% throughout pregnancy, yet it increased to 50%, 50%, 53%, and 54% at 20 to 23 6/7, 24 to 27 6/7, 28 to 31 6/7, and 32 to 35 6/7 weeks of gestation, respectively, for a low, customized percentile (McNemar test, P<.001 for all). When a cervical length <25 mm was compared to the customized screening at 20 to 23 6/7 weeks of gestation by using a customized percentile cutoff value that ensured the same negative likelihood ratio for both screening methods, the customized approach had a significantly higher (about double) positive likelihood ratio in predicting spontaneous preterm birth at <33, <34, <35, <36, and <37 weeks of gestation. Among symptomatic women, the difference in survival between women with a customized cervical length percentile of ≥10th and those with a customized cervical length percentile of <10th was greater than the difference in survival between women with a cervical length ≥25 mm and those with a cervical length <25 mm. CONCLUSION: Compared to the use of a cervical length <25 mm, a customized cervical length assessment (1) identifies more women at risk of spontaneous preterm birth and (2) improves the distinction between patients at risk for impending preterm birth in those who have an episode of preterm labor.

Clinical chorioamnionitis at term X: microbiology, clinical signs, placental pathology, and neonatal bacteremia - implications for clinical care.

OBJECTIVES: Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5-12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. The objectives of this study were to determine the (1) amniotic fluid microbiology using cultivation and molecular microbiologic techniques; (2) diagnostic accuracy of the clinical criteria used to identify patients with intra-amniotic infection; (3) relationship between acute inflammatory lesions of the placenta (maternal and fetal inflammatory responses) and amniotic fluid microbiology and inflammatory markers; and (4) frequency of neonatal bacteremia. METHODS: This retrospective cross-sectional study included 43 women with the diagnosis of clinical chorioamnionitis at term. The presence of microorganisms in the amniotic cavity was determined through the analysis of amniotic fluid samples by cultivation for aerobes, anaerobes, and genital mycoplasmas. A broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry was also used to detect bacteria, select viruses, and fungi. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin-6 (IL-6) concentration ≥2.6 ng/mL. RESULTS: (1) Intra-amniotic infection (defined as the combination of microorganisms detected in amniotic fluid and an elevated IL-6 concentration) was present in 63% (27/43) of cases; (2) the most common microorganisms found in the amniotic fluid samples were Ureaplasma species, followed by Gardnerella vaginalis; (3) sterile intra-amniotic inflammation (elevated IL-6 in amniotic fluid but without detectable microorganisms) was present in 5% (2/43) of cases; (4) 26% of patients with the diagnosis of clinical chorioamnionitis had no evidence of intra-amniotic infection or intra-amniotic inflammation; (5) intra-amniotic infection was more common when the membranes were ruptured than when they were intact (78% [21/27] vs. 38% [6/16]; p=0.01); (6) the traditional criteria for the diagnosis of clinical chorioamnionitis had poor diagnostic performance in identifying proven intra-amniotic infection (overall accuracy, 40-58%); (7) neonatal bacteremia was diagnosed in 4.9% (2/41) of cases; and (8) a fetal inflammatory response defined as the presence of severe acute funisitis was observed in 33% (9/27) of cases. CONCLUSIONS: Clinical chorioamnionitis at term, a syndrome that can result from intra-amniotic infection, was diagnosed in approximately 63% of cases and sterile intra-amniotic inflammation in 5% of cases. However, a substantial number of patients had no evidence of intra-amniotic infection or intra-amniotic inflammation. Evidence of the fetal inflammatory response syndrome was frequently present, but microorganisms were detected in only 4.9% of cases based on cultures of aerobic and anaerobic bacteria in neonatal blood.

Clinical chorioamnionitis at term IX: in vivo evidence of intra-amniotic inflammasome activation.

Background The inflammasome has been implicated in the mechanisms that lead to spontaneous labor at term. However, whether the inflammasome is activated in the amniotic cavity of women with clinical chorioamnionitis at term is unknown. Herein, by measuring extracellular ASC [apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (CARD)], we investigated whether there is in vivo inflammasome activation in amniotic fluid of patients with clinical chorioamnionitis at term with sterile intra-amniotic inflammation and in those with intra-amniotic infection. Methods This was a retrospective cross-sectional study that included amniotic fluid samples collected from 76 women who delivered after spontaneous term labor with diagnosed clinical chorioamnionitis. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin (IL)-6 concentration ≥2.6 ng/mL, and intra-amniotic infection was diagnosed by the presence of microbial invasion of the amniotic cavity (MIAC) accompanied by intra-amniotic inflammation. Patients were classified into the following groups: (1) women without intra-amniotic inflammation or infection (n=16); (2) women with MIAC but without intra-amniotic inflammation (n=5); (3) women with sterile intra-amniotic inflammation (n=15); and (4) women with intra-amniotic infection (n=40). As a readout of in vivo inflammasome activation, extracellular ASC was measured in amniotic fluid by enzyme-linked immunosorbent assay. Acute inflammatory responses in the amniotic fluid and placenta were also evaluated. Results In clinical chorioamnionitis at term: (1) amniotic fluid concentrations of ASC (extracellular ASC is indicative of in vivo inflammasome activation) and IL-6 were greater in women with intra-amniotic infection than in those without intra-amniotic inflammation, regardless of the presence of MIAC; (2) amniotic fluid concentrations of ASC and IL-6 were also higher in women with sterile intra-amniotic inflammation than in those without intra-amniotic inflammation, regardless of the presence of MIAC; (3) amniotic fluid concentrations of IL-6, but not ASC, were more elevated in women with intra-amniotic infection than in those with sterile intra-amniotic inflammation; (4) a positive and significant correlation was observed between amniotic fluid concentrations of ASC and IL-6; (5) no differences were observed in amniotic fluid ASC and IL-6 concentrations between women with and without MIAC in the absence of intra-amniotic inflammation; (6) women with intra-amniotic infection had elevated white blood cell counts and reduced glucose levels in amniotic fluid compared to the other three study groups; and (7) women with intra-amniotic infection presented higher frequencies of acute maternal and fetal inflammatory responses in the placenta than those with sterile intra-amniotic inflammation. Conclusion The intra-amniotic inflammatory response, either induced by alarmins or microbes, is characterized by the activation of the inflammasome - as evidenced by elevated amniotic fluid concentrations of extracellular ASC - in women with clinical chorioamnionitis at term. These findings provide insight into the intra-amniotic inflammatory response in women with clinical chorioamnionitis at term.

Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals up-regulation of leukotriene B4.

Bioactive lipids derived from the metabolism of polyunsaturated fatty acids are important mediators of the inflammatory response. Labor per se is considered a sterile inflammatory process. Intra-amniotic inflammation (IAI) due to microorganisms (i.e., intra-amniotic infection) or danger signals (i.e., sterile IAI) has been implicated in the pathogenesis of preterm labor and clinical chorioamnionitis at term. Early and accurate diagnosis of microbial invasion of the amniotic cavity (MIAC) requires analysis of amniotic fluid (AF). It is possible that IAI caused by microorganisms is associated with a stereotypic lipidomic profile, and that analysis of AF may help in the identification of patients with this condition. To test this hypothesis, we analyzed the fatty acyl lipidome of AF by liquid chromatography-mass spectrometry from patients in spontaneous labor at term and preterm gestations. We report that the AF concentrations of proinflammatory lipid mediators of the 5-lipoxygenase pathway are significantly higher in MIAC than in cases of sterile IAI. These results suggest that the concentrations of 5-lipoxygenase metabolites of arachidonic acid, 5-hydroxyeicosatetraenoic acid, and leukotriene B4 in particular could serve as potential biomarkers of MIAC. This finding could have important implications for the rapid identification of patients who may benefit from anti-microbial treatment.-Maddipati, K. R., Romero, R., Chaiworapongsa ,T., Chaemsaithong, P., Zhou, S.-L., Xu, Z., Tarca, A. L., Kusanovic, J. P., Gomez, R., Chaiyasit, N., Honn, K. V. Lipidomic analysis of patients with microbial invasion of the amniotic cavity reveals up-regulation of leukotriene B4.

Clinical chorioamnionitis at term VIII: a rapid MMP-8 test for the identification of intra-amniotic inflammation.

OBJECTIVE: Clinical chorioamnionitis is the most common infection/inflammatory process diagnosed in labor and delivery units worldwide. The condition is a syndrome that can be caused by (1) intra-amniotic infection, (2) intra-amniotic inflammation without demonstrable microorganisms (i.e. sterile intra-amniotic inflammation), and (3) maternal systemic inflammation that is not associated with intra-amniotic inflammation. The presence of intra-amniotic inflammation is a risk factor for adverse maternal and neonatal outcomes in a broad range of obstetrical syndromes that includes clinical chorioamnionitis at term. Although the diagnosis of intra-amniotic infection has relied on culture results, such information is not immediately available for patient management. Therefore, the diagnosis of intra-amniotic inflammation could be helpful as a proxy for intra-amniotic infection, while results of microbiologic studies are pending. A rapid test is now available for the diagnosis of intra-amniotic inflammation, based on the determination of neutrophil collagenase or matrix metalloproteinase-8 (MMP-8). The objectives of this study were (1) to evaluate the diagnostic indices of a rapid MMP-8 test for the identification of intra-amniotic inflammation/infection in patients with the diagnosis of clinical chorioamnionitis at term, and (2) to compare the diagnostic performance of a rapid MMP-8 test to that of a conventional enzyme-linked immunosorbent assay (ELISA) interleukin (IL)-6 test for patients with clinical chorioamnionitis at term. MATERIALS AND METHODS: A retrospective cohort study was conducted. A transabdominal amniocentesis was performed in patients with clinical chorioamnionitis at term (n=44). Amniotic fluid was analyzed using cultivation techniques (for aerobic and anaerobic bacteria as well as genital Mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). Amniotic fluid IL-6 concentrations were determined by ELISA, and rapid MMP-8 results were determined by Yoon's MMP-8 Check®. Intra-amniotic inflammation was defined as an elevated amniotic fluid IL-6 concentration ≥2.6 ng/mL, and intra-amniotic infection was diagnosed by the presence of microorganisms in the amniotic fluid accompanied by intra-amniotic inflammation. The diagnostic indices of Yoon's MMP-8 Check® for the identification of intra-amniotic inflammation were calculated. In order to objectively compare Yoon's MMP-8 Check® with the ELISA IL-6 test for the identification of intra-amniotic inflammation, we used an amniotic fluid white blood cell (WBC) count ≥50 cells/mm3 to define intra-amniotic inflammation. RESULTS: (1) A positive rapid MMP-8 test had a sensitivity of 82.4% (28/34), specificity of 90% (9/10), positive predictive value of 96.6% (28/29), negative predictive value of 60% (9/15), positive likelihood ratio 8.2 (95% CI 1.3-53.2), and negative likelihood ratio 0.2 (95% CI 0.1-0.4) for the identification of intra-amniotic inflammation (prevalence 77.3%); (2) a positive rapid MMP-8 test had a sensitivity of 91.7% (22/24), specificity of 65% (13/20), positive predictive value of 75.9% (22/29), negative predictive value of 86.7% (13/15), positive likelihood ratio of 2.6 (95% CI 1.4-4.8), and negative likelihood ratio of 0.1 (95% CI 0.03-0.5) for the identification of intra-amniotic infection; (3) the rapid MMP-8 test had a significantly higher specificity than the ELISA IL-6 test in the identification of intra-amniotic inflammation as determined by an amniotic fluid WBC count ≥50 cells/mm3. The sensitivity and accuracy of the rapid MMP-8 test were comparable to those of the ELISA IL-6 test; and (4) importantly, the rapid MMP-8 test had 100% sensitivity and 100% negative predictive value in the identification of neonates affected with fetal inflammatory response syndrome (FIRS). CONCLUSION: The rapid diagnosis of intra-amniotic inflammation is possible by analysis of amniotic fluid using a point-of-care test for MMP-8. Patients with a positive test are at risk of delivering a neonate affected with systemic inflammation, a risk factor for adverse neonatal outcome.

Clinical chorioamnionitis at term: the amniotic fluid fatty acyl lipidome.

Clinical chorioamnionitis at term (TCC) is the most common obstetrical infliction diagnosed in labor and delivery units worldwide and is associated with a substantial increase in maternal and neonatal morbidity and mortality. This obstetrical complication is a heterogeneous condition, as only half of patients have detectable microorganisms in the amniotic cavity. Because bioactive lipids play a key role in the initiation and resolution of an inflammatory response, we aimed to characterize the amniotic fluid lipidome in patients with TCC. We studied the amniotic fluid of patients in the following groups: 1) spontaneous labor at term without clinical chorioamnionitis (TLB) and 2) spontaneous labor at term with clinical chorioamnionitis (TCC). The TCC group was subdivided into a) those with microbial invasion of the amniotic cavity (TCC-MIAC) and b) those without microbial invasion of the amniotic cavity (TCC-noMIAC). The amniotic fluid concentration of proinflammatory lipid mediators did not differ between patients in TLB with TCC. In contrast, concentration of lipids with anti-inflammatory/proresolution properties was significantly lower in all patients with TCC than in those with TLB. These results suggest that while proinflammatory lipid mediators are involved in infection-driven intra-amniotic inflammation, a relative deficiency of anti-inflammatory/proresolution lipid mediator biosynthesis is a characteristic of TCC.

Placental biomarkers and angiogenic factors in oral fluids of patients with preeclampsia.

OBJECTIVES: The objectives of this study are to explore the feasibility of measuring endothelial and placental biomarkers in saliva and gingival crevicular fluid (GCF) and to determine if patients with preeclampsia (PE) have a different profile of these biomarkers in oral fluids. METHOD: A case-control study was conducted, including patients with PE (n = 10) and a control group with normal pregnancies randomly selected (n = 20) admitted at the Sótero del Río Hospital in Santiago, Chile. A complete periodontal and obstetric history that involved the collection of oral fluids was performed at the same gestational age. Levels of Cd63(+) extracellular vesicles, placental alkaline phosphatase (PLAP), placental growth factor (PlGF), and sFlt-1 levels were determined by ELISA assays. Data analysis was performed with chi-square or Fisher's exact test, and Mann-Whitney U-test for continuous variables. The association was assessed using a multiple logistic regression model. RESULTS: sFlt-1 concentrations in saliva and GCF were significantly higher in patients with PE (p = 0.045 and p = 0.033 respectively). Concentrations of PLAP were elevated in GCF of patients with PE (p = 0.049). The PLAP/CD63(+) ratio in GCF of patients with PE was significantly higher (p = 0.0008). No differences in PlGF levels were observed. CONCLUSION(S): GCF of patients with PE concentrates higher levels of biomarkers related with the PE development. © 2016 John Wiley & Sons, Ltd.

Characterization of visceral and subcutaneous adipose tissue transcriptome in pregnant women with and without spontaneous labor at term: implication of alternative splicing in the metabolic adaptations of adipose tissue to parturition.

OBJECTIVE: The aim of this study was to determine gene expression and splicing changes associated with parturition and regions (visceral vs. subcutaneous) of the adipose tissue of pregnant women. STUDY DESIGN: The transcriptome of visceral and abdominal subcutaneous adipose tissue from pregnant women at term with (n=15) and without (n=25) spontaneous labor was profiled with the Affymetrix GeneChip Human Exon 1.0 ST array. Overall gene expression changes and the differential exon usage rate were compared between patient groups (unpaired analyses) and adipose tissue regions (paired analyses). Selected genes were tested by quantitative reverse transcription-polymerase chain reaction. RESULTS: Four hundred and eighty-two genes were differentially expressed between visceral and subcutaneous fat of pregnant women with spontaneous labor at term (q-value <0.1; fold change >1.5). Biological processes enriched in this comparison included tissue and vasculature development as well as inflammatory and metabolic pathways. Differential splicing was found for 42 genes [q-value <0.1; differences in Finding Isoforms using Robust Multichip Analysis scores >2] between adipose tissue regions of women not in labor. Differential exon usage associated with parturition was found for three genes (LIMS1, HSPA5, and GSTK1) in subcutaneous tissues. CONCLUSION: We show for the first time evidence of implication of mRNA splicing and processing machinery in the subcutaneous adipose tissue of women in labor compared to those without labor.

Eicosanomic profiling reveals dominance of the epoxygenase pathway in human amniotic fluid at term in spontaneous labor.

Lipid mediators play an important role in reproductive biology, especially, in parturition. Enhanced biosynthesis of eicosanoids, such as prostaglandin E2 (PGE2) and PGF2α, precedes the onset of labor as a result of increased expression of inducible cyclooxygenase 2 (COX-2) in placental tissues. Metabolism of arachidonic acid results in bioactive lipid mediators beyond prostaglandins that could significantly influence myometrial activity. Therefore, an unbiased lipidomic approach was used to profile the arachidonic acid metabolome of amniotic fluid. In this study, liquid chromatography-mass spectrometry was used for the first time to quantitate these metabolites in human amniotic fluid by comparing patients at midtrimester, at term but not in labor, and at term and in spontaneous labor. In addition to exposing novel aspects of COX pathway metabolism, this lipidomic study revealed a dramatic increase in epoxygenase- and lipoxygenase-pathway-derived lipid mediators in spontaneous labor with remarkable product selectivity. Despite their recognition as anti-inflammatory lipid mediators and regulators of ion channels, little is known about the epoxygenase pathway in labor. Epoxygenase pathway metabolites are established regulators of vascular homeostasis in cardiovascular and renal physiology. Their presence as the dominant lipid mediators in spontaneous labor at term portends a yet undiscovered physiological function in parturition.

Effectiveness of a normative nutrition intervention (diet, physical activity and breastfeeding) on maternal nutrition and offspring growth: the Chilean maternal and infant nutrition cohort study (CHiMINCs).

BACKGROUND: Maternal obesity before and during pregnancy predicts maternal and infant risks of obesity and its associated metabolic conditions. Dietary and physical activity recommendations during pregnancy as well as weight monitoring are currently available in the Chilean primary health care system. However some of these recommendations are not updated and most of them are poorly implemented. We seek to assess the effectiveness of an intervention that enhances the implementation of updated nutrition health care standards (diet, physical activity, and breastfeeding promotion) during pregnancy on maternal weight gain and infant growth. DESIGN & SETTING: Cluster randomized controlled trial. The cluster units will be 12 primary health care centers from two counties (La Florida and Puente Alto) from the South-East Area of Santiago randomly allocated to: 1) enhanced nutrition health care standards (intervention group) or 2) routine care (control group). PARTICIPANTS: Women seeking prenatal care before 15 weeks of gestation, residing within a catchment area of selected health centers, and who express that they are not planning to change residence will be invited to participate in the study. Pregnant women classified as high risk according to the Chilean norms (i.e age <16 or >40 years, multiple gestation, pre-gestational medical conditions, previous pregnancy-related issues) and/or underweight will be excluded. INTERVENTION: Pregnant women who attend intervened health care centers starting at their first prenatal visit will receive advice regarding optimal weight gain during pregnancy and diet and physical activity counseling-support. Pregnant women who attend control health clinics will receive routine antenatal care according to national guidelines. We plan to recruit 200 women in each health center. Assuming a 20% loss to follow up, we expect to include 960 women per arm. MAIN OUTCOME MEASURES: 1) Achievement of adequate weight gain based on IOM 2009 recommendations and adequate glycaemic control at 24-28 weeks of pregnancy according to ADA 2011, and 2) healthy infant growth during the first year of age based on WHO standards. DISCUSSION: We expect that the intervention will benefit the participants in achieving adequate weight gain & metabolic control during pregnancy as well as adequate infant growth as a result of an increased impact of standard nutrition and health care practices. Gathered information should contribute to a better understanding of how to develop effective interventions to halt the maternal obesity epidemic and its associated co-morbidities in the Chilean population. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01916603.

Maternal plasma concentrations of angiogenic/antiangiogenic factors in the third trimester of pregnancy to identify the patient at risk for stillbirth at or near term and severe late preeclampsia.

OBJECTIVE: To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) at 30-34 weeks of gestation can identify patients at risk for stillbirth, late preeclampsia, and delivery of small-for-gestational-age (SGA) neonates. STUDY DESIGN: A prospective cohort study included 1269 singleton pregnant women from whom blood samples were obtained at 30-34 weeks of gestation and who delivered at >34 weeks of gestation. Plasma concentrations of PlGF, sEng, and sVEGFR-1 were determined by enzyme-linked immunosorbent assay. RESULTS: The prevalence of late (>34 weeks of gestation) preeclampsia, severe late preeclampsia, stillbirth, and SGA was 3.2% (n = 40), 1.8% (n = 23), 0.4% (n = 5), and 8.5% (n = 108), respectively. A plasma concentration of PlGF/sEng <0.3 MoM was associated with severe late preeclampsia (adjusted odds ratio, 16); the addition of PlGF/sEng to clinical risk factors increased the area under the receiver-operating characteristic curve from 0.76 to 0.88 (P = .03). The ratio of PlGF/sEng or PlGF/sVEGFR-1 in the third trimester outperformed those obtained in the first or second trimester and uterine artery Doppler velocimetry at 20-25 weeks of gestation for the prediction of severe late preeclampsia (comparison of areas under the receiver-operating characteristic curve; each P ≤ .02). Both PlGF/sEng and PlGF/sVEGFR-1 ratios achieved a sensitivity of 74% with a fixed false-positive rate of 15% for the identification of severe late preeclampsia. A plasma concentration of PlGF/sVEGFR-1 <0.12 MoM at 30-34 weeks of gestation had a sensitivity of 80%, a specificity of 94%, and a likelihood ratio of a positive test of 14 for the identification of subsequent stillbirth. Similar findings (sensitivity 80%; specificity 93%) were observed in a separate case-control study. CONCLUSION: Risk assessment for stillbirth and severe late preeclampsia in the third trimester is possible with the determination of maternal plasma concentrations of angiogenic and antiangiogenic factors at 30-34 weeks of gestation.

The fetal cardiovascular response to increased placental vascular impedance to flow determined with 4-dimensional ultrasound using spatiotemporal image correlation and virtual organ computer-aided analysis.

OBJECTIVE: We sought to determine if increased placental vascular impedance to flow is associated with changes in fetal cardiac function using spatiotemporal image correlation and virtual organ computer-aided analysis. STUDY DESIGN: A cross-sectional study was performed in fetuses with umbilical artery pulsatility index >95th percentile (abnormal [ABN]). Ventricular volume (end-systole, end-diastole), stroke volume, cardiac output (CO), adjusted CO, and ejection fraction were compared to those of 184 normal fetuses. RESULTS: A total of 34 fetuses were evaluated at a median gestational age of 28.3 (range, 20.6-36.9) weeks. Mean ventricular volumes were lower for ABN than normal cases (end-systole, end-diastole) with a proportionally greater decrease for left ventricular volume (vs right). Mean left and right stroke volume, CO, and adjusted CO were lower for ABN (vs normal) cases. Right ventricular volume, stroke volume, CO, and adjusted CO exceeded the left in ABN fetuses. Mean ejection fraction was greater for ABN than normal cases. Median left ejection fraction was greater (vs right) in ABN fetuses. CONCLUSION: Increased placental vascular impedance to flow is associated with changes in fetal cardiac function.

miR-210 targets iron-sulfur cluster scaffold homologue in human trophoblast cell lines: siderosis of interstitial trophoblasts as a novel pathology of preterm preeclampsia and small-for-gestational-age pregnancies.

This study was performed to assess the biological significance of miR-210 in preeclampsia and small-for-gestational-age (SGA) pregnancies. Placental miR-210 expression was evaluated by quantitative RT-PCR (RT-qPCR) in the following groups: i) appropriate-for-gestational-age pregnancies (n = 72), ii) preeclampsia (n = 52), iii) SGA (n = 66), and iv)preeclampsia with SGA (n = 31). The effects of hypoxia (1% O(2)) on miR-210 and iron-sulfur cluster scaffold homologue (ISCU) expressions and miR-210 binding to ISCU 3' UTR were examined in Swan 71 and BeWo cell lines. Perls' reaction (n = 229) and electron microscopy (n = 3) were conducted to verify siderosis of trophoblasts. miR-210 expression was increased in preeclampsia and SGA cases and was decreased with birth weight and gestational age. In both cell lines, miR-210 was induced by hypoxia, whereas ISCU expression was decreased. The luciferase assay confirmed miR-210 binding to ISCU mRNA 3' UTR. RNA interference knockdown of ISCU expression in Swan 71, but not in BeWo, cells resulted in autophagosomal and siderosomal iron accumulation and a fourfold decrease of Matrigel invasion (P = 0.004). Placental ISCU expression was decreased in preeclampsia (P = 0.002) and SGA (P = 0.002) cases. Furthermore, hemosiderin-laden trophoblasts were more frequent in the placental bed of preterm preeclampsia and/or SGA births than in control cases (48.7% versus 17.9%; P = 0.004). Siderosis of interstitial trophoblasts is a novel pathological feature of preeclampsia and SGA. The findings herein suggest that ISCU down-regulation by miR-210 perturbing trophoblast iron metabolism is associated with defective placentation.

Surfactant protein-A as an anti-inflammatory component in the amnion: implications for human pregnancy.

The mechanism of mouse parturition is thought to involve myometrial infiltration by amniotic fluid (AF) macrophages, activated by surfactant protein-A (SP-A). In humans, the concentration of AF SP-A decreases during labor, and no fetal macrophages are found in the myometrium after labor. Therefore, it appears that the mechanisms of labor in mice and humans are different. We investigated a potential role for SP-A in human pregnancy and parturition by examining SP-A expression patterns in AF and amnion. High molecular mass (>250 kDa) oligomeric SP-A was increased in AF with advancing gestation. Interestingly, these oligomers were more abundant in placental amnion before labor at term, while they increased primarily in reflected amnion during labor (p < 0.05). Immunoblotting showed a binding of high molecular mass SP-A in AF to amnion. In C57BL/6 mice, oligomeric SP-A was also readily detected in AF from E15 onwards, but not in amnion. Macrophage density in mice myometrium did not change with advancing gestational age. Microarray analysis of human amnion explants incubated with SP-A revealed a molecular signature of inhibited cytokine-cytokine receptor interaction with downregulation of IL-1beta, CXCL2, and CXCL5 mRNA expression. The findings in this study strongly suggest that SP-A signals amniotic anti-inflammatory response via AF during pregnancy. We propose that an SP-A interaction among AF, placental amnion, and reflected amnion is a unique mechanism for immunoregulation in human pregnancy akin to that established in lung biology. However, AF SP-A and fetal macrophages by themselves do not seem to be exclusive effectors of parturition in humans.

Characterization of amniotic fluid sludge in preterm and term gestations.

OBJECTIVE: To describe the characteristics of amniotic fluid sludge obtained from patients in term and preterm gestations. METHODS: This cross-sectional study included patients with dense aggregates of particulate matter detected in amniotic fluid, observed with transvaginal sonography. All patients were in labor and had an impending delivery, either preterm or at term. Echogenic material contained within amniotic fluid was retrieved transvaginally by needle amniotomy under direct visualization. The amniotic fluid analysis consisted of a Gram stain, cultures for aerobic/anaerobic bacteria and genital mycoplasmas, and a white blood cell count. RESULTS: Twenty-five patients ranging from 18 to 41 weeks of gestation were included in the study. We observed the following: (1) the appearance of amniotic fluid was consistent with pus-like material, vernix, or meconium by naked eye examination; (2) samples collected before 33 weeks of gestation (n = 13) had a pus-like appearance; however, after this gestational age, most of the samples [83% (10/12)] appeared to be consistent with vernix; (3) amniotic fluid cultures were positive for microorganisms in 13 patients, of which 10 were preterm gestations before 33 weeks; (4) the most frequent microorganisms retrieved by culture were genital mycoplasmas (Ureaplasma urealyticum [46% (6/13)]), followed by Mycoplasma hominis [31% (4/13)] and Candida albicans [15% (2/13)]; and (5) patients with sonographic particulate matter in preterm gestations frequently presented acute histologic chorioamnionitis and funisitis, but these conditions were rare in patients at term. CONCLUSION: The nature of amniotic fluid particulate material varies as a function of gestational age. The material obtained in preterm gestations is frequently related to an inflammatory process, while that obtained at term is often consistent with vernix and appears to represent a maturational process.

Effect of a model based on education and teleassistance for the management of obstetric emergencies in 10 rural populations from Colombia.

Introduction: Pregnant women and health providers in rural areas of low-income and middle-income countries face multiple problems concerning high-quality obstetric care. This study was performed to identify changes in maternal and perinatal indicators after implementing a model based on education and telecare between a high-complexity hospital in 10 low-complexity hospitals in a southwestern region of Colombia. Methods: A quasiexperimental study with a historic control group and without a pretest was conducted between 2017 and 2019 to make comparisons before and after obstetric emergency care through the use of teleassistance from 10 primary care centers to the referral center (Fundación Valle del Lili, FVL). Results: A total of 470 patients were treated before teleassistance implementation and 154 patients were treated after teleassistance implementation. After program implementation, the maternal clinical indicators showed a 65% reduction in the number of obstetric patients who were referred with obstetric emergencies. The severity of maternal disease that was measured at the time of admission to level IV through the Modified Early Obstetric Warning System score was observed to decrease. Conclusion: The implementation of a model based on education and teleassistance between low-complexity hospitals and tertiary care centers generated changes in indicators that reflect greater access to rural areas, lower morbidity at the time of admission, and a decrease in the total number of emergency events.

Nifedipine in the management of preterm labor: a systematic review and metaanalysis.

OBJECTIVE: To determine the efficacy and safety of nifedipine as a tocolytic agent in women with preterm labor. STUDY DESIGN: A systematic review and metaanalysis of randomized controlled trials. RESULTS: Twenty-six trials (2179 women) were included. Nifedipine was associated with a significant reduction in the risk of delivery within 7 days of initiation of treatment and before 34 weeks' gestation, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, neonatal jaundice, and admission to the neonatal intensive care unit when compared with ß2-adrenergic-receptor agonists. There was no difference between nifedipine and magnesium sulfate in tocolytic efficacy. Nifedipine was associated with significantly fewer maternal adverse events than ß2-adrenergic-receptor agonists and magnesium sulfate. Maintenance nifedipine tocolysis was ineffective in prolonging gestation or improving neonatal outcomes when compared with placebo or no treatment. CONCLUSION: Nifedipine is superior to ß2-adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor.

Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: a systematic review and metaanalysis.

OBJECTIVE: To determine whether supplementation with vitamins C and E during pregnancy reduces the risk of preeclampsia and other adverse maternal and perinatal outcomes. STUDY DESIGN: Systematic review and metaanalysis of randomized controlled trials. RESULTS: Nine trials involving a total of 19,810 women were included. Overall, there were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (9.6% vs 9.6%; relative risk, 1.00, 95% confidence interval, 0.92-1.09). Similar results were obtained when subgroup analyses were restricted to women at high risk or low/moderate risk for preeclampsia. Women supplemented with vitamins C and E were at increased risk of developing gestational hypertension and premature rupture of membranes, and decreased risk of abruptio placentae. There were no significant differences between the vitamin and placebo groups in the risk of other adverse maternal or fetal/perinatal outcomes. CONCLUSION: Supplementation with vitamins C and E during pregnancy does not prevent preeclampsia.