Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.

Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.

Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value.

Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-ß-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free ß-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free ß-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-ß-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.

Pharmacologic and nonpharmacologic options for pain relief during labor: an expert review.

Labor pain is among the most severe types of physical pain that women may experience during their lifetime. Thus, pain relief is an essential part of medical care during childbirth. Epidural analgesia is considered to be the most efficient method of pain relief during labor. Nevertheless, patient preferences, contraindications, limited availability, and technical failure may require the use of alternative pain reliving methods during labor including systemic pharmacologic agents, and nonpharmacologic methods. Nonpharmacologic methods for pain alleviation during vaginal birth have become popular over the years, either as a complement to pharmacologic agents or at times as the principal therapy. Methods such as relaxation techniques (ie, yoga, hypnosis, and music), manual techniques (ie, massage, reflexology, and shiatsu), acupuncture, birthing ball, and transcutaneous electrical nerve stimulation are considered safe, although the evidence supporting their effectiveness for pain relief is not as robust as it is for pharmacologic agents. Systemic pharmacologic agents are mostly administered by inhalation (nitrous oxide) or through the parenteral route. These agents include opioids such as meperidine, nalbuphine, tramadol, butorphanol, morphine, and remifentanil, and non-opioid agents such as parenteral acetaminophen and nonsteroidal anti-inflammatory drugs. Systemic pharmacologic agents suggest a diverse armamentarium of medication for pain management during labor. Their efficacy in treating pain associated with labor varies, and some continue to be used even though they have not been proven effective for pain relief. In addition, the maternal and perinatal side effects differ markedly among these agents. There is a relative abundance of data regarding the effectiveness of analgesic drugs compared with epidural, but the data regarding comparisons among the different types of alternative analgesic agents are scarce, and there is no consistency regarding the drug of choice for women who do not receive epidural pain management. This review aims to present the available data regarding the effectiveness of the different methods of relieving pain during labor other than epidural. The data presented are mainly based on recent level I evidence regarding pharmacologic and nonpharmacologic methods for pain relief during labor.

Preeclampsia at term can be classified into 2 clusters with different clinical characteristics and outcomes based on angiogenic biomarkers in maternal blood.

BACKGROUND: An antiangiogenic state has emerged as a mechanism of disease in preeclampsia. Angiogenic biomarkers are used in the risk assessment of this syndrome, particularly of early disease. The role of an antiangiogenic state in late preeclampsia is unclear. OBJECTIVE: This study aimed to determine the prevalence, characteristics, and clinical significance of angiogenic/antiangiogenic factor abnormalities in women with preeclampsia stratified according to gestational age at delivery. STUDY DESIGN: Two studies were conducted: (1) a longitudinal nested case-control study comprising women with preeclampsia (n=151) and a control group (n=540); and (2) a case series of patients with preeclampsia (n=452). In patients with preeclampsia, blood was collected at the time of diagnosis. Plasma concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 were determined by enzyme-linked immunosorbent assays. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 expressed as a multiple of the median <10th percentile for gestational age based on values derived from the longitudinal study. The proportion of patients diagnosed with preeclampsia who had an abnormal angiogenic profile was determined in the case-series participants and stratified by gestational age at delivery into early (≤34 weeks), intermediate (34.1-36.9 weeks), and term (≥37 weeks) preeclampsia. The demographics, clinical characteristics, and pregnancy outcomes of women with preeclampsia with and without an abnormal angiogenic profile were compared. RESULTS: The prevalence of an abnormal angiogenic profile was higher in preterm than in term preeclampsia (for early, intermediate, and term in the case-control study: 90%, 100%, and 39%; for the case series: 98%, 80%, and 55%, respectively). Women with preeclampsia at term who had an abnormal angiogenic profile were more frequently nulliparous (57% vs 35%), less likely to smoke (14% vs 26%), at greater risk for maternal (14% vs 5%) or neonatal (7% vs 1%) complications, and more often had placental lesions consistent with maternal vascular malperfusion (42% vs 23%; all, P<.05) than those without an abnormal profile. Women with preeclampsia at term who had a normal angiogenic profile had a higher frequency of chronic hypertension (36% vs 21%) and were more likely to have class ≥2 obesity (41% vs 23%) than those with an abnormal profile (both, P<.05). CONCLUSION: Patients with early preeclampsia had an abnormal angiogenic profile in virtually all cases, whereas only 50% of women with preeclampsia at term had such abnormalities. The profile of angiogenic biomarkers can be used to classify patients with preeclampsia at term, on the basis of mechanisms of disease, into 2 clusters, which have different demographics, clinical characteristics, and risks of adverse maternal and neonatal outcomes. These findings provide a simple approach to classify preeclampsia at term and have implications for future clinical care and research.

Perturbations in kinetics of the thrombin generation assay identify women at risk of preeclampsia in the first trimester and provide the rationale for a preventive approach.

BACKGROUND: Activation of the coagulation system and increased thrombin generation have been implicated in the pathophysiology of preeclampsia, and this rationale supports the administration of low-molecular-weight heparin to prevent this syndrome in patients at risk. Yet, randomized trials of this prophylactic measure have yielded contradictory results. A possible explanation is that only a subset of patients with preeclampsia have excessive thrombin generation and would benefit from the administration of low-molecular-weight heparin. Therefore, the key questions are whether and when patients who subsequently develop preeclampsia present evidence of abnormal thrombin generation. OBJECTIVE: This study aimed to determine (1) the kinetics of thrombin generation throughout gestation in women with a normal pregnancy and in those with early and late preeclampsia, and (2) the diagnostic performance of in vivo thrombin generation parameters to predict the development of preeclampsia. STUDY DESIGN: This retrospective, nested case-control study was based on a prospective longitudinal cohort of singleton gestations. Cases comprised women who developed preeclampsia (n=49), and controls consisted of patients with a normal pregnancy (n=45). Preeclampsia was classified into early-onset (n=24) and late-onset (n=25). Longitudinal changes in the parameters of the thrombin generation assay (lag time, time to peak thrombin concentration, peak thrombin concentration, endogenous thrombin generation, and velocity index) throughout gestation were compared between the study groups, and normal pregnancy percentiles were derived from the control group. We tested whether a single parameter or a combination of parameters, derived from the kinetics of thrombin generation, could identify patients who subsequently developed preeclampsia. Time-related parameters <10th percentile were considered short, and concentration-related parameters >90th percentile were considered high. RESULTS: (1) Patients who developed preeclampsia (early- and late-onset) had abnormal thrombin generation kinetics as early as 8 to 16 weeks of pregnancy; (2) patients with a combination of a short lag time and high peak thrombin concentration at 8 to 16 weeks of pregnancy had an odds ratio of 43.87 for the subsequent development of preeclampsia (area under the curve, 0.79; sensitivity, 56.8%; specificity, 92.7%; positive likelihood ratio, 7.76); (3) at 16 to 22 weeks of gestation, patients with a combination of a short lag time and a high velocity index had an odds ratio of 16 for the subsequent development of preeclampsia (area under the curve, 0.78; sensitivity, 62.2%; specificity, 92.5%; positive likelihood ratio, 8.29). CONCLUSION: During early pregnancy, the thrombin generation assay can identify the subset of patients at a greater risk for the development of preeclampsia owing to accelerated and enhanced production of thrombin. This observation provides a rationale for testing the efficacy of low-molecular-weight heparin in this subset of patients. We propose that future research on the efficacy of low-molecular-weight heparin and other interventions targeting the coagulation system to prevent preeclampsia should be focused on patients with abnormal kinetics of thrombin generation.

Ambient temperature and preeclampsia: A historical cohort study.

Previous studies found inconsistent associations between ambient temperature during pregnancy and the risk of preeclampsia. If such associations are causal, they may impact the future burden of preeclampsia in the context of climate change. We used a historical cohort of 129,009 pregnancies (5074 preeclampsia cases) from southern Israel that was merged with temperature assessments from a hybrid satellite-based exposure model. Distributed-lag and cause-specific hazard models were employed to study time to all preeclampsia cases, followed by stratification according to early (≤34 weeks) and late (>34 weeks) onset disease and identify critical exposure periods. We found a positive association between temperature and preeclampsia during gestation, which was stronger in the 3rd trimester. For example, during week 33, compared to the reference temperature of 22.4 °C, the cause-specific hazard ratio (HRCS) of preeclampsia was 1.01 (95% confidence interval (CI): 1.01-1.02) when exposed to 30 °C, 1.05 (95%CI: 1.03-1.08) at 35 °C, and 1.07 (95%CI: 1.04-1.10) at 37 °C. The associations existed with both early- and late-onset preeclampsia; however, the associations with the early-onset disease were somewhat stronger, limited to the first weeks of pregnancy and the third trimester, and with larger confidence intervals. The HRCS for early preeclampsia onset, when exposed to 37 °C compared to 22.4 °C during week 33, was 1.12 (95%CI: 0.96-1.30), and for late-onset preeclampsia, the HRCS was 1.09 (95%CI: 1.05-1.13). To conclude, exposure to high temperatures at the beginning and, particularly, the end of gestation is associated with an increased risk of preeclampsia in southern Israel.

Maternal plasma cytokines and the subsequent risk of uterine atony and postpartum hemorrhage.

OBJECTIVES: To determine whether the maternal plasma concentrations of cytokines are higher in pregnant women with postpartum hemorrhage (PPH) compared to pregnant women without PPH. METHODS: A retrospective case-control study included 36 women with PPH and 72 matched controls. Cases and controls were matched for gestational age at delivery, labor status, delivery route, parity, and year of sample collection. Maternal plasma samples were collected up to 3 days prior to delivery. Comparison of the plasma concentrations of 29 cytokines was performed by using linear mixed-effects models and included adjustment for covariates and multiple testing. A false discovery rate adjusted p-value <0.1 was used to infer significance. Random forest models with evaluation by leave-one-out and 9-fold cross-validation were used to assess the combined value of the proteins in predicting PPH. RESULTS: Concentrations of interleukin (IL)-16, IL-6, IL-12/IL-23p40, monocyte chemotactic protein 1 (MCP-1), and IL-1ß were significantly higher in PPH than in the control group. This difference remained significant after adjustment for maternal age, clinical chorioamnionitis, and preeclampsia. Multi-protein random forest proteomics models had moderate cross-validated accuracy for prediction of PPH [area under the ROC curve, 0.69 (0.58-0.81) by leave-one-out cross validation and 0.73 (0.65-0.81) by 9-fold cross-validation], and the inclusion of clinical and demographic information did not increase the prediction performance. CONCLUSIONS: Pregnant women with severe PPH had higher median maternal plasma concentrations of IL-16, IL-6, IL-12/IL-23p40, MCP-1, and IL-1ß than patients without PPH. These cytokines could serve as biomarkers or their pathways may be therapeutic targets.

Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention.

OBJECTIVES: The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. METHODS: Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways. RESULTS: Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease. CONCLUSIONS: This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention.

The Light-weight Mid-urethral Sling Implant for Female Stress Urinary Incontinence Treatment: A One-Year Postoperative Follow-up Study.

BACKGROUND: Serasis® (Serag-Wiessner KG, Naila, Germany) is a light-weight mid-urethral sling for treating stress urinary incontinence (SUI). Its insertion is considered less traumatic than other mid-urethral slings. OBJECTIVES: To define postoperative outcomes following Serasis implantation. To compare the efficacy and complication rates of the implant to those of other common techniques. METHODS: Our retrospective study evaluated patients who underwent Serasis mid-urethral sling surgery for SUI. Data were collected from medical records prior to and at the time of surgery and by telephonic interview for postoperative pain and complications. Follow-up of patients was performed for up to one year postoperatively. Patients rated pain or discomfort according to the Visual Analogue Scale (VAS). The primary outcome was the development of early postoperative pain during the first month after surgery. Secondary outcomes were relief of SUI symptoms, groin pain or discomfort, and other postoperative complications up to 12 months after surgery. RESULTS: The study cohort included 50 consecutive patients aged 31 to 68 years. All patients underwent Serasis implantation procedures by a single surgeon and completed interviews. In total, 35 patients underwent concomitant anterior colporrhaphy. In the immediate postoperative period and at one month after the procedure, complaints were mild. No complaints were recorded during the 12-month follow-up period. Overall, 90% and 92% of the patients were free of SUI symptoms at one month and 12 months after surgery, respectively. CONCLUSIONS: Serasis mid-urethral sling is safe, effective, and associated with mild postoperative pain and a low incidence of complications.

Preeclampsia and eclampsia: the conceptual evolution of a syndrome.

Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the placenta and cured only by delivery. This article traces the condition from its origins-once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)-to the present time when preeclampsia is conceptualized primarily as a vascular disorder. We review the epidemiologic data that led to the recommendation to use diastolic hypertension and proteinuria as diagnostic criteria, as their combined presence was associated with an increased risk of fetal death and the birth of small-for-gestational-age neonates. However, preeclampsia is a multisystemic disorder with protean manifestations, and the condition can be present even in the absence of hypertension and proteinuria. Toxins gaining access to the maternal circulation have been proposed to mediate the clinical manifestations-hence, the term "toxemia of pregnancy," which was used for several decades. The search for putative toxins has challenged investigators for more than a century, and a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome. The discovery that the placenta can produce antiangiogenic factors, which regulate endothelial cell function and induce intravascular inflammation, has been a major step forward in the understanding of preeclampsia. We view the release of antiangiogenic factors by the placenta as an adaptive response to improve uterine perfusion by modulating endothelial function and maternal cardiovascular performance. However, this homeostatic response can become maladaptive and lead to damage of target organs during pregnancy or the postpartum period. Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis. Preeclampsia, as it is understood today, is essentially vascular dysfunction unmasked or caused by pregnancy. A subset of patients diagnosed with preeclampsia are at greater risk of the subsequent development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease. However, these adverse events may be the result of a preexisting vascular pathologic process; it is not known if the occurrence of preeclampsia increases the baseline risk. Therefore, the understanding, prediction, prevention, and treatment of preeclampsia are healthcare priorities.

The etiology of preeclampsia.

Preeclampsia is one of the "great obstetrical syndromes" in which multiple and sometimes overlapping pathologic processes activate a common pathway consisting of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This article reviews the potential etiologies of preeclampsia. The role of uteroplacental ischemia is well-established on the basis of a solid body of clinical and experimental evidence. A causal role for microorganisms has gained recognition through the realization that periodontal disease and maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with preeclampsia. The recent reports indicating that SARS-CoV-2 infection might be causally linked to preeclampsia are reviewed along with the potential mechanisms involved. Particular etiologic factors, such as the breakdown of maternal-fetal immune tolerance (thought to account for the excess of preeclampsia in primipaternity and egg donation), may operate, in part, through uteroplacental ischemia, whereas other factors such as placental aging may operate largely through syncytiotrophoblast stress. This article also examines the association between gestational diabetes mellitus and maternal obesity with preeclampsia. The role of autoimmunity, fetal diseases, and endocrine disorders is discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve treatment and prevention.

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.

Cord Blood Cell-Free DNA Concentration: A Novel Marker for Neonatal Wellbeing.

OBJECTIVE: Cord gas values and Apgar scores, currently used as markers for newborn wellbeing and postpartum complications, provide rough estimates, and their use remains elusive. Circulating cell-free DNA (cfDNA) may better represent newborn status at birth and the effect of parturition on the fetus. This pilot study investigates the association between cord blood (CB) cfDNA and neonatal outcomes. STUDY DESIGN: In a prospective cohort study, cfDNA concentration was measured in immediately following delivery collected CB sera of newborns using our rapid fluorescent assay. RESULTS: During the study period, blood samples from umbilical cords of 100 newborns were collected. Vaginal delivery was associated with a higher median CB cfDNA than cesarean delivery (277 [95% confidence interval [CI] 199-377] vs. 100 [95% CI 43-265] ng/mL, p < 0.01). cfDNA levels were significantly associated with gestational age at delivery (rho = 0.308, p = 0.002) and CB base deficit (BD, r = 0.252, p = 0.017). According to maternal and fetal complications, CB cfDNA was elevated in fetuses with category II of heart rate tracing (p < 0.05), with maternal positive vaginal culture (p < 0.01), and with premature rupture of membranes (PROM, p < 0.001). Logistic regression models of CB cfDNA fourth quartiles demostrate a double odds ratio for elevated BD (>3mmol/L) and for worse heart rate tracing category. CONCLUSION: Serum CB cfDNA concentration reflects the newborn's status and hazards with an excellent association with CB BD, fetal heart rate category, and maternal risk factors for infection (positive vaginal culture and PROM). This preliminary observation suggests that cfDNA can serve as a point of care biomarker for newborn status at the time of delivery. KEY POINTS: · CB cfDNA levels correlated with newborn's BD.. · CB cfDNA levels reflect parturition stress and inflammation.. · cfDNA serve as a diagnostic and prediction tool for the identification of newborns at risk for morbidity..

Cervical insufficiency a prologue for future pelvic organ prolapse?

BACKGROUND: Preliminary evidence suggests that women with cervical oss insufficiency may have an increased risk to develop pelvic organ prolapse later in life, suggesting a common underlying collagen-oriented mechanism. OBJECTIVE: The objective of this study was to determine the association between cervical oss insufficiency and the subsequent development of pelvic organ prolapse. STUDY DESIGN: A matched, case-control study, including women who delivered at the Soroka University Medical Center. Cases were women diagnosed or treated with pelvic organ prolapse (n = 1463), and controls were a representative sample of women of the same age group without pelvic organ prolapse (n = 5637). The association between pelvic organ prolapse and prior preterm birth was tested. Univariate analysis was performed using a conditional logistic regression to assess the association between preterm labor and pelvic organ prolapse. Statistically and clinically significant variables in the univariate analysis were included in the multivariable regression. RESULTS: The rate of spontaneous preterm birth did not differ between the study groups [pelvic organ prolapse - 4.0% (59/1463) vs. non- pelvic organ prolapse - 4.9% (276/5637), p = 0.16]. The median number of preterm births was higher among women without pelvic organ prolapse (controls) than in those with pelvic organ prolapse (cases) (p = 0.004). Among those who delivered preterm, the individual proportion of preterm deliveries was higher among the controls' group (p = 0.03). Similarly, the rate of cesarean deliveries was also higher among the controls group (p = 0.003). The rate of small for gestational age neonates was higher in the controls group (p = 0.0007), while that of large for gestational age neonates was higher in the case group (p = 0.02). In the univariate analysis, birthweight, vaginal delivery, and prior surgery were associated with subsequent development of pelvic organ prolapse. The multivariable analysis exhibited the same association- having birthweight, vaginal delivery, and all types of prior surgery independently associated with subsequent development of pelvic organ prolapse. CONCLUSIONS: Obstetrics characteristics associated with pelvic organ prolapse included vaginal delivery and birthweight along with non-obstetrical factors such as prior surgery. There was no association between preterm birth and subsequent development of pelvic organ prolapse. Our findings suggest that the effort during labor at term required for the delivery of appropriate for gestational age or large for gestational age newborns affects the pelvic floor and is a major contributor for the subsequent development of pelvic organ prolapse.

Unfolding the pathophysiology of congenital thrombotic thrombocytopenic purpura in pregnancy: lessons from a cluster of familial cases.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), a rare, potentially life-threatening thrombotic microangiopathy, manifests either as congenital TTP or acquired forms. It is caused by the absence or severe depletion of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) protease, leading to the accumulation of ultra large von Willebrand factor multimers as well as extensive platelet adhesion and clumping, which can ultimately cause severe secondary end-organ damage. Pregnancy can provoke or exacerbate TTP, leading to maternal and fetal complications. OBJECTIVE: In this report, we focused on pregnancy outcomes in a recently recognized cohort of congenital TTP patients of Bedouin Arab descent in southern Israel who were all homozygous for a novel c.3772delA variant of the ADAMTS13 gene, leading to the clinical manifestations of TTP largely during pregnancy. STUDY DESIGN: All patients presented in this study belong to 2 closely related families of Arab Bedouin descent and were found to be homozygous for a novel ADAMTS13-c.3772delA variant. The cohort consisted of 19 females; 16 of them had congenital TTP and had been pregnant and were thus included. Patient data were collected from electronic medical records. RESULTS: Of note, 13 women from our cohort, who delivered 14 fetuses (owing to 1 twin pregnancy), were diagnosed with congenital TTP following complicated pregnancies, which included recurrent pregnancy loss, stillbirth, early onset preeclampsia (both mild and severe), hemolysis, elevated liver enzymes and low platelet count syndrome, intrauterine growth restriction with abnormal Doppler flow, preterm premature rupture of membranes, and a total perinatal mortality rate of 30.7% (4/13). An additional 3 women, who were diagnosed owing to complications outside of pregnancy and at older ages, experienced TTP during their pregnancies, which occurred before diagnosis. Subsequent pregnancies were treated with fresh frozen plasma leading to a 100% fetal survival rate in the pregnancies that reached fetal viability. All placentas had lesions consistent with maternal vascular underperfusion. However, the severity and frequency of these lesions were lower in the 8 placentas from pregnancies treated with fresh frozen plasma. CONCLUSION: This case series details a distinctive cohort of congenital TTP patients, all homozygous for the same, novel ADAMTS13 variant, who presented with clinical complications during pregnancy and maternal vascular lesions of underperfusion in the placenta. Our findings imply that the variant identified in the ADAMTS13 gene in our cohort may have a specific functional impact on the placenta, and that treatment with fresh frozen plasma during pregnancy ameliorates the course of the disease, leading to a milder phenotype or a normal pregnancy in the majority of cases.

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.

Differences in environmental factors contributing to preterm labor and PPROM - Population based study.

BACKGROUND: Previous reports indicate an association between ambient temperature (Ta) and air pollution exposure during pregnancy and preterm birth (PTB). Nevertheless, information regarding the association between environmental factors and specific precursors of spontaneous preterm birth is lacking. We aimed to determine the association between Ta and air pollution during gestation and the precursors of spontaneous preterm parturition, i.e. preterm labor (PTL) and preterm prelabor rupture of membranes (PPROM). METHODS: From 2003 to 2013 there were 84,476 deliveries of singleton gestation that comprised the study cohort. Exposure data during pregnancy included daily measurements of temperature and particulate matter <2.5 µm and <10 µm, PM2.5 and PM10, respectively. Deliveries were grouped into PPROM, PTL and non-spontaneous preterm and term deliveries. Exposure effect was tested in windows of a week and two days prior to admission for delivery and adjusted to gestational age and socio-economic status. Poisson regression models were used for analyses. RESULTS: There is an association of environmental exposure with the precursors of spontaneous preterm parturition; PPROM was more sensitive to Ta fluctuations than PTL. This effect was modified by the ethnicity, Bedouin-Arabs were susceptible to elevated Ta, especially within the last day prior to admission with PPROM (Relative Risk (RR) =1.19 [95% CI, 1.03; 1.37]). Jews, on the other hand, were susceptible to ambient pollutants, two (RR=1.025 [1.010; 1.040]) and one (RR= 1.017 [1.002; 1.033]) days prior to spontaneous PTL with intact membranes resulting in preterm birth. CONCLUSION: High temperature is an independent risk factor for PPROM among Bedouin-Arabs; ambient pollution is an independent risk factor for spontaneous PTL resulting in preterm birth. Thus, the precursors of spontaneous preterm parturition differ in their association with environmental factors.

Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor.

OBJECTIVES: Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. METHODS: A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. RESULTS: Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). CONCLUSIONS: Disorders of villous maturation are present in nearly one-third of the cases of spontaneous 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.

The effect of exposure to particulate matter during pregnancy on lower respiratory tract infection hospitalizations during first year of life.

BACKGROUND: Lower respiratory tract infections (LRTI) in early life, including pneumonia, bronchitis and bronchiolitis, can lead to decreased lung function, persistent lung damage and increased susceptibility to various respiratory diseases such as asthma. In-utero exposure to particulate matter (PM) during pregnancy may disrupt biological mechanisms that regulate fetal growth, maturation and development. We aimed to estimate the association between intrauterine exposure to PM of size < 2.5 µm in diameter (PM2.5) and incidence of LRTIs during the first year of life. METHODS: A retrospective population-based cohort study in a population of mothers and infants born in Soroka University Medical Center (SUMC) in the years 2004-2012. All infants < 1 year old that were hospitalized due to LRTIs were included. The main exposure assessment was based on a hybrid model incorporating daily satellite-based predictions at 1 km2 spatial resolution. Data from monitoring stations was used for imputation of main exposure and other pollutants. Levels of environmental exposures were assigned to subjects based on their residential addresses and averaged for each trimester. Analysis was conducted by a multivariable generalized estimating equation (GEE) Poisson regression. Data was analyzed separately for the two main ethnic groups in the region, Jewish and Arab-Bedouin. RESULTS: The study cohort included 57,331 deliveries that met the inclusion criteria. Overall, 1871 hospitalizations of infants < 1 year old due to pneumonia or bronchiolitis were documented. In a multivariable analysis, intrauterine exposure to high levels of PM2.5 (> 24 µg/m3) in the first and second trimesters was found to be adversely associated with LRTIs in the Arab-Bedouin population (1st trimester, RR = 1.31, CI 95% 1.08-1.60; 2nd trimester: RR = 1.34, CI 95% 1.09-1.66). CONCLUSION: Intrauterine exposure to high levels of PM2.5 is associated with a higher risk of hospitalizations due to lower respiratory tract infections in Arab-Bedouin infants.