Role of mitochondrial DNA level in epidural-related maternal fever: a single-centre, observational, pilot study.

INTRODUCTION: Epidural analgesia has been associated with intrapartum maternal fever development. Epidural-related maternal fever (ERMF) is believed to be based on a non-infectious inflammatory reaction. Circulating cell-free mitochondrial deoxyribonucleic acid (mtDNA) is one of the possible triggers of sterile inflammatory processes; however, a connection has not been investigated so far. Therefore, this study aimed to investigate cell-free mtDNA alterations in women in labour with ERMF in comparison with non-febrile women. MATERIAL AND METHODS: A total of 60 women in labour were assessed for maternal temperature every 4 h and blood samples were obtained at the beginning and after delivery. Depending on the analgesia and the development of fever (axillary temperature ≥ 37.5 °C), the women were allocated either to the group of no epidural analgesia (n = 17), to epidural analgesia no fever (n = 34) or to ERMF (n = 9). Circulating cell-free mtDNA was analysed in the maternal plasma for the primary outcome whereas secondary outcomes include the evaluation of inflammatory cytokine release, as well as placental inflammatory signs. RESULTS: Of the women with epidural analgesia, 20% (n = 9) developed ERMF and demonstrated a decrease of circulating mtDNA levels during labour (p = 0.04), but a trend towards higher free nuclear DNA. Furthermore, women with maternal pyrexia showed a 1.5 fold increased level of Interleukin-6 during labour. A correlation was found between premature rupture of membranes and ERMF. CONCLUSIONS: The pilot trial revealed an evident obstetric anaesthesia phenomenon of maternal fever due to epidural analgesia in 20% of women in labour, demonstrating counterregulated free mtDNA and nDNA. Further work is urgently required to understand the connections between the ERMF occurrence and circulating cell-free mtDNA as a potential source of sterile inflammation. TRIAL REGISTRATION: NCT0405223 on clinicaltrials.gov (registered on 25/07/2019).

Transcriptome changes in maternal peripheral blood during term parturition mimic perturbations preceding spontaneous preterm birth†.

The complex physiologic process of parturition includes the onset of labor, which requires the orchestrated stimulation of a common pathway involving uterine contractility, cervical ripening, and chorioamniotic membrane activation. However, the labor-specific processes taking place in these tissues have limited use as predictive biomarkers unless they can be probed in non-invasive samples, such as the peripheral blood. Herein, we utilized a transcriptomic dataset to assess labor-specific changes in the peripheral blood of women who delivered at term. We identified a set of genes that were differentially expressed with labor and enriched for immunological processes, and these gene expression changes were strongly correlated with results from prior studies, providing in silico validation of our findings. We then identified significant correlations between labor-specific transcriptomic changes in the maternal circulation and those detected in the chorioamniotic membranes, myometrium, and cervix of women at term, demonstrating that tissue-specific labor signatures are partly mirrored in the peripheral blood. Finally, we demonstrated a significant overlap between the peripheral blood transcriptomic changes in term parturition and those observed in asymptomatic women, prior to the diagnosis of preterm prelabor rupture of the membranes, who ultimately delivered preterm. Collectively, we provide evidence that the normal process of labor at term is characterized by a unique immunological expression signature, which may serve as a useful tool for assessing labor status and for potentially identifying women at risk for preterm birth.

Stereoselective Analysis of Methadone and EDDP in Laboring Women and Neonates in Plasma and Dried Blood Spots and Association with Neonatal Abstinence Syndrome.

OBJECTIVE: This pilot study evaluated the relationship between maternal and neonatal R- and S-methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) exposure and the severity of neonatal abstinence syndrome (NAS). The use of dried blood spots (DBS) as an alternative for plasma in assessing methadone and EDDP was also assessed. STUDY DESIGN: Women receiving methadone for medication assisted treatment of opioid use disorder during pregnancy were eligible for recruitment. Plasma and DBS samples were collected from mothers during labor, from cord blood, and from newborns during genetic screen. R-/S-methadone and EDDP were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS). Associations between methadone exposure, neonatal morphine requirements, and severity of NAS were examined. RESULTS: Twenty women and infants completed the study. Maternal methadone dose at delivery was 112 mg/day (range = 60-180 mg/day). Sixteen neonates experienced NAS requiring morphine; three also required phenobarbital. Higher cord blood concentrations of R-methadone, R- and S-EDDP were associated with higher maximum doses of morphine (p < 0.05). CONCLUSION: Maternal methadone and cord blood concentration at delivery are variable and may be potential markers of neonatal abstinence syndrome.

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term.

Prior to and during the process of human labor, maternal circulating leukocytes infiltrate the maternal-fetal interface (choriodecidua) and become activated resembling choriodecidual leukocytes. Since, there is no evidence comparing maternal circulating and choriodecidual leukocytes, herein, we characterized their transcriptome and explored the biological processes enriched in choriodecidual leukocytes. From women undergoing spontaneous term labor we isolated circulating and choriodecidual leukocytes, performed microarray analysis (n = 5) and qRT-PCR validation (n = 9) and interaction network analysis with up-regulated genes. We found 270 genes up-regulated and only 17 genes down-regulated in choriodecidual leukocytes compared to maternal circulating leukocytes. The most up-regulated genes were CCL18, GPNMB, SEPP1, FN1, RNASE1, SPP1, C1QC, and PLTP. The biological processes enriched in choriodecidual leukocytes were cell migration and regulation of immune response, chemotaxis, and humoral immune responses. Our results show striking differences between the transcriptome of choriodecidual and maternal circulating leukocytes. Choriodecidual leukocytes are enriched in immune mediators implicated in the spontaneous process of labor at term.

Maternal plasma levels of oxytocin during physiological childbirth - a systematic review with implications for uterine contractions and central actions of oxytocin.

BACKGROUND: Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. METHODS: An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. RESULTS: Basal levels of oxytocin increased 3-4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. CONCLUSIONS: Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother's brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.

Functional fibrinogen (FLEV-TEG) versus the Clauss method in an obstetric population: a comparative study.

BACKGROUND: Hemostasis is the dynamic equilibrium between coagulation and fibrinolysis. During pregnancy, the balance shifts toward a hypercoagulative state; however placental abruption and abnormal placentations may lead to rapidly evolving coagulopathy characterized by the increased activation of procoagulant pathways. These processes can result in hypofibrinogenemia, with fibrinogen levels dropping to 2 g/L or less and an associated increased risk of post-partum hemorrhage. The aim of the present study was to evaluate the concordance between two methods of functional fibrinogen measurement: the Thromboelastography (TEG) method (also known as FLEV) vs. the Clauss method. Three patient groups were considered: healthy volunteers; non-pathological pregnant patients; and pregnant patients who went on to develop postpartum hemorrhage. METHODS: A prospective observational study. Inclusion criteria were: healthy volunteer women of childbearing age, non-pathological pregnant women at term, and pregnant hemorrhagic patients subjected to elective or urgent caesarean section (CS), with blood loss exceeding 1000 mL. Exclusion criteria were age < 18 years, a history of coagulopathy, and treatment with contraceptives, anticoagulants, or antiplatelet agents. RESULTS: Bland-Altman plots showed a significant overestimation with the FLEV method in all three patient groups: bias was - 133.36 mg/dL for healthy volunteers (95% IC: - 257.84; - 8.88. Critical difference: 124.48); - 56.30 mg/dL for healthy pregnant patients (95% IC: - 225.53; 112.93. Critical difference: 169.23); and - 159.05 mg/dL for hemorrhagic pregnant patients (95% IC: - 333.24; 15.148. Critical difference: 174.19). Regression analyses detected a linear correlation between FLEV and Clauss for healthy volunteers, healthy pregnant patients, and hemorrhagic pregnant patients (R2 0.27, p value = 0.002; R2 0.31, p value = 0.001; R2 0.35, p value = 0.001, respectively). ANOVA revealed a statistically significant difference in fibrinogen concentration between all three patients groups when assayed using the Clauss method (p value < 0.001 for all the comparisons), but no statistically significant difference between the two patients groups of pregnant women when using the FLEV method. CONCLUSIONS: The FLEV method does not provide a valid alternative to the Clauss method due to the problem of fibrinogen overestimation, and for this reason it should not be recommended for the evaluation of patients with an increased risk of hypofibrinogenemia.

Assessment of glucose kinetics with real-time continuous glucose monitoring during labor.

AIM: Changes in glucose levels during labor have not been sufficiently investigated in pregnant women. Using real-time continuous glucose monitoring, we aimed to assess glucose kinetics during labor among pregnant women with gestational diabetes mellitus (PwGDM), and those with normal glucose tolerance (PwNGT). METHODS: Japanese PwGDM and PwNGT who had planned a transvaginal delivery at Okayama University Hospital were enrolled. The correlation between changes in glucose levels during labor among the PwGDM and PwNGT groups at four time periods was assessed: (i) active phase of 1st stage of labor; (ii) 2nd stage of labor; (iii) postpartum 0-12 h; and (iv) postpartum 12-48 h. RESULTS: In total, 18 and 22 PwGDM and PwNGT, respectively, were enrolled. During labor, both groups had similar changes in glucose levels over time, which peaked during period 3. The main effect of glucose level changes was the labor period (P < 0.001), not the presence of gestational diabetes mellitus. Furthermore, differences in glucose levels in the PwGDM group were observed between periods 1 and 2 (P = 0.037), 1 and 3 (P = 0.024), 3 and 4 (P = 0.005); differences in glucose levels in the PwNGT group were observed between periods 3 and 4 (P = 0.024). CONCLUSION: During labor, both PwGDM and PwNGT groups showed similar changes in glucose levels over time. During delivery, the PwGDM who regularly measured their own glucose levels could be managed using the same nutritional management methods as those for PwNGT.

Normal Range for Maternal Lactic Acid during Pregnancy and Labor: A Systematic Review and Meta-Analysis of Observational Studies.

OBJECTIVE: This article systematically reviews the literature to establish the normal range of lactic acid in healthy pregnant women. STUDY DESIGN: Ovid MEDLINE, Embase.com, and Clinicaltrials.gov were searched to identify studies that reported maternal lactic acid in healthy pregnant women. Pooled aggregate means and two standard deviations for each time period were computed using the inverse variance weighting technique. Analyses were performed separately for 1st, 2nd, and 3rd trimesters, scheduled cesarean delivery, early labor, active labor, 2nd stage of labor, and delivery. RESULTS: Overall, 22 studies met the inclusion criteria. There were 1,193 patients, and 2,008 observations identified. All time periods had maternal venous lactic acid aggregate means and two-standard-deviation ranges less than 4 mmol/L. Outside of labor, all ranges were less than 2 mmol/L. All labor periods had a range higher than 2 mmol/L. While the pooled ranges were less than 4 mmol/L, many individual studies reported ranges > 4 mmol/L during labor. CONCLUSION: This meta-analysis suggests that venous lactic acid levels can be used as a screening tool in pregnant women just as the test would be used in nonpregnant women, except that elevations may be seen during labor, especially later in labor when there is maximal skeletal muscle contraction.

Incident HIV infection and perinatal transmission rates among HIV negative pregnant women who retested in labor in a tertiary health centre, South East Nigeria.

BACKGROUND: To reduce the number of new HIV infections among children, retesting of HIV negative pregnant women in labor to identify new infections and instituting appropriate modified obstetrics practices (MOP) has a huge role to play. AIMS AND OBJECTIVES: This study evaluated the HIV sero-positivity in labor among pregnant women who earlier tested negative in antenatal clinic, associated risk factors and the corresponding rate of mother-to-child transmission of HIV infection. METHODS: This was a prospective observational study where pregnant women in labor who had earlier tested HIV negative in the antenatal clinic at Imo State University Teaching Hospital Orlu, Imo state, Nigeria, were retested. The infants of the women who seroconverted were tested for HIV infection at 6 weeks using Deoxyribonucleic acid polymerase chain reaction (DNA PCR) by collecting Dried Blood Sample. This study was conducted from October 2015 to March 2016. RESULT: Out of the 163 patients studied, 6 demonstrated HIV seroconversion giving a seroconversion rate of 3.7%. Deliveries from the seroconverted patients were 5 live births and 1 intrauterine fetal death. All the 5 live babies tested HIV negative at 6 weeks of age. Predictors of seroconversion in late pregnancy include spouse's HIV status and number of other sexual partners. CONCLUSION: Retesting of HIV negative pregnant women in labor to identify new infections and instituting appropriate modified obstetrics practices has a huge role to play in the prevention of mother to child transmission of HIV infection.

Lipoprotein particle concentration measured by nuclear magnetic resonance spectroscopy is associated with gestational age at delivery: a prospective cohort study.

OBJECTIVE: To estimate the association between lipoprotein particle concentrations in pregnancy and gestational age at delivery. DESIGN: Prospective cohort study. SETTING: The study was conducted in the USA at the University of North Carolina. POPULATION: We assessed 715 women enrolled in the Pregnancy, Infection, and Nutrition study from 2001 to 2005. METHODS: Fasting blood was collected at two time points (<20 and 24-29 weeks of gestation). Nuclear magnetic resonance (NMR) quantified lipoprotein particle concentrations [low-density lipoprotein (LDL), high-density lipoprotein (HDL), very-low density lipoprotein (VLDL)] and 10 subclasses of lipoproteins. Concentrations were assessed as continuous measures, with the exception of medium HDL which was classified as any or no detectable level, given its distribution. Cox proportional hazards models estimated hazard ratios (HR) for gestational age at delivery adjusting for covariates. MAIN OUTCOME MEASURES: Gestational age at delivery, preterm birth (<37 weeks of gestation), and spontaneous preterm birth. RESULTS: At <20 weeks of gestation, three lipoproteins were associated with later gestational ages at delivery [large LDLNMR (HR 0.78, 95% CI 0.64-0.96), total VLDLNMR (HR 0.77, 95% CI 0.61-0.98), and small VLDLNMR (HR 0.78, 95% CI 0.62-0.98], whereas large VLDLNMR (HR 1.19, 95% CI 1.01-1.41) was associated with a greater hazard of earlier delivery. At 24-28 weeks of gestation, average VLDLNMR (HR 1.25, 95% CI 1.03-1.51) and a detectable level of medium HDLNMR (HR 1.90, 95% CI 1.19-3.02) were associated with earlier gestational ages at delivery. CONCLUSION: In this sample of pregnant women, particle concentrations of VLDLNMR , LDLNMR , IDLNMR , and HDLNMR were each independently associated with gestational age at delivery for all deliveries or spontaneous deliveries <37 weeks of gestation. These findings may help formulate hypotheses for future studies of the complex relationship between maternal lipoproteins and preterm birth. TWEETABLE ABSTRACT: Nuclear magnetic resonance spectroscopy may identify lipoprotein particles associated with preterm delivery.

Maternal plasma leptin levels in relation to the duration of the active phase of labor.

INTRODUCTION: Obese women have increased leptin levels and longer duration of labor compared with normal-weight women. Leptin has an inhibitory effect on myometrial contractility in vitro. Our purpose was to examine whether maternal leptin levels in active labor were associated with the duration of the active phase of labor. MATERIAL AND METHODS: This prospective cohort study included 914 women. Maternal blood samples were collected in active labor. The plasma-leptin concentration was obtained using a direct sandwich-based ELISA. Bivariate and multiple linear regression analyses were used to study the association between leptin levels and the duration of labor. RESULTS: A 1 ng/mL increase in maternal plasma leptin was associated with a 0.015 hour increase in duration of labor (P < .007). This association was not statistically significant in the adjusted analyses nor when analyzing nulliparous and multiparous women separately. In women with spontaneous labor (n = 766) leptin levels were not associated with an increase in duration of labor in the adjusted analyses. CONCLUSIONS: There was no significant association between leptin levels and duration of the active phase of labor. Leptin in vivo might display a similar dose-response effect on myometrial contractility as demonstrated in in vitro studies. Future studies need to explore the association between leptin levels and time in labor in obese women with high leptin levels to evaluate a possible dose-response effect.

Immunophenotyping and activation status of maternal peripheral blood leukocytes during pregnancy and labour, both term and preterm.

The onset of labour in rodents and in humans is associated with physiological inflammation which is manifested by infiltration of activated maternal peripheral leukocytes (mPLs) into uterine tissues. Here, we used flow cytometry to immunophenotype mPLs throughout gestation and labour, both term and preterm. Peripheral blood was collected from non-pregnant women and pregnant women in the 1st, 2nd and 3rd trimesters. Samples were also collected from women in active labour at term (TL) or preterm (PTL) and compared with women term not-in-labour (TNIL) and preterm not-in-labour (PTNIL). Different leukocyte populations were identified by surface markers such as CD45, CD14, CD15, CD3, CD4, CD8, CD19 and CD56. Their activation status was measured by the expression levels of CD11b, CD44, CD55, CD181 and CD192 proteins. Of all circulating CD45+ leukocytes, we detected significant increases in CD15+ granulocytes (i) in pregnant women versus non-pregnant; (ii) in TL women versus TNIL and versus pregnant women in the 1st/2nd/3rd trimester; (iii) in PTL women versus PTNIL. TL was characterized by (iv) increased expressions of CD11b, CD55 and CD192 on granulocytes; (v) increased mean fluorescent intensity (MFI) of CD55 and CD192 on monocytes; (vi) increased CD44 MFI on CD3+ lymphocytes as compared to late gestation. In summary, we have identified sub-populations of mPLs that are specifically activated in association with gestation (granulocytes) or with the onset of labour (granulocytes, monocytes and lymphocytes). Additionally, beta regression analysis created a set of reference values to rank this association between immune markers of pregnancy and to identify activation status with potential prognostic and diagnostic capability.

Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin.

BACKGROUND: Although oxytocin commonly is used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly among women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene. OBJECTIVES: To identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements. STUDY DESIGN: Term, nulliparous women requiring oxytocin doses of ≤4 mU/min (low-dose-requiring, n = 83) or ≥20 mU/min (high-dose-requiring, n = 104) for labor augmentation or induction provided consent to a postpartum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage >30×) with MiSeq (Illumina) was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. The Fisher exact or χ2 tests were used for categorical variables, and Student t tests or Wilcoxon rank sum tests were used for continuous variables. A P value < .05 was considered statistically significant. RESULTS: The high-dose-requiring women had greater rates of obesity and diabetes and were more likely to have undergone labor induction and required prostaglandins. High-dose-requiring women were more likely to undergo cesarean delivery for first-stage arrest and less likely to undergo cesarean delivery for nonreassuring fetal status. Targeted sequencing of the oxytocin receptor gene in the total cohort (n = 187) revealed 30 distinct coding variants: 17 nonsynonymous, 11 synonymous, and 2 small structural variants. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine nonsynonymous variants were unique to the high-dose-requiring group. These included 3 known variants (R151C, G221S, and W228C) and 6 novel variants (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173R were predicted by Scale-Invariant Feature Transform algorithm to damage oxytocin receptor function. There was no statistically significant association between the numbers of synonymous and nonsynonymous substitutions in the patient groups. CONCLUSION: Obesity, diabetes, and labor induction were associated with the requirement for high doses of oxytocin. We did not identify significant differences in the prevalence of oxytocin receptor variants between low-dose-requiring and high-dose-requiring women, but novel oxytocin receptor variants were enriched in the high-dose-requiring women. We also found 3 oxytocin receptor variants (2 novel, 1 known) that were predicted to damage oxytocin receptor function and would likely increase an individual's risk for requiring a high oxytocin dose. Further investigation of oxytocin receptor variants and their effects on protein function will inform precision medicine in pregnant women.

Women Serum Concentrations of the IL-10 Family of Cytokines and IFN-γ Decrease from the Third Trimester of Pregnancy to Active Labor.

Labor is regarded as increased myometrial activity with a regular contractility pattern. At this final stage of pregnancy, myometrial quiescence is lost, accompanied by altered immune homeostasis. It is well known that the interleukin (IL)-10 family of cytokines modulates immunological responses mainly in epithelial cells, including the endometrium. To investigate their inflammatory profile during labor, we performed a longitudinal study in a group of healthy pregnant women (n = 20) with uncomplicated pregnancies in the third trimester of pregnancy and during active labor. Blood was sampled from pregnant women in the third trimester (gestational age 32-38 weeks, mean 36 ± 2 weeks) and during active labor (39-41 weeks of gestation, mean 40 ± 1 weeks). Serum levels of several cytokines were measured using multiplex immunoassays for both stages, indicating that the concentrations of IL-10, IL-20, IL-22, IL-28A, and interferon (IFN)-γ were significantly decreased during active labor in comparison with third-trimester levels (p < 0.05). Our analysis did not find significant correlations between IL-10, IL-20, IL-22, IL-28A, and IFN-γ levels and gestational age. However, our data suggest that the systemic downregulation of several members of the IL-10 family of cytokines plays an important role in the activation of myometrial smooth cells associated with uterine contractions during active labor. Downregulation of this IL-10 family of cytokines seems to coincide with the well-reported functional progesterone withdrawal during labor. Likewise, lower plasma IFN-γ concentrations may indicate a role for IFN-γ in active labor.

Pregnant human peripheral leukocyte migration during several late pregnancy clinical conditions: a cross-sectional observational study.

BACKGROUND: Parturition at term and preterm is characterized by sterile inflammatory processes occurring in the absence of infection whereby peripheral leukocytes infiltrate gestational tissues in response to chemotactic signals. In response to a homing signal, recruited leukocytes undergo diapedesis and extravasate through capillaries, migrating into stromal tissue. There they interact with resident immune and stromal cells to produce a mixture of matrix metalloproteinases, prostaglandins and cytokines including interleukin-1ß (IL-1ß) and IL-6 that in turn transform the uterus from pregnancy to parturition. Since migration is an early parturitional event our purpose was to study the migration of maternal peripheral blood leukocytes in response to a standard chemotactic signal during several different conditions of late pregnancy. METHODS: We used a cross-sectional observational study design. Subjects were (sTL) spontaneous normal labour delivered vaginally at term, (TNL) elective caesarean section at term without labour, (PTL) preterm in labour, (PTNL) preterm not in labour, (TPTL) threatened preterm labour, and (pPROM) preterm with premature rupture of membranes. Leukocytes (100,000) obtained by venipuncture and chemotactic factor isolated from term labour fetal membranes were placed in the upper and lower halves, respectively, of a Boyden chamber separated by a filter with 3µm pores. Migrated leukocytes were assessed by flow cytometry. The number of leukocytes that migrated in 90 min was the primary outcome measure. RESULTS: Increased numbers of leukocytes from peripheral blood of women in labour (TL or PTL) or soon to go into labour (PPROM) migrated towards a chemotactic signal than did leukocytes from women not in labour (TNL, PTNL, or TPTL) (p < 0.0001). All pPROM delivered within 7d; TPTL delivered >30d. Receiver operating characteristic curve parameters indicated the cut-off point for delivery within 7d to be 37,082 leukocytes with sensitivity 78.1%, specificity 88.9%, positive predictive value 91.4%, negative predictive value 72.7%, and area under the curve 0.83. CONCLUSION: Leukocyte migration to a fetal membrane signal varies in a predictable fashion during various clinical situations of late gestation. This principle has the potential to be improved to become a clinical test to predict delivery.

Reference values for Lactate Pro 2™ in fetal blood sampling during labor: a cross-sectional study.

OBJECTIVE: Lactate Pro™ (LP1) is the only lactate meter evaluated for fetal scalp blood sampling (FBS) in intrapartum use. The reference values for this meter are: normal value <4.2 mmol/L, preacidemia 4.2-4.8 mmol/L, and acidemia >4.8 mmol/L. The production of this meter has been discontinued. An updated version, Lactate Pro 2TM (LP2), has been launched and is shown to be differently calibrated. The aims of the study were to retrieve a conversion equation to convert lactate values in FBS measured with LP2 to an estimated value if using LP1 and to define reference values for clinical management when using LP2. STUDY DESIGN: A cross-sectional study was conducted at a university hospital in Sweden. A total of 113 laboring women with fetal heart rate abnormalities on cardiotocography (CTG) had FBS carried out. Lactate concentration was measured bedside with both LP1 and LP2 from the same blood sample capillary. A linear regression model was constructed to retrieve a conversion equation to convert LP2 values to LP1 values. RESULTS: LP2 measured higher values than LP1 in all analyses. We found that 4.2 mmol/L with LP1 corresponded to 6.4 mmol/L with LP2. Likewise, 4.8 mmol/L with LP1 corresponded to 7.3 mmol/L with LP2. The correlation between the analyses was excellent (Spearman's rank correlation, r=0.97). CONCLUSION: We recommend the following guidelines when interpreting lactate concentration in FBS with LP2: <6.4 mmol/L to be interpreted as normal, 6.4-7.3 mmol/L as preacidemia indicating a follow-up FBS within 20-30 min, and >7.3 mmol/L as acidemia indicating intervention.

Prevalence of anemia and associations between neonatal iron status, hepcidin, and maternal iron status among neonates born to pregnant adolescents.

BACKGROUND: Little is known about anemia and iron status in US newborns because screening for anemia is typically not undertaken until 1 y of age. This study was undertaken to characterize and identify determinants of iron status in newborns born to pregnant adolescents. METHODS: Pregnant adolescents (≤ 18 y, n = 193) were followed from ≥ 12 wk gestation until delivery. Hemoglobin, ferritin, soluble transferrin receptor, serum iron, hepcidin, erythropoietin (EPO), IL-6, and C-reactive protein were assessed in maternal and cord blood. RESULTS: At birth, 21% of the neonates were anemic (Hb < 13.0 g/dl) and 25% had low iron stores (ferritin < 76 µg/l). Cord serum ferritin concentrations were not significantly associated with gestational age (GA) at birth across the range of 37-42 wk. Neonates born to mothers with ferritin < 12 µg/l had significantly lower ferritin (P = 0.003) compared to their counterparts. Hepcidin and IL-6 were significantly (P < 0.05) higher in neonates born to mothers with longer durations of active labor. CONCLUSION: Given the importance of the iron stores at birth on maintenance of iron homeostasis over early infancy, additional screening of iron status at birth is warranted among those born to this high risk obstetric population.

The Relationship Between Plasma Inflammatory Cytokines and Labor Pain.

BACKGROUND: Proinflammatory cytokines are increased in maternal blood at term pregnancy and are associated with cervical ripening and the initiation of labor. We hypothesize that maternal plasma cytokines also affect the sensitivity to labor pain. METHODS: By using a previously validated model describing labor pain, we used a deidentified database derived from healthy nulliparous parturients who delivered singleton pregnancies at term. Numerical rating scores for pain were recorded after the onset of regular contractions using an 11-point scale. Maternal blood was drawn for the measurement of interleukin (IL)-1ß, IL-4, IL-6, IL-8, and IL-10; interferon-γ; and tumor necrosis factor-α on admission or at the onset of painful contractions, whichever occurred later. Individual demographic, physiognomic, and cytokine variables that significantly affected labor pain at P < 0.05 were reported and included stepwise into a multivariable model. RESULTS: One hundred sixty parturients provided 411 numerical analog scores for pain that were evaluated with our model. The relationship between numerical analog scores and cervical dilation was significantly affected by the type of membrane rupture, membrane status, induction, oxytocin administration, maternal race, and plasma IL-1ß concentration as individual variables. Only the association between the highest IL-1ß quartile and slower acceleration of pain during labor remained significant in the multivariate model (P = 0.0003). Women with IL-1ß concentration in the highest quartile arrived at the labor room with a more dilated cervix than those with lower plasma concentrations of IL-1ß (5.1 ± 3.0 vs 4.1 ± 2.6 cm; P < 0.02) and had faster labor progress. CONCLUSIONS: Inflammatory cytokines including IL-1ß play a role in cervical ripening. High maternal plasma concentrations of IL-1ß may serve as a marker of advanced cervical ripening and readiness for labor that proceeds with less pain.

Effect of labor on plasma concentrations and postpartum clearance of cell-free, pregnancy-associated, placenta-specific microRNAs.

OBJECTIVE: This study aimed to investigate the effect of labor on plasma concentrations of cell-free, pregnancy-associated, placenta-specific microRNAs (miRNAs) before and after delivery. METHOD: In the non-labor group (32 women), cesarean section (C/S) was performed before the beginning of labor. In the labor group (32 women), C/S was performed after the beginning of labor. Plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs (miR-515-3p, miR-517a, miR-517c, and miR-518b) were measured by real-time quantitative PCR. Each miRNA concentration was compared between the non-labor and labor groups. RESULTS: Before C/S, plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs in the labor group were significantly higher than those in the non-labor group (P = 0.001 for 515-3p, P = 0.002 for 517a, P = 0.001 for 517c, and P = 0.003 for 518b). Twenty-four hours after delivery, plasma concentrations of cell-free, pregnancy-associated, placenta-specific miRNAs in the labor group were significantly higher than those in the non-labor group (P = 0.002 for 515-3p, P = 0.017 for 517a, P = 0.043 for 517c, and P = 0.009 for 518b). CONCLUSION: The presence of labor affects cell-free, pregnancy-associated, placenta-specific miRNA levels in maternal plasma. Labor also affects postpartum clearance of these miRNAs 24 h after delivery.