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.

Place of birth and outcomes associated with large volume transfusion: an observational study.

BACKGROUND: Guidelines recommend that women at high risk of postpartum haemorrhage deliver at facilities able to handle heavy bleeding. However postpartum haemorrhage is often unexpected. This study aims to compare outcomes and health service use related to transfusion of ≥4 units of red blood cells between women delivering in tertiary and lower level hospitals. METHODS: The study population was women giving birth in public hospitals in New South Wales, Australia, between July 2006 and December 2010. Data were obtained from linked hospital, birth and blood bank databases. The exposure of interest was transfusion of four or more units of red cells during admission for delivery. Outcomes included maternal morbidity, length of stay, neonatal morbidity and need for other blood products or transfer to higher care. Multivariable regression models were developed to predict need of transfusion of ≥4 units of red cells using variables known early in pregnancy and those known by the birth admission. RESULTS: Data were available for 231,603 births, of which 4309 involved a blood transfusion, with 1011 (0.4%) receiving 4 or more units. Women giving birth in lower level and/or smaller hospitals were more likely to receive ≥4 units of red cells. Women receiving ≥4 units in tertiary settings were more likely to receive other blood products and have longer hospital stays, but morbidity, readmission and hysterectomy rates were similar. Although 46% of women had no identifiable risk factors early in pregnancy, 20% of transfusions of ≥4 units occurred within this group. By the birth admission 70% of women had at least one risk factor for requiring ≥4 units of red cells. CONCLUSIONS: Overall outcomes for women receiving ≥4 units of red cells were comparable between tertiary and non-tertiary facilities. This is important given the inability of known risk factors to predict many instances of postpartum haemorrhage.

Effect of Maternal Nutritional Status and Mode of Delivery on Zinc and Iron Stores at Birth.

Zinc and iron deficiencies among infants aged under 6 months may be related with nutrient store at birth. This study aimed to investigate the association between zinc and iron stores at birth with maternal nutritional status and intakes during pregnancy. 117 pregnant women were enrolled at the end of second trimester and followed until delivery. Clinical data during pregnancy, including pre-pregnancy body mass index (BMI) and at parturition were collected from medical record. Zinc and iron intakes were estimated from a food frequency questionnaire. Serum zinc and ferritin were determined in maternal blood at enrollment and cord blood. Mean cord blood zinc and ferritin were 10.8 ± 2.6 µmol/L and 176 ± 75.6 µg/L, respectively. Cord blood zinc was associated with pre-pregnancy BMI (adj. ß 0.150; p = 0.023) and serum zinc (adj. ß 0.115; p = 0.023). Cord blood ferritin was associated with pre-pregnancy BMI (adj. ß -5.231; p = 0.009). Cord blood zinc and ferritin were significantly higher among those having vaginal delivery compared to cesarean delivery (adj. ß 1.376; p = 0.007 and 32.959; p = 0.028, respectively). Maternal nutritional status and mode of delivery were significantly associated with zinc and iron stores at birth. Nutrition during preconception and pregnancy should be ensured to build adequate stores of nutrients for infants.

Low CETP activity and unique composition of large VLDL and small HDL in women giving birth to small-for-gestational age infants.

Cholesteryl ester transfer protein (CETP) regulates high density lipoproteins (HDL)-cholesterol (C) and HDL-C is essential for fetal development. We hypothesized that women giving birth to large-for-gestational-age (LGA) and small-for-gestational age (SGA) infants differed in longitudinal changes in lipoproteins, CETP activity and HDL-C and that placentas from women with higher or lower circulating HDL-C displayed differential expression of mRNAs involved in cholesterol/nutrient transport, insulin signaling, inflammation/ extracellular matrix (ECM) remodeling. Circulating lipids and CETP activity was measured during pregnancy, NMR lipidomics in late pregnancy, and associations with LGA and SGA infants investigated. RNA sequencing was performed in 28 placentas according to higher and lower maternal HDL-C levels. Lipidomics revealed high triglycerides in large VLDL and lipids/cholesterol/cholesteryl esters in small HDL in women giving birth to SGA infants. Placentas from women with higher HDL-C had decreased levels of CETP expression which was associated with mRNAs involved in cholesterol/nutrient transport, insulin signaling and inflammation/ECM remodeling. Both placental and circulating CETP levels were associated with growth of the fetus. Low circulating CETP activity at 36-38 weeks was associated with giving birth to SGA infants. Our findings suggest a link between increased maternal HDL-C levels, low CETP levels both in circulation and placenta, and SGA infants.

Association between serum calcium dynamics around parturition and common postpartum diseases in dairy cows.

The objective of this study was to compare periparturient serum Ca dynamics (CaDyn) in cows with and without diseases in early lactation. The study enrolled 1,949 cows from a commercial dairy farm in northern Germany. Blood samples were drawn 7 d before expected calving date and on d 0, 1, 3, and 7 after calving and analyzed for serum Ca concentration. Cows were monitored for clinical hypocalcemia (CH), ketosis, left displaced abomasum (LDA), retained placenta, acute puerperal metritis (APM), mastitis, and pneumonia. To evaluate the association between CaDyn and diseases during the transition period, repeated measures ANOVA with first-order autoregressive covariance were performed. Serum CaDyn of healthy cows (i.e., without any of the aforementioned diseases) was compared with CaDyn of cows with one of the aforementioned diseases (CH, ketosis, APM, mastitis, LDA, and pneumonia), and cows with multiple diseases (CH+, ketosis+, APM+, mastitis+, LDA+, and pneumonia+). Separate models were built for primiparous and multiparous cows. For primiparous cows, we evaluated the association between CaDyn and ketosis (healthy cows vs. cows with ketosis vs. cows with ketosis+) and CaDyn and APM (healthy cows vs. cows with APM vs. cows with APM+). The same models were built for multiparous cows. Three additional models were built for multiparous cows to evaluate the association between CaDyn and CH (healthy cows vs. cows with CH vs. cows with CH+), mastitis (healthy cows vs. cows with mastitis vs. cows with mastitis+), or LDA (healthy cows vs. cows with LDA vs. cows with LDA+). In primiparous cows, serum Ca concentrations of cows with ketosis, APM, and APM+ were significantly reduced on d 3 and 7 after calving, compared with healthy cows. Serum Ca concentrations of primiparous cows with ketosis+ were reduced on d 3, but not on d 7 after calving. Multiparous cows with CH had significantly reduced serum Ca concentrations on d 0, 1, and 3 compared with healthy cows. On d 3 and 7, serum Ca concentration of CH+ cows was significantly reduced compared with healthy multiparous cows. Multiparous cows with ketosis and ketosis+ had significantly reduced serum Ca concentrations on d 1 and 3 compared with healthy cows. Cows with APM+ had significantly increased serum Ca concentrations on d 0 and reduced serum Ca concentrations on d 3, compared with healthy cows. Whereas multiparous cows with mastitis had a reduced serum Ca concentration on d 1, mastitis+ cows had a reduced serum Ca concentration on d 1 and 3, compared with healthy multiparous cows. Overall, multiparous cows with LDA+ had reduced serum Ca concentrations. Especially a delayed onset of hypocalcemia (d 3 and 7) was indicative for the development of disease in primiparous cows. In multiparous cows, reduced serum Ca concentrations on d 1 and 3 were associated with occurrence of diseases. Future studies should evaluate whether reduced serum Ca concentrations are a cause or concomitant circumstance of diseases in early lactation.

Birth signalling hormones and the developmental consequences of caesarean delivery.

Rates of delivery by caesarean section (CS) are increasing around the globe and, although several epidemiological associations have already been observed between CS and health outcomes in later life, more are sure to be discovered as this practice continues to gain popularity. The components of vaginal delivery that protect offspring from the negative consequences of CS delivery in later life are currently unknown, although much attention to date has focused on differences in microbial colonisation. Here, we present the case that differing hormonal experiences at birth may also contribute to the neurodevelopmental consequences of CS delivery. Levels of each of the 'birth signalling hormones' (oxytocin, arginine vasopressin, epinephrine, norepinephrine and the glucocorticoids) are lower following CS compared to vaginal delivery, and there is substantial evidence for each that manipulations in early life results in long-term neurodevelopmental consequences. We draw from the research traditions of neuroendocrinology and developmental psychobiology to suggest that the perinatal period is a sensitive period, during which hormones achieve organisational effects. Furthermore, there is much to be learned from research on developmental programming by early-life stress that may inform research on CS, as a result of shared neuroendocrine mechanisms at work. We compare and contrast the effects of early-life stress with those of CS delivery and propose new avenues of research based on the links between the two bodies of literature. The research conducted to date suggests that the differences in hormone signalling seen in CS neonates may produce long-term neurodevelopmental consequences.

Concentrations of fat-soluble nutrients and blood inflammatory compounds in mother-infant dyads at birth.

BACKGROUND: Perinatal inflammation adversely affects health. Therefore, aims of this IRB-approved study are: (1) compare inflammatory compounds within and between maternal and umbilical cord blood samples at the time of delivery, (2) assess relationships between inflammatory compounds in maternal and cord blood with birth characteristics/outcomes, and (3) assess relationships between blood and placental fat-soluble nutrients with blood levels of individual inflammatory compounds. METHODS: Mother-infant dyads were enrolled (n = 152) for collection of birth data and biological samples of maternal blood, umbilical cord blood, and placental tissue. Nutrient levels included: lutein + zeaxanthin; lycopene; α-, ß-carotene; ß-cryptoxanthin; retinol; α-, γ-, δ-tocopherol. Inflammatory compounds included: tumor necrosis factor-α, superoxide dismutase, interleukins (IL) 1ß, 2, 6, 8, 10. RESULTS: Median inflammatory compound levels were 1.2-2.3 times higher in cord vs. maternal blood, except IL2 (1.3 times lower). Multiple significant correlations existed between maternal vs. infant inflammatory compounds (range of r = 0.22-0.48). While relationships existed with blood nutrient levels, the most significant were identified in placenta where all nutrients (except δ-tocopherol) exhibited relationships with inflammatory compounds. Relationships between anti-inflammatory nutrients and proinflammatory compounds were primarily inverse. CONCLUSION: Inflammation is strongly correlated between mother-infant dyads. Fat-soluble nutrients have relationships with inflammatory compounds, suggesting nutrition is a modifiable factor. IMPACT: Mother and newborn inflammation status are strongly interrelated. Levels of fat-soluble nutrients in blood, but especially placenta, are associated with blood levels of proinflammatory and anti-inflammatory compounds in both mother and newborn infant. As fat-soluble nutrient levels are associated with blood inflammatory compounds, nutrition is a modifiable factor to modulate inflammation and improve perinatal outcomes.

Leptin at birth and at age 7 in relation to appetitive behaviors at age 7 and age 10.

Leptin contributes to the control of food intake and energy balance. However, its association with appetitive behaviors during childhood is not well understood. We aimed to investigate the association between leptin, assessed at birth and at 7 years of age (y), and appetitive behaviors assessed at 7 and 10 y. Children from a Portuguese cohort with assessment of leptin levels at birth from umbilical cord blood (n = 645) and at 7 y from venous blood samples (n = 587), were included. The Children's Eating Behavior Questionnaire assessed appetitive behaviors at 7 and 10 y. Weight and height were measured at 7 and 10 y to derive BMI z-scores (BMIz). A series of Generalized Linear Models tested relationships between leptin and appetitive behaviors, adjusting for potential confounders (maternal age, education, pre-pregnancy BMI, smoking during pregnancy, child physical activity and child BMIz), and interaction terms for child sex and child BMIz. At 7 y, 116 boys and 118 girls were classified as having overweight/obesity, and these children had higher leptin levels. Cross-sectional analyses using the 7 y data produced the strongest results. Higher leptin at 7 y was significantly associated with lower scores on Satiety Responsiveness, Food Fussiness and Slowness in Eating, and higher scores on Food Responsiveness, Enjoyment of Food and Emotional Overeating at 7 y. Only the association with Emotional Overeating remained when adjusting for child BMIz. Significant interaction effects between child sex and leptin were found for appetite at 7 y, such that higher leptin was associated with higher Food Responsiveness (p < 0.001) and lower Slowness in Eating (p < 0.001) to a greater extent among boys. Umbilical cord blood leptin was not associated with appetitive behaviors at 7 or 10 y. Our results show that leptin levels are positively associated with food approach and negatively with food avoidant behaviors. Associations were more consistent in cross-sectional analyses (at 7 y), were largely dependent on child weight, and tended to be stronger among boys. Our findings support a role for leptin in affecting appetite, with potential consequences for current weight status and future weight gain.

A Pilot Study of the Maternal-Fetal Pharmacokinetics of Furosemide in Plasma, Urine, and Amniotic Fluid of Hypertensive Parturient Women Under Cesarean Section.

The third trimester of pregnancy is related to physiological changes that can modify the process of absorption, distribution, metabolism, and excretion and, consequently, the efficacy and toxicity of drugs. However, little is known about furosemide pharmacokinetics and placental transfer in pregnancy. This study evaluated the maternal-fetal pharmacokinetics and distribution to amniotic fluid of furosemide in hypertensive parturient women under cesarean section. Twelve hypertensive parturient women under methyldopa (250 mg/8 h) and/or pindolol (10 mg/12 h) treatment received a 40-mg single oral dose of furosemide 1 to 10 hours before delivery by cesarean section. Blood and urine samples were collected for 12 hours after furosemide administration. At delivery, samples were obtained from maternal and umbilical cord blood (n = 8) to assess the transplacental transfer. Amniotic fluid (n = 4) was collected at the time of delivery. The following furosemide pharmacokinetic parameters were obtained as median (interquartile range): Cmax , 403 ng/mL (229 to 715 ng/mL); Tmax , 2.00 hours (1.50 to 4.83 hours); elimination half-life (t1/2 ), 2.50 hours (1.77 to 2.97 hours); AUC0-12 h , 1366 ng⋅h/mL (927 to 2531 ng⋅h/mL); AUC0-∞ , 1580 ng⋅h/mL (1270 to 2881 ng⋅h/mL); CL/F 25.3 L/h (13.8 to 31.4 L/h); CLR, 2.50 L/h (1.77 to 2.97 L/h); CLNR, 22.7 L/h (12.1 to 25.6 L/h); and Vd /F 82.8 L (34.4 to 173 L). The transplacental transfer of furosemide was 0.43 (0.10 to 0.73), and the amniotic fluid concentration was 11.0 ng/mL (5.51 to 14.6 ng/mL). From a clinical point of view, these results suggest that substrates of uridine diphosphate-glucuronosyltransferase isoenzymes such as furosemide may have increased clearance during pregnancy and could require dose adjustment in this population.

Is placental blood a reliable source for the evaluation of neonatal hemostasis at birth?

BACKGROUND: Phlebotomy is among the main determinants of anemia of prematurity. Blood sparing policies endorsed umbilical cord blood (here called placental) as an alternative source for laboratory testing. Little is known on the suitability of placental blood to evaluate neonatal hemostasis of newborn infants. We aimed to compare the hemostatic profile of paired placental and infant venous blood, by means of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, antithrombin, protein C, thromboelastography (TEG) and thrombin generation assay (TGA). STUDY DESIGN: This was an observational single-center study. METHODS: We collected at birth venous citrated blood from both placental and infant venous source and performed PT, APTT, fibrinogen, antithrombin, protein C, TEG (reaction time-R; kinetics-K alpha angle-α, maximum amplitude-MA and lysis at 30 minutes-LY30), and TGA (endogenous thrombin potential-ETP). RESULTS: We enrolled 60 neonates with a median gestational age (range) of 37 weeks (28+1 -41) and birth-weight 2417 g (950-4170). Based on TEG and TGA, placental blood showed a procoagulant imbalance as indicated by lower median R (4.0 vs. 6.1 min; p < 0.001) and K (1.3 vs. 2.2 min; p < 0.001); higher α-angle (69.7 vs. 57.4°; p < 0.001) and ETP (1260 vs. 1078; p = 0.002) than those observed for infant venous blood. PT and APTT did not differ significantly between the two groups. CONCLUSIONS: While placental and neonatal blood samples are equally suitable to measure the standard coagulation tests PT and APTT, placental blood leads to a procoagulant imbalance when testing is performed with TEG or TGA. These effects should be considered when interpreting results stemming from investigation of neonatal hemostasis.

Clinical utility of plasma progesterone and blood and plasma glucose concentrations in predicting parturition in Holstein cows.

An accurate, practical, and low-cost method for predicting parturition is urgently needed in the dairy industry. The objective of this study was to evaluate changes in plasma progesterone concentration ([prog]) and glucose concentration in whole blood ([gluc]b) and plasma ([gluc]p) as predictors of parturition within 6, 12, and 24 h in primiparous and multiparous Holstein cows. Blood samples were obtained daily at approximately 0900 h from 34 primiparous and 72 multiparous Holstein cows in late gestation and the time of calving recorded to the nearest hour. Plasma [prog] was measured using an ELISA, and [gluc]b and [gluc]p using a low-cost point-of-care glucose meter. The optimal cut-point for predicting parturition was determined using binomial logistic regression with general estimating equations, because the data set consisted of repeated measures for each cow. Diagnostic test performance was evaluated by comparing the area under the receiver operating characteristic curve (AUC) and calculating the sensitivity, specificity, and κ at the optimal cut-point for predicting parturition. Plasma [prog] was the most accurate predictor of parturition within 24 h (AUC = 0.96) and 12 h (AUC = 0.93), whereas [gluc]b was the most accurate predictor of parturition within 6 h (primiparous, AUC = 0.96; multiparous, AUC = 0.86). We conclude that a decrease in plasma [prog] is currently the most accurate test for predicting calving within 24 h. Measurement of [gluc]b is a promising new test for the cow-side prediction of parturition in dairy cows due to its accuracy, practicality, and low cost.

Contraction-associated proteins expression by human uterine smooth muscle cells depends on maternal serum and progranulin associated with gestational weight gain.

Pregnant women with obesity are at increased risk of parturition dysfunction; however, the biological mechanism has remained unknown. We hypothesized that molecules circulating in the serum of pregnant women with obesity may induce the aberrant expression of contraction-associated proteins (CAPs), leading to insufficient uterine contractions. This study aimed to investigate the effects of maternal serum on CAPs expression by human uterine smooth muscle cells (UtSMCs) and elucidate the influence of maternal obesity. Blood samples were collected from singleton pregnant women at 36-41 weeks of gestation before the onset of labor. UtSMCs were incubated in the serum, and the mRNA expressions of PTGFR, OXTR, GJA1, and PTGS2 were examined by RT-PCR. Progranulin (PGRN) is a circulating glycoprotein associated with insulin resistance characterized by the accumulation of visceral fat. The serum PGRN levels of the samples were measured by ELISA. After incubated with PGRN (100-1,000 ng/mL), mRNA expression of PTGFR, OXTR, and GJA1 and protein expression of CX43 were examined by RT-PCR and western blotting, respectively. The mRNA expressions of PTGFR, OXTR, and GJA1 showed significantly negative correlations with gestational weight gain (GWG). Serum PGRN levels showed a significantly positive correlation with GWG. High levels of PGRN suppressed the mRNA expression of GJA1 and the protein expression of CX43. The change in maternal serum induced by GWG suppressed the CAPs expression by UtSMCs. PGRN is one of the factors in the serum responsible for inhibiting the expression of CX43.

Cell-Free Fetal DNA Increases Prior to Labor at Term and in a Subset of Preterm Births.

Cell-free fetal DNA in the maternal circulation has been associated with the onset of labor at term. Moreover, clinical studies have suggested that cell-free fetal DNA has value to predict pregnancy complications such as spontaneous preterm labor leading to preterm birth. However, a mechanistic link between cell-free fetal DNA and preterm labor and birth has not been established. Herein, using an allogeneic mouse model in which a paternal green fluorescent protein (GFP) can be tracked in the fetuses, we established that cell-free fetal DNA (Egfp) concentrations were higher in late gestation compared to mid-pregnancy and were maintained at increased levels during the onset of labor at term, followed by a rapid decrease after birth. A positive correlation between cell-free fetal DNA concentrations and the number of GFP-positive pups was also observed. The increase in cell-free fetal DNA concentrations prior to labor at term was not linked to a surge in any specific cytokine/chemokine; yet, specific chemokines (i.e., CCL2, CCL7, and CXCL2) increased as gestation progressed and maintained elevated levels in the postpartum period. In addition, cell-free fetal DNA concentrations increased prior to systemic inflammation-induced preterm birth, which was associated with a strong cytokine response in the maternal circulation. However, cell-free fetal DNA concentrations were not increased prior to intra-amniotic inflammation-induced preterm birth, but in this model, a mild inflammatory response was observed in the maternal circulation. Collectively, these findings suggest that an elevation in cell-free fetal DNA concentrations in the maternal circulation precedes the physiological process of labor at term and the pathological process of preterm labor linked with systemic inflammation, but not that associated with intra-amniotic inflammation.

Involvement of Plasma Endocannabinoids and the Hypothalamic Endocannabinoid System in Increasing Feed Intake after Parturition of Dairy Cows.

The endocannabinoids (ECs) N-arachidonylethanolamide (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) participate in the control of feed intake and energy metabolism. Most mammals increase their feed intake after parturition to cope with the increased energy and nutrient requirements for milk synthesis, thereby increasing their metabolic rate. Here we investigated in experiment 1 the regulation of plasma AEA and 2-AG concentrations during the transition from late pregnancy to early lactation in dairy cows, and analyzed in experiment 2 the expression of the EC system in the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the hypothalamus of late and early lactating cows using immunohistochemistry. Cows in experiment 1 were retrospectively grouped based on peak plasma fatty acid concentrations to a high (H) or low (L) group. Feed intake was not different between groups before parturition, but was lower in H than L cows during early lactation. Plasma AEA and 2-AG concentrations increased 2.2- to 2.4-fold during early lactation, in which time plasma AEA concentrations rose faster in H cows than in L cows postpartum. Upregulation of N-acyl phosphatidylethanolamine-specific phospholipase D together with tending increased cannabinoid receptor 1 (CB1) expression, and downregulation of fatty acid amide hydrolase in early lactating cows suggested an increased PVN AEA tone. The abundance of CB1 in the ARC and diacylglycerol lipase-alpha was not different between late and early lactating cows, but PVN monoacylglycerol lipase expression was 30% higher in early lactating cows, indicating diminished PVN 2-AG concentrations. The results show a potential involvement of AEA in stimulating feed intake and of 2-AG in regulating energy metabolism of early lactating cows.

Impact of parturition on maternal cardiovascular and neuronal integrity in a high risk cohort - a prospective cohort study.

BACKGROUND: To better understand the profound multisystem changes in maternal physiology triggered by parturition, in particular in the underexplored neuronal system, by deploying a panel of pre- vs post-delivery maternal serum biomarkers, most notably the neuronal cytoskeleton constituent neurofilament light chain (NfL). This promising fluid biomarker is not only increasingly applied to investigate disease progression in numerous brain diseases, particularly in proteopathies, but also in detection of traumatic brain injury or monitoring neuroaxonal injury after ischemic stroke. METHODS: The study was nested within a prospective cohort study of pregnant women at risk of developing preeclampsia at the University Hospital of Basel. Paired ante- and postpartum levels of progesterone, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin (CT-proAVP), and NfL were measured in 56 women with complete clinical data. RESULTS: Placental delivery significantly decreased all placental markers: progesterone 4.5-fold, PlGF 2.2-fold, and sFlt-1 1.7-fold. Copeptin and MR-proANP increased slightly (1.4- and 1.2-fold, respectively). Unexpectedly, NfL levels (median [interquartile range]) increased significantly post-partum: 49.4 (34.7-77.8) vs 27.7 (16.7-31.4) pg/ml (p < 0.0001). Antepartum NfL was the sole independent predictor of NfL peri-partum change; mode of delivery, duration of labor, clinical characteristics and other biomarkers were all unrelated. Antepartum NfL levels were themselves independently predicted only by maternal age. CONCLUSIONS: Parturition per se increases maternal serum NfL levels, suggesting a possible impact of parturition on maternal neuronal integrity.

Infrastructural and human-resource factors associated with return of infant HIV test results to caregivers: secondary analysis of a nationally representative situational assessment, South Africa, 2010.

BACKGROUND: In June 2015, South Africa introduced early infant HIV diagnosis (EID) at birth and ten weeks postpartum. Guidelines recommended return of birth results within a week and ten weeks postpartum results within four weeks. Task shifting was also suggested to increase service coverage. This study aimed to understand factors affecting return of EID results to caregivers. METHODS: Secondary analysis of data gathered from 571 public-sector primary health care facilities (PHCs) during a nationally representative situational assessment, was conducted. The assessment was performed one to three months prior to facility involvement in the 2010 evaluation of the South African programme to prevent mother-to-child HIV transmission (SAPMTCTE). Self-reported infrastructural and human resource EID-related data were collected from managers and designated staff using a structured questionnaire. The main outcome variable was 'EID turn-around-time (TAT) to caregiver' (caregiver TAT), measured as reported number of weeks from infant blood draw to caregiver receipt of results. This was dichotomized as either short (≤3 weeks) or delayed (> 3 weeks) caregiver TAT. Logit-based risk difference analysis was used to assess factors associated with short caregiver TAT. Analysis included TAT to facility (facility TAT), defined as reported number of weeks from infant blood draw to facility receipt of results. RESULTS: Overall, 26.3% of the 571 PHCs reported short caregiver TAT. In adjusted analyses, short caregiver TAT was less achieved when facility TAT was > 7 days (versus ≤7 days) (adjusted risk difference (aRD): - 0.2 (95% confidence interval - 0.3-(- 0.1)), p = 0.006 for 8-14 days and - 0.3 (- 0.5-(- 0.1)), p = 0.006 for > 14 days), and in facilities with staff nurses (compared to those without) (aRD: - 9.4 (- 16.6-(- 2.2), p = 0.011). CONCLUSION: Although short caregiver TAT for EID was only reported in approximately 26% of facilities, these facilities demonstrate that achieving EID TAT of ≤3 weeks is possible, making timely ART initiation within 3 weeks of diagnosis feasible within the public health sector. Our adjusted analyses underpin the need for quick return of results to facilities. They also raise questions around staff mentoring: we hypothesise that facilities with staff nurses were likely to have fewer professional nurses, and thus inadequate senior support.

Exploring Inflammatory Mediators in Fetal and Maternal Compartments During Human Parturition.

OBJECTIVE: To examine inflammatory mediators in three fetomaternal biological compartments to inform theory related to the fetal and maternal inflammatory contributions to parturition at term and preterm. METHODS: We conducted a cross-sectional study of amniotic fluid, cord blood, and maternal plasma from women with singleton pregnancies. Women had one of four conditions: term labor (n=11), term not in labor (n=13), spontaneous preterm birth with intact membranes (preterm birth; n=13), or preterm prelabor rupture of membranes (PROM; n=8). We measured two damage-associated molecular pattern markers (high-mobility group box-1 [HMGB1] and uric acid) and two acute phase response markers (interleukin [IL]-6 and C-reactive protein [CRP]) using enzyme-linked immunosorbent assay. The distribution of each analyte within amniotic fluid, cord blood, and maternal plasma across the four conditions (term not in labor, term labor, preterm birth, and preterm PROM) were calculated. To explore whether there were distributional differences in each analyte across each of the four labor conditions, we used a nonparametric Kruskal-Wallis test. For analytes that differed across groups, we further compared distributions by labor group (term labor vs term not in labor, and preterm PROM vs preterm birth). RESULTS: Fetal compartments (amniotic fluid and cord blood) showed higher HMGB1 in term labor vs term not in labor and preterm PROM vs preterm birth. Amniotic fluid IL-6, cord blood CRP and cord blood uric acid were higher in term vs term not in labor. Cord blood uric acid was higher in preterm PROM vs preterm birth. Only maternal plasma IL-6 was higher in term labor vs term not in labor. CONCLUSION: Accumulation of HMGB1 and an overall increase in inflammation observed on the fetal side, but not the maternal side, may be signals of parturition. Understanding fetal-derived proparturition inflammatory signals at term and preterm, especially in preterm PROM, might provide fetal-specific biomarkers and identify underlying mechanisms and targets for interventions to reduce the risk of preterm birth and preterm PROM.

Plasma steroid hormone concentrations and their relationships in Suffolk ewes during gestation and parturition.

In this study, we measured plasma concentrations of progesterone, pregnenolone, estradiol, estrone, estrone sulfate, and cortisol and analyzed the correlations between these hormones during gestation in 13 Suffolk ewes, the main breed in Japan. Progesterone increased during gestation and decreased a few days before parturition; however, this pattern was different in samples with high progesterone concentrations (P4 spike samples). This P4 spike was associated with a high pregnenolone concentration. Apart from the P4 spike, the progesterone change was similar to that in other sheep breeds. Pregnenolone increased during gestation and decreased after parturition. A significant correlation between progesterone and pregnenolone was observed a few days before parturition. Estrone sulfate and estradiol concentrations increased during gestation, but estrone did not. They increased shortly before parturition, and then decreased immediately after parturition. At parturition, the correlation between estrone and estrone sulfate was significantly stronger. Moreover, a strong correlation between estrone sulfate and estradiol was observed after parturition. Cortisol did not change during gestation and increased shortly before parturition. The results showed steroid hormone dynamics in normal pregnant Suffolk ewes, which were mostly in line with those of other sheep breeds. It should be noted that high progesterone concentrations altered the typical patterns.

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.