Placental pathology and neonatal morbidity: exploring the impact of gestational age at birth.

AIM: To evaluate placental pathology in term and post-term births, investigate differences in clinical characteristics, and assess the risk of adverse neonatal outcome. METHODS: This prospective observational study included 315 singleton births with gestational age (GA) > 36 weeks + 6 days meeting the local criteria for referral to placental histopathologic examination. We applied the Amsterdam criteria to classify the placentas. Births were categorized according to GA; early-term (37 weeks + 0 days to 38 weeks + 6 days), term (39 weeks + 0 days to 40 weeks + 6 days), late-term (41 weeks + 0 days to 41 weeks + 6 days), and post-term births (≥ 42 weeks + 0 days). The groups were compared regarding placental pathology findings and clinical characteristics. Adverse neonatal outcomes were defined as 5-minute Apgar score < 7, umbilical cord artery pH < 7.0, admission to the neonatal intensive care unit or intrauterine death. A composite adverse outcome included one or more adverse outcomes. The associations between placental pathology, adverse neonatal outcomes, maternal and pregnancy characteristics were evaluated by logistic regression analysis. RESULTS: Late-term and post-term births exhibited significantly higher rates of histologic chorioamnionitis (HCA), fetal inflammatory response, clinical chorioamnionitis (CCA) and transfer to neonatal intensive care unit (NICU) compared to early-term and term births. HCA and maternal smoking in pregnancy were associated with adverse outcomes in an adjusted analysis. Nulliparity, CCA, emergency section and increasing GA were all significantly associated with HCA. CONCLUSIONS: HCA was more prevalent in late and post-term births and was the only factor, along with maternal smoking, that was associated with adverse neonatal outcomes. Since nulliparity, CCA and GA beyond term are associated with HCA, this should alert the clinician and elicit continuous intrapartum monitoring for timely intervention.

Is the fetus fit for labor? Introducing fast-and-frugal trees (FFTrees) to simplify triage of women for STAN monitoring: An interobserver agreement comparison with traditional classification.

INTRODUCTION: It is a shortcoming of traditional cardiotocography (CTG) classification table formats that CTG traces are frequently classified differently by different users, resulting in poor interobserver agreements. A fast-and-frugal tree (FFTree) flow chart may help provide better concordance because it is straightforward and has clearly structured binary questions with understandable "yes" or "no" responses. The initial triage to determine whether a fetus is suitable for labor when utilizing fetal ECG ST analysis (STAN) is very important, since a fetus with restricted capacity to respond to hypoxic stress may not generate STAN events and therefore may become falsely negative. This study aimed to compare physiology-focused FFTree CTG interpretation with FIGO classification for assessing the suitability for STAN monitoring. MATERIAL AND METHODS: A retrospective study of 36 CTG traces with a high proportion of adverse outcomes (17/36) selected from a European multicenter study database. Eight experienced European obstetricians evaluated the initial 40 minutes of the CTG recordings and judged whether STAN was a suitable fetal surveillance method and whether intervention was indicated. The experts rated the CTGs using the FFTree and FIGO classifications at least 6 weeks apart. Interobserver agreements were calculated using proportions of agreement and Fleiss' kappa (κ). RESULTS: The proportions of agreement for "not suitable for STAN" were for FIGO 47% (95% confidence interval [CI] 42%-52%) and for FFTree 60% (95% CI 56-64), ie a significant difference; the corresponding figures for "yes, suitable" were 74% (95% CI 71-77) and 70% (95% CI 67-74). For "intervention needed" the figures were 52% (95% CI 47-56) vs 58% (95% CI 54-62) and for "expectant management" 74% (95% CI 71-77) vs 72% (95% CI 69-75). Fleiss' κ agreement on "suitability for STAN" was 0.50 (95% CI 0.44-0.56) for the FIGO classification and 0.57 (95% CI 0.51-0.63) for the FFTree classification; the corresponding figures for "intervention or expectancy" were 0.53 (95% CI 0.47-0.59) and 0.57 (95% CI 0.51-0.63). CONCLUSIONS: The proportion of agreement among expert obstetricians using the FFTree physiological approach was significantly higher compared with the traditional FIGO classification system in rejecting cases not suitable for STAN monitoring. That might be of importance to avoid false negative STAN recordings. Other agreement figures were similar. It remains to be shown whether the FFTree simplicity will benefit less experienced users and how it will work in real-world clinical scenarios.

Neonatal outcomes associated with time from a high fetal blood lactate concentration to operative delivery.

INTRODUCTION: Adjunctive technologies to cardiotocography intend to increase the specificity of the diagnosis of fetal hypoxia. If correctly diagnosed, time to delivery could affect neonatal outcome. In the present study, we aimed to investigate the effect of time from when fetal distress is indicated by a high fetal blood sample (FBS) lactate concentration to operative delivery on the risk of adverse neonatal outcomes. MATERIAL AND METHODS: We conducted a prospective observational study. Deliveries with a singleton fetus in cephalic presentation at 36+0 weeks of gestation or later were included. Adverse neonatal outcomes, related to decision-to-delivery interval (DDI), were investigated in operative deliveries indicated by an FBS lactate concentration of at least 4.8 mmol/L. We applied logistic regression to estimate crude and adjusted odds ratios (aOR) of various adverse neonatal outcomes, with associated 95% confidence intervals (CI), for a DDI exceeding 20 minutes, compared with a DDI of 20 minutes or less. CLINICALTRIALS: gov Identifier: NCT04779294. RESULTS: The main analysis included 228 women with an operative delivery indicated by an FBS lactate concentration of 4.8 mmol/L or greater. The risk of all adverse neonatal outcomes was significantly increased for both DDI groups compared with the reference group (deliveries with an FBS lactate below 4.2 mmol/L within 60 minutes before delivery). In operative deliveries indicated by an FBS lactate concentration of 4.8 mmol/L or more, there was a significantly increased risk of a 5-minute Apgar score less than 7 if the DDI exceeded 20 minutes, compared with a DDI of 20 minutes or less (aOR 8.1, 95% CI 1.1-60.9). We found no statistically significant effect on other short-term outcomes for deliveries with DDI longer than 20 minutes, compared with those with DDI of 20 minutes or less (pH ≤7.10: aOR 2.0, 95% CI 0.5-8.4; transfer to the neonatal intensive care unit: aOR 1.1, 95% CI 0.4-3.5). CONCLUSIONS: After a high FBS lactate measurement, the increased risk of adverse neonatal outcome is further augmented if the DDI exceeds 20 minutes. These findings give support to current Norwegian guidelines for intervention in cases of fetal distress.

Double-vs single-balloon catheter for induction of labor: Systematic review and individual participant data meta-analysis.

INTRODUCTION: Evidence comparing double-balloon vs single-balloon catheter for induction of labor is divided. We aim to compare the efficacy and safety of double-vs single-balloon catheters using individual participant data. MATERIAL AND METHODS: A search of Ovid MEDLINE, Embase, Ovid Emcare, CINAHL Plus, Scopus, and clinicaltrials.gov was conducted for randomized controlled trials published from March 2019 until April 13, 2021. Earlier trials were identified from the Cochrane Review on Mechanical Methods for Induction of Labour. Randomized controlled trials that compared double-balloon with single-balloon catheters for induction of labor in singleton gestations were eligible. Participant-level data were sought from trial investigators and an individual participant data meta-analysis was performed. The primary outcomes were rates of vaginal birth achieved, a composite measure of adverse maternal outcomes and a composite measure of adverse perinatal outcomes. We used a two-stage random-effects model. Data were analyzed from the intention-to-treat perspective. RESULTS: Of the eight eligible randomized controlled trials, three shared individual-level data with a total of 689 participants, 344 women in the double-balloon catheter group and 345 women in the single-balloon catheter group. The difference in the rate of vaginal birth between double-balloon catheter and single-balloon catheter was not statistically significant (relative risk [RR] 0.93, 95% confidence interval [CI] 0.86-1.00, p = 0.050; I2 0%; moderate-certainty evidence). Both perinatal outcomes (RR 0.81, 95% CI 0.54-1.21, p = 0.691; I2 0%; moderate-certainty evidence) and maternal composite outcomes (RR 0.65, 95% CI 0.15-2.87, p = 0.571; I2 55.46%; low-certainty evidence) were not significantly different between the two groups. CONCLUSIONS: Single-balloon catheter is at least comparable to double-balloon catheter in terms of vaginal birth rate and maternal and perinatal safety outcomes.

Put your weight behind it-Effect of body mass index on the active second stage of labour: A retrospective cohort study.

OBJECTIVE: To explore the duration of the active phase of the second stage of labour in relation to maternal pre-pregnant body mass index (BMI). DESIGN: Retrospective cohort study. SETTING: Labour wards of three Norwegian university hospitals, 2012-2019. POPULATION: Nulliparous and parous women without previous caesarean section with a live singleton fetus in cephalic presentation and spontaneous onset of labour, corresponding to the Ten Group Classification System (TGCS) group 1 and 3. METHODS: Women were stratified to BMI groups according to WHO classification, and estimated median duration of the active phase of the second stage of labour was calculated using survival analyses. Caesarean sections and operative vaginal deliveries during the active phase were censored. MAIN OUTCOME MEASURES: Estimated median duration of the active phase of second stage of labour. RESULTS: In all, 47 942 women were included in the survival analyses. Increasing BMI was associated with shorter estimated median duration of the active second stage in both TGCS groups. In TGCS group 1, the estimated median durations (interquartile range) were 44 (26-75), 43 (25-71), 39 (22-70), 33 (18-63), 34 (19-54) and 29 (16-56) minutes in BMI groups 1-6, respectively. In TGCS group 3, the corresponding values were 11 (6-19), 10 (6-17), 10 (6-16), 9 (5-15), 8 (5-13) and 7 (4-11) minutes. Increasing BMI remained associated with shorter estimated median duration in analyses stratified by oxytocin augmentation and epidural analgesia. CONCLUSION: Increasing BMI was associated with shorter estimated median duration of the active second stage of labour.

Placental histology predicted adverse outcomes in extremely premature neonates in Norway-population-based study.

AIM: We evaluated the role of placental pathology in predicting adverse outcomes for neonates born extremely preterm (EPT) before 28 weeks of gestation. METHODS: This was a prospective observational study of 123 extremely preterm singletons born in a hospital in western Norway, and the placentas were classified according to the Amsterdam criteria. The associations between histologic chorioamnionitis (HCA), by the presence or the absence of a foetal inflammatory response (FIR+ or FIR-), maternal vascular malperfusion (MVM) as a whole and adverse neonatal outcomes were evaluated by logistic regression analyses. Adverse outcomes were defined as perinatal death, necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD), brain pathology by magnetic resonance imaging at term-equivalent age, retinopathy of prematurity and early-onset neonatal sepsis. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: HCA was associated with NEC (OR 12.2, 95% CI 1.1 to 137.1). HCA/FIR+ was associated with BPD (OR 14.9, 95% CI 1.8-122.3) and brain pathology (OR 9.8, 95% CI 1.4-71.6), but HCA/FIR- was not. The only neonatal outcome that MVM was associated with was low birthweight. CONCLUSION: Placental histology provided important information when assessing the risk of adverse neonatal outcomes following EPT birth.

Recurrence of postpartum hemorrhage, maternal and paternal contribution, and the effect of offspring birthweight and sex: a population-based cohort study.

PURPOSE: This study examines individual aggregation of postpartum hemorrhage (PPH), paternal contribution and how offspring birthweight and sex influence recurrence of PPH. Further, we wanted to estimate the proportion of PPH cases attributable to a history of PPH or current birthweight. METHODS: We studied all singleton births in Norway from 1967 to 2017 using data from Norwegian medical and administrational registries. Subsequent births in the parents were linked. Multilevel logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PPH defined as blood loss > 500 ml, blood loss > 1500 ml, or the need for blood transfusion in parous women. Main exposures were previous PPH, high birthweight, and fetal sex. We calculated adjusted population attributable fractions for previous PPH and current high birthweight. RESULTS: Mothers with a history of PPH had three- and sixfold higher risks of PPH in their second and third deliveries, respectively (adjusted OR 2.9; 95% CI 2.9-3.0 and 6.0; 5.5-6.6). Severe PPH (> 1500 ml) had the highest risk of recurrence. The paternal contribution to recurrence of PPH in deliveries with two different mothers was weak, but significant. If the neonate was male, the risk of PPH was reduced. A history of PPH or birthweight ≥ 4000 g each accounted for 15% of the total number of PPH cases. CONCLUSION: A history of PPH and current birthweight exerted strong effects at both the individual and population levels. Recurrence risk was highest for severe PPH. Occurrence and recurrence were lower in male fetuses, and the paternal influence was weak.

Recurrence of postpartum hemorrhage in relatives: A population-based cohort study.

INTRODUCTION: Studies on the family aggregation of postpartum hemorrhage (PPH) are scarce and with inconsistent results, and to what extent current birthweight influences recurrence between relatives remains to be studied. Further, family aggregation of PPH has been studied from an individual, but not from a public heath perspective. We aimed to investigate family aggregation of PPH in Norway, how birthweight influences these effects, and to estimate the proportion of PPH cases attributable to a family history of PPH and current birthweight. MATERIAL AND METHODS: Using data from the Medical Birth Registry of Norway, Statistics Norway, and Central Population Registry of Norway we identified individuals as newborns, parents, grandparents, and full and half-siblings, and studied 1 002 687 mother-offspring, 841 164 father-offspring, and 761 011 both-parents-offspring pairs. We used multilevel logistic regression to calculate odds ratios (OR) with 95% CI. RESULTS: If the birth of the mother but not of the father involved PPH, then the OR of PPH (>500 mL) in the next generation was 1.44 (95% CI 1.39-1.49). If the birth of the father but not of the mother involved PPH, then OR was 1.12 (95% CI 1.08-1.16). These effects were stronger in severe PPH. Recurrence between siblings was highest between full sisters (OR 1.47, 95% CI 1.41-1.52), followed by maternal half-sisters, paternal half-sisters, and partners of full brothers. A family history of PPH or birthweight of 4000 g or more accounted for ≤5% and 15% of the total number of PPH cases, respectively. CONCLUSIONS: A history of PPH in relatives influenced the recurrence risk of PPH in a dose-response pattern consistent with the anticipated proportion of shared genes. The recurrence was highest through the maternal line.

Isolated single umbilical artery and the risk of adverse perinatal outcome and third stage of labor complications: A population-based study.

INTRODUCTION: Isolated single umbilical artery (iSUA) refers to single umbilical artery cords with no other fetal malformations. The association of iSUA to adverse outcome of pregnancy has not been consistently reported, and whether iSUA carries increased risk of third stage of labor complications has not been studied. We aimed to investigate the risk of adverse perinatal outcome, third stage of labor complications, and associated placental and cord characteristics in pregnancies with iSUA. A further aim was to assess the risk of recurrence of iSUA and anomalous cord or placenta characteristics in Norway. MATERIAL AND METHODS: This was a population-based study of all singleton pregnancies with gestational age >16 weeks at birth using data from the Medical Birth Registry of Norway from 1999 to 2014 (n = 918 933). Odds ratios (OR) with 95% confidence intervals were calculated for adverse perinatal outcome (preterm birth, perinatal and intrauterine death, low Apgar score, transferral to neonatal intensive care ward, placental and cord characteristics [placental weight, cord length and knots, anomalous cord insertion, placental abruption and previa]), and third stage of labor complications (postpartum hemorrhage and the need for manual placental removal or curettage) in pregnancies with iSUA, and recurrence of iSUA using generalized estimating equations and logistic regression. RESULTS: Pregnancies with iSUA carried increased risk of adverse perinatal outcome (OR 5.06, 95% confidence interval [CI] 4.26-6.02) and perinatal and intrauterine death (OR 5.62, 95% CI 4.69-6.73), and a 73% and 55% increased risk of preterm birth and small-for-gestational-age neonate, respectively. The presence of iSUA also carried increased risk of a small placenta, placenta previa and abruption, anomalous cord insertion, long cord, cord knot and third stage of labor complications. Women with iSUA, long cord or anomalous cord insertion in one pregnancy carried increased risk of iSUA in the subsequent pregnancy. CONCLUSIONS: The presence of ISUA was associated with a more than five times increased risk of intrauterine and perinatal death and with placental and cord complications. The high associated risk of adverse outcome justifies follow up with assessment of fetal wellbeing in the third trimester, intrapartum surveillance and preparedness for third stage of labor complications.

Estimated date of delivery based on second trimester fetal head circumference: A population-based validation of 21 451 deliveries.

INTRODUCTION: Fetal biometry is used for determining gestational age and estimated date of delivery (EDD). However, the accuracy of the EDD depends on the assumed length of pregnancy included in the calculation. This study aimed at assessing the actual pregnancy length and accuracy of EDD prediction based on fetal head circumference measured at the second trimester. MATERIAL AND METHODS: This was a population-based observational study with the following inclusion criteria: singleton pregnancy, head circumference dating in the second trimester, spontaneous onset or induction of delivery ≥ 294 days of gestation, live birth. The EDD was set anticipating a pregnancy length of 282 days. Bias in the prediction of EDD was defined as the difference between the actual date of birth and the EDD. RESULTS: Head circumference measurements were available for 21 451 pregnancies. Ultrasound-dated pregnancies had a median pregnancy length of 283.03 days, corresponding to a method bias of 1.03 days (95% CI; 0.89-1.16). This bias was dependent on the head circumference at dating, ranging from -1.58 days (95% CI; -3.54 to 1.12) to 3.42 days (95% CI; 1.98-4.31). The median pregnancy length, based on the last menstrual period of women with a regular menstrual cycle (n = 12 985), was 283.15 days (95% CI; 282.91-283.31). A total of 5685 (22.9%, 95% CI; 22.4% to 23.4%) and 886 women (3.6%, 95% CI; 3.3%-3.8%) were still pregnant 7 and 14 days after the EDD, respectively. CONCLUSIONS: Second trimester head circumference measurements can be safely used to predict EDD. A revision of the pregnancy length to 283 days will reduce the bias of EDD prediction to a level comparable with other methods.

Maternal diabetes alters the development of ductus venosus shunting in the fetus.

INTRODUCTION: Despite adequate glycemic control, the risks of fetal macrosomia and perinatal complications are increased in diabetic pregnancies. Adjustments of the umbilical venous distribution, including increased ductus venosus shunting, can be important fetal compensatory mechanisms, but the impact of pregestational diabetes on umbilical venous and ductus venosus flow is not known. MATERIAL AND METHODS: In this prospective study, 49 women with pregestational diabetes mellitus underwent monthly ultrasound examinations from gestational week 20 to 36. The blood velocity and the mean diameters of the umbilical vein and ductus venosus were used for calculating blood flow volumes. The development of the umbilical venous flow, ductus venosus flow and ductus venosus shunt fraction (% of umbilical venous blood shunted through the ductus venosus) was compared with a reference population, and the effect of HbA1c on the ductus venosus flow was assessed. RESULTS: The umbilical venous flow was larger in pregnancies with pregestational diabetes mellitus than in low-risk pregnancies (p < 0.001) but smaller when normalized for fetal weight (p = 0.036). The distributional pattern of the ductus venosus flow developed differently in diabetic pregnancies, particularly during the third trimester, being smaller (p = 0.007), also when normalized for fetal weight (p < 0.001). Correspondingly, the ductus venosus shunt fraction was reduced (p < 0.0001), most prominently at 36 weeks. There were negative relations between the maternal HbA1c and the ductus venosus flow velocity, flow volume and shunt fraction. CONCLUSIONS: In pregnancies with pregestational diabetes mellitus, prioritized umbilical venous distribution to the fetal liver and lower ductus venosus shunt capacity reduce the compensatory capability of the fetus and may represent an augmented risk during hypoxic challenges during late pregnancy and birth.

Effect of uterine contractions on fetal heart rate in pregnancy: a prospective observational study.

INTRODUCTION: The new Holter monitoring technology enables long-term electrocardiographic recording of the fetal heart rate without discomfort for the mother. The aim of the study was to assess the feasibility of a fetal Holter monitor. This technology was further used to study fetal heart rate outside the hospital setting during normal daily activities and to test the hypothesis that uterine activity during pregnancy influences fetal heart rate. MATERIAL AND METHODS: Prospective observational study including 12 healthy pregnant women at 20-40 weeks of gestation. Data were collected using the Monica AN24 system. Outcome measures were fetal heart rate, maternal heart rate, and uterine activity categorized according to the strength of the electrohysterographic signal. RESULTS: The recordings had a median length of 18.8 h, and fetal heart rate and maternal heart rate were obtained with success rates of 73.1 and 99.9%, respectively. Uterine activity was found to affect fetal heart rate in all participants. Compared with the basal tone and mild levels of uterine activity, moderate and strong levels of uterine activity were associated with increases in fetal heart rate of 4.0 and 5.7 beats/min, respectively. At night, the corresponding increases were 4.9 and 7.6 beats/min. Linear correlations were found between maternal heart rate and fetal heart rate in 11 of the 12 cases, with a mean coefficient beta of 0.189. Both maternal heart rate and fetal heart rate exhibited a diurnal pattern, with lower heart rates being recorded at night. CONCLUSIONS: Uterine activity during pregnancy is associated with a graded response in fetal heart rate and may represent a physiological challenge for the development and adaptation of the fetal cardiovascular system.

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity.

Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cell-released soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and down-regulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells.

QRS abnormalities of the fetal electrocardiogram, and their implications for ST-interval analysis during labor.

INTRODUCTION: The objective of this study was to describe the QRS complex of the fetal electrocardiogram (fECG) in relation to fetal presentation, and explore the effect of abnormal QRS on automated ST-interval analysis (STAN). MATERIAL AND METHODS: A case-control study was carried out at a University Hospital in Norway, between the years of 2004-2008. High-risk singleton deliveries with a gestational age >35(+6) weeks, were monitored with cardiotocography and STAN. Cases included breech presentations (n = 433) and controls included cephalic presentations (n = 433). The main outcome measures were QRS-complex abnormalities and fECG abnormalities. RESULTS: An abnormal QRS complex was found in 13.9% of the cases and 16.6% of the controls (p = 0.257). Split R (8.4%) and deep S (8.2%) were the most common abnormalities, and deep Q (4.4% vs. 0.7%, p ≤ 0.001) and split Q (1.8% vs. 0, p ≤ 0.005) were more common in breech than in cephalic presentations. QRS abnormalities impacted on the fECG in 114/866 (13.2%) of the total population. The most common finding was an ambiguous placement of R and S in cases of a split vector (n = 112, 12.9%). Deviance of the ECG baseline above null occurred less frequently (n = 33, 3.8%), and was more common in breech presentation (5.3 vs. 2.3%, p = 0.021). ST events due to an erroneous identification of the QRS vectors and/or a misplacement of the ECG baseline were found in 26 (3.0%) fetuses, with no significant difference in frequency between cases and controls. CONCLUSIONS: The appearance of the QRS complex of fECG is dependent upon the fetal presentation. QRS abnormalities impact automated fECG tracing and subsequent ST analysis. Clinicians should be aware of this finding in clinical practice.

The bispecific immunoligand ULBP2-aCEA redirects natural killer cells to tumor cells and reveals potent anti-tumor activity against colon carcinoma.

NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.

Rescue of impaired NK cell activity in hodgkin lymphoma with bispecific antibodies in vitro and in patients.

Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically.

Delay in intervention increases neonatal morbidity in births monitored with cardiotocography and ST-waveform analysis.

OBJECTIVE: To assess the effect of the time interval from indication of hypoxia to delivery on neonatal outcome in high-risk pregnancies monitored with cardiotocography (CTG) and ST-waveform analysis. DESIGN: Prospective observational study. SETTING: University hospital, Norway, 2004-08. POPULATION: Singleton high-risk births with a gestational age above 35(+6) weeks, monitored with CTG and ST-waveform analysis. METHODS: Logistic regression analysis and Kaplan-Meier survival plots. MAIN OUTCOME MEASURE: Neonatal morbidity in relation to the rapidity of intervention. RESULTS: Of 6010 deliveries monitored with ST-waveform analysis, 1131 (19%) had an indication to intervene for fetal distress according to clinical guidelines. Those fetuses were at increased risk of an adverse neonatal outcome, and if delivered later than 20 min after the indication of hypoxia their risk increased further; i.e. transfer to the neonatal intensive care unit (NICU) from an odds ratio of 1.6 (95% confidence interval 1.2-2.2) to an odds ratio of 3.3 (95% confidence interval 2.5-4.3). The indication-to-delivery interval was longer for neonates with a 5-min Apgar score of <7, transfer to NICU and neonatal encephalopathy than for those without adverse outcome. CONCLUSION: In deliveries monitored with CTG and ST-waveform analysis, the risk of an adverse neonatal outcome was dependent on the time between indication of hypoxia and delivery. Nonadherence to the specific clinical guidelines increased the risk of neonatal morbidity.