Background International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However,... Show moreBackground International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However, clamping the cord prior to lung aeration may severely limit circulatory adaptation resulting in a reduction in cardiac output and hypoxia. Delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) allows for an adequately established pulmonary circulation and results in a more stable circulatory transition. The decline in cardiac output following time-based delayed cord clamping (TBCC) may thus be avoided. We hypothesise that PBCC, compared to TBCC, results in a more stable transition in very preterm infants, leading to improved clinical outcomes. The primary objective is to compare the effect of PBCC on intact survival with TBCC. Methods The Aeriation, Breathing, Clamping 3 (ABC3) trial is a multicentre randomised controlled clinical trial. In the interventional PBCC group, the umbilical cord is clamped after the infant is stabilised, defined as reaching heart rate > 100 bpm and SpO(2) > 85% while using supplemental oxygen < 40%. In the control TBCC group, cord clamping is time based at 30-60 s. The primary outcome is survival without major cerebral and/or intestinal injury. Preterm infants born before 30 weeks of gestation are included after prenatal parental informed consent. The required sample size is 660 infants. Discussion The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management in very preterm infants at birth. Show less
In this thesis we have investigated spontaneous breathing as a possible driving force for placental transfusion and the implementation of PBCC in a clinical setting. Spontaneous breathing at birth,... Show moreIn this thesis we have investigated spontaneous breathing as a possible driving force for placental transfusion and the implementation of PBCC in a clinical setting. Spontaneous breathing at birth, and lung aeration, is pivotal to accomplish the increase in pulmonary blood flow and decrease in pulmonary vascular resistance needed for a successful transition to extra-uterine life. Indeed, we demonstrated spontaneous breathing to influence umbilical blood flow and to potentially create a preferential blood flow from the placenta towards the infant. Based on this thesis we have therefore concluded that spontaneous breathing is likely to be a driving force in placental transfusion. In addition, we investigated physiological-based cord clamping (PBCC). Experimental studies clearly demonstrated the beneficial physiological effects of PBCC and that lung aeration, with the subsequent increase in pulmonary blood flow, is vital for the success of this approach. The studies in this thesis demonstrate the proof of concept for performing PBCC in preterm infants in a clinical setting: that it is both possible and safe, and that a similar effect can be observed as in an experimental setting. We also demonstrated that resuscitation on the cord is at least as effective, while allowing longer and variable cord clamping times. Show less
Background: Cardiovascular changes during the transition from intra- to extrauterine life, alters the pressure gradient across the ductus arteriosus (DA). DA flow ratio (R-L/L-R) has been suggested... Show moreBackground: Cardiovascular changes during the transition from intra- to extrauterine life, alters the pressure gradient across the ductus arteriosus (DA). DA flow ratio (R-L/L-R) has been suggested to reflect the infant's transitional status and could potentially predict neonatal outcomes after preterm birth.Aim: Determine whether DA flow ratio correlates with oxygenation parameters in preterm infants at 1 h after birth.Methods: Echocardiography was performed in preterm infants born < 32 weeks gestational age (GA), as part of an ancillary study. DA flow was measured at 1 h after birth. DA flow ratio was correlated with FiO(2), SpO(2), and SpO(2)/FiO(2) (SF) ratio. The DA flow ratio of infants receiving physiological-based cord clamping (PBCC) or time-based cord clamping (TBCC) were compared.Results: Measurements from 16 infants were analysed (median [IQR] GA 29 [27-30] weeks; birthweight 1,176 [951-1,409] grams). R-L DA shunting was 16 [17-27] ml/kg/min and L-R was 110 [81-124] ml/kg/min. The DA flow ratio was 0.18 [0.11-0.28], SpO(2) 94 [93-96]%, FiO(2) was 23 [21-28]% and SF ratio 4.1 [3.3-4.5]. There was a moderate correlation between DA flow ratio and SpO(2) [correlation coefficient (CC) -0.415; p = 0.110], FiO(2) (CC 0.384; p = 0.142) and SF ratio (CC -0.356; p = 0.175). There were no differences in DA flow measurements between infants where PBBC or TBCC was performed.Conclusion: In this pilot study we observed a non-significant positive correlation between DA flow ratio at 1 h after birth and oxygenation parameters in preterm infants. Show less
Brouwer, E.; Knol, R.; Kroushev, A.; Akker, T. van den; Hooper, S.B.; Roest, A.A.; Pas, A.B. te 2021
Real-time echocardiographic monitoring of blood flow in the ductus venosus and hepatic vein was undertaken during perinatal transition with intact umbilical cord of term born infants. Antegrade... Show moreReal-time echocardiographic monitoring of blood flow in the ductus venosus and hepatic vein was undertaken during perinatal transition with intact umbilical cord of term born infants. Antegrade flow increased during inspiration, preferentially directing blood flow from the ductus venosus into the right atrium.Objective To investigate the effect of spontaneous breathing on venous return in term infants during delayed cord clamping at birth. Methods Echocardiographic ultrasound recordings were obtained directly after birth in healthy term-born infants. A subcostal view was used to obtain an optimal view of the inferior vena cava (IVC) entering the right atrium, including both the ductus venosus (DV) and the hepatic vein (HV). Colour Doppler was used to assess flow direction and flow velocity. Recordings continued until the umbilical cord was clamped and were stored in digital format for offline analyses. Results Ultrasound recordings were obtained in 15 infants, with a median (IQR) gestational age of 39.6 (39.0-40.9) weeks and a birth weight of 3560 (3195-4205) g. Flow was observed to be antegrade in the DV and HV in 98% and 82% of inspirations, respectively, with flow velocity increasing in 74% of inspirations. Retrograde flow in the DV was observed sporadically and only occurred during expiration. Collapse of the IVC occurred during 58% of inspirations and all occurred caudal to the DV inlet (100%). Conclusion Spontaneous breathing was associated with collapse of the IVC and increased antegrade DV and HV flow velocity during inspiration. Therefore, inspiration appears to preferentially direct blood flow from the DV into the right atrium. This indicates that inspiration could be a factor driving placental transfusion in infants. Show less
Rogier, C.; Dijk, B.T. van; Brouwer, E.; Jong, P.H.P. de; Helm-van Mil, A.H.M. van der 2021
Objectives. To assess whether the presence of arthritis autoantibodies alongside IgG ACPA predicts clinically suspect arthralgia in ACPA-positive subjects without RA.Methods. In the population... Show moreObjectives. To assess whether the presence of arthritis autoantibodies alongside IgG ACPA predicts clinically suspect arthralgia in ACPA-positive subjects without RA.Methods. In the population-based Lifelines cohort (n=40 136), 308 IgG ACPA-positive individuals without RA were present. Serum levels of IgA ACPA, IgA and IgM RF, and IgG anti-carbamylated antibodies were measured at baseline. Individuals were divided based on the Connective tissue disease Screening Questionnaire after 2 years follow-up. Antibodies to Porphyromonas gingivalis were determined at baseline and related to presence of periodontitis and joint complaints at 2 years follow-up.Results. Of 308 subjects 53.6% were also seropositive for IgA ACPA, 42.2% for IgM RF, 23.7% for IgA RF and 13.6% for anti-carbamylated antibodies. We defined 75 persons with clinically suspect arthralgia at risk for RA based on CTD Screening Questionnaire at follow-up. Significantly more seropositivity for IgM RF and higher levels of IgG ACPA, IgA ACPA and IgM RF were found in clinically suspect arthralgia compared with no-clinically suspect arthralgia. In multivariate logistic regression correcting for age, gender and never smoking, positivity for three or more extra autoantibodies was significantly associated with clinically suspect arthralgia. Although levels of anti-P. gingivalis were not different between groups, they were significantly correlated to levels of both RFs, and both ACPAs in clinically suspect arthralgia.Conclusions. ACPA-positive individuals without RA who develop clinically suspect arthralgia have more and higher levels of other arthritis autoantibodies at baseline. Levels of anti-P. gingivalis are not related to self-reported periodontitis or clinically suspect arthralgia, but are correlated to arthritis autoantibodies in clinically suspect arthralgia. Show less
Objectives To assess whether the presence of arthritis autoantibodies alongside IgG ACPA predicts clinically suspect arthralgia in ACPA-positive subjects without RA. Methods In the population-based... Show moreObjectives To assess whether the presence of arthritis autoantibodies alongside IgG ACPA predicts clinically suspect arthralgia in ACPA-positive subjects without RA. Methods In the population-based Lifelines cohort (n = 40 136), 308 IgG ACPA-positive individuals without RA were present. Serum levels of IgA ACPA, IgA and IgM RF, and IgG anti-carbamylated antibodies were measured at baseline. Individuals were divided based on the Connective tissue disease Screening Questionnaire after 2 years follow-up. Antibodies to Porphyromonas gingivalis were determined at baseline and related to presence of periodontitis and joint complaints at 2 years follow-up. Results Of 308 subjects 53.6% were also seropositive for IgA ACPA, 42.2% for IgM RF, 23.7% for IgA RF and 13.6% for anti-carbamylated antibodies. We defined 75 persons with clinically suspect arthralgia at risk for RA based on CTD Screening Questionnaire at follow-up. Significantly more seropositivity for IgM RF and higher levels of IgG ACPA, IgA ACPA and IgM RF were found in clinically suspect arthralgia compared with no-clinically suspect arthralgia. In multivariate logistic regression correcting for age, gender and never smoking, positivity for three or more extra autoantibodies was significantly associated with clinically suspect arthralgia. Although levels of anti-P. gingivalis were not different between groups, they were significantly correlated to levels of both RFs, and both ACPAs in clinically suspect arthralgia. Conclusions ACPA-positive individuals without RA who develop clinically suspect arthralgia have more and higher levels of other arthritis autoantibodies at baseline. Levels of anti-P. gingivalis are not related to self-reported periodontitis or clinically suspect arthralgia, but are correlated to arthritis autoantibodies in clinically suspect arthralgia. Show less
Knol, R.; Brouwer, E.; Akker, T. van den; DeKoninck, P.; Geloven, N. van; Polglase, G.R.; ... ; Pas, A.B. te 2020
Aim: To test whether stabilising very preterm infants while performing physiological-based cord clamping (PBCC) is at least as effective as the standard approach of time-based delayed cord clamping... Show moreAim: To test whether stabilising very preterm infants while performing physiological-based cord clamping (PBCC) is at least as effective as the standard approach of time-based delayed cord clamping (DCC).Methods: A randomised controlled non-inferiority study was performed in two centres from May until November 2018, including preterm infants born below 32 weeks of gestational age. Infants were allocated to PBCC or standard DCC. Infants receiving PBCC were stabilised on a purpose-built resuscitation table with an intact umbilical cord. The cord was clamped when the infant had regular spontaneous breathing, heart rate >= 100 bpm and SpO(2) 90% while using FiO(2) 0.40. In infants receiving DCC, the cord was clamped at 30 60 seconds after birth before they were transferred to the standard resuscitation table for further treatment and stabilisation. Primary outcome was time to reach respiratory stability.Results: Thirty-seven infants (mean gestational age 29+0 weeks) were included. Mean cord clamping time was 5:49 +/- 2:37 min in the PBCC (n = 20) and 1:02 +/- 0:30 min in the DCC group (n = 17). Infants receiving PBCC needed less time to reach respiratory stability (PBCC 5:54 +/- 2:27 min; DCC 7:07 +/- 2:54 min; mean difference corrected for gestational age 1:19 min, 95 degrees 6 CI [3:04 0:27]), showing non-inferiority with the pre-defined limit of 1:15 min. No significant differences between the groups were found for maternal blood loss, postpartum haemorrhage, infant temperature at admission or short-term neonatal outcomes.Conclusion: Stabilisation of very preterm infants with physiological-based cord clamping is at least as effective as with standard DCC. Show less
Introduction During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would... Show moreIntroduction During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would enhance placental transfusion in spontaneously breathing preterm lambs.Objective Investigate the effect of spontaneous breathing on umbilical venous flow and body weight in preterm lambs.Methods Pregnant sheep were instrumented at 132-133 days gestational age to measure fetal common umbilical venous, pulmonary and cerebral blood flows as well as arterial and intrapleural (IP) pressures. At delivery, doxapram and caffeine were administered to promote breathing. Lamb body weights were measured continuously and breathing was assessed by IP pressure changes.Results In 6 lambs, 491 out of 1117 breaths were analysed for change in body weight. Weight increased in 46.6% and decreased in 47.5% of breaths. An overall mean increase of 0.02 +/- 2.5 g per breath was calculated, and no net placental transfusion was observed prior to cord clamping (median difference in body weight 52.3 [-54.9-166.1] g, p=0.418). Umbilical venous (UV) flow transiently decreased with each inspiration, and in some cases ceased, before UV flow normalised during expiration. The reduction in UV flow was positively correlated with the standardised reduction in (IP) pressure, increasing by 109 mL/min for every SD reduction in IP pressure. Thus, the reduction in UV flow was closely related to inspiratory depth.Conclusions Spontaneous breathing had no net effect on body weight in preterm lambs at birth. UV blood flow decreased as inspiratory effort increased, possibly due to constriction of the inferior vena cava caused by diaphragmatic contraction, as previously observed in human fetuses. Show less
Dijk, B. van; Steenbergen, H.W. van; Niemantsverdriet, E.; Brouwer, E.; Helm-van Mil, A. van der 2020
Objectives Healthcare professionals other than rheumatologists experience difficulties in detecting early inflammatory arthritis (IA) by joint examination. Self-reported symptoms are increasingly... Show moreObjectives Healthcare professionals other than rheumatologists experience difficulties in detecting early inflammatory arthritis (IA) by joint examination. Self-reported symptoms are increasingly considered as helpful and could be incorporated in online tools to assist healthcare professionals, but first their discriminative ability must be assessed. As part of this effort, we evaluated whether inquiring about functional impairments could aid early IA identification. Design Cross-sectional derivation and validation study. Setting Data from two Early Arthritis Recognition Clinics (EARC) in the Netherlands were studied, which are easy access outpatient rheumatology clinics intermediary between primary and secondary care for patients in whom general practitioners suspect but are unsure about IA presence. Participants Between 2010 and 2014, 997 patients consecutively visited the Leiden-EARC (derivation cohort). Patients consecutively visiting the Groningen EARC (2010-2014, n=506) and Leiden-EARC (2015-2018, n=557) served as validation cohorts. Primary and secondary outcome measures Physical functioning was assessed with the Health Assessment Questionnaire Disability-Index (HAQ); IA presence by physical joint examination by rheumatologists. HAQ questions were studied individually regarding discriminative ability for IA presence. For the best discriminating question, ORs and positive predictive values (PPVs) for IA presence were determined. Results IA was ascertained in 43% (derivation cohort), 53% and 35% (validation cohorts). In the derivation cohort, IA presence associated with higher mean HAQ scores (0.84 vs 0.73, p=0.003). One question on difficulties with dressing equalled discriminative ability of the total HAQ score. 'Difficulties with dressing' yielded ORs for IA presence of 1.8 (95% CI 1.4 to 2.4) in the derivation cohort; 2.0 (1.4 to 2.9) and 2.1 (1.5 to 3.1) in the validation cohorts. After adjustments for clinical characteristics these were 1.7 (1.3 to 2.3), 1.6 (1.1 to 2.5) and 1.9 (1.2 to 2.9). PPVs (probabilities of IA for positive answers) ranged 42%-60% and negative predictive values (probabilities of no IA for negative answers) ranged 57%-74%. Conclusions Patient-reported difficulties with dressing in patients with suspected IA associated with actual IA presence. Although further validation is required, for example, in primary care, this simple question could be of help in future early IA detection tools for healthcare professionals with limited experience in joint examination. Show less
Introduction: During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would... Show moreIntroduction: During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would enhance placental transfusion in spontaneously breathing preterm lambs.Objective: Investigate the effect of spontaneous breathing on umbilical venous flow and body weight in preterm lambs.Methods: Pregnant sheep were instrumented at 132-133 days gestational age to measure fetal common umbilical venous, pulmonary and cerebral blood flows as well as arterial and intrapleural (IP) pressures. At delivery, doxapram and caffeine were administered to promote breathing. Lamb body weights were measured continuously and breathing was assessed by IP pressure changes.Results: In 6 lambs, 491 out of 1117 breaths were analysed for change in body weight. Weight increased in 46.6% and decreased in 47.5% of breaths. An overall mean increase of 0.02±2.5 g per breath was calculated, and no net placental transfusion was observed prior to cord clamping (median difference in body weight 52.3 [-54.9-166.1] g, p=0.418). Umbilical venous (UV) flow transiently decreased with each inspiration, and in some cases ceased, before UV flow normalised during expiration. The reduction in UV flow was positively correlated with the standardised reduction in (IP) pressure, increasing by 109 mL/min for every SD reduction in IP pressure. Thus, the reduction in UV flow was closely related to inspiratory depth.Conclusions: Spontaneous breathing had no net effect on body weight in preterm lambs at birth. UV blood flow decreased as inspiratory effort increased, possibly due to constriction of the inferior vena cava caused by diaphragmatic contraction, as previously observed in human fetuses.Keywords: animal research; neonatology; physiology; placental transfusion; resuscitation Show less
Knol, R.; Brouwer, E.; Klumper, F.J.C.M.; Akker, T. van den; Dekoninck, P.; Hutten, G.J.; ... ; Pas, A.B. te 2019
