Background & Aims Little is known about in utero exposure to and postnatal clearance of anti–tumor necrosis factor (anti-TNF) agents in neonates. We investigated the concentrations of adalimumab and ...infliximab in umbilical cord blood of newborns and rates of clearance after birth, and how these correlated with drug concentrations in mothers at birth and risk of infection during the first year of life. Methods We performed a prospective study of 80 pregnant women with inflammatory bowel diseases at tertiary hospitals in Denmark, Australia, and New Zealand from March 2012 through November 2014: 36 received adalimumab and 44 received infliximab; 39 received concomitant thiopurines during pregnancy. Data were collected from medical records on disease activity and treatment before, during, and after pregnancy. Concentrations of anti-TNF agents were measured in blood samples from women at delivery and in umbilical cords, and in infants for every 3 months until the drug was no longer detected. Results The time from last exposure to anti-TNF agent during pregnancy correlated inversely with the concentration of the drugs in the umbilical cord (adalimumab: r = -0.64, P = .0003; infliximab: r = -0.77, P < .0001) and in mothers at time of birth (adalimumab, r = -0.80; infliximab, r = -0.80; P < .0001 for both). The median ratio of infant:mother drug concentration at birth was 1.21 for adalimumab (95% confidence interval CI, 0.94–1.49) and 1.97 for infliximab (95% CI, 1.50–2.43). The mean time to drug clearance in infants was 4.0 months for adalimumab (95% CI, 2.9–5.0) and 7.3 months for infliximab (95% CI, 6.2–8.3; P < .0001). Drugs were not detected in infants after 12 months of age. Bacterial infections developed in 4 infants (5%) and viral infections developed in 16 (20%), all with benign courses. The relative risk for infection was 2.7 in infants whose mothers received the combination of an anti-TNF agent and thiopurine, compared with anti-TNF monotherapy (95% CI, 1.09–6.78; P = .02). Conclusions In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.
Fetal heart rate variability (FHRV) has shown potential in fetal surveillance. Therefore, we aimed to evaluate the reliability of time domain and spectral domain parameters based on non-invasive ...fetal electrocardiography (NI-FECG).
NI-FECG, with a sampling frequency of 1 kHz, was obtained in 75 healthy, singleton pregnant women between gestational age (GA) 20+0 to 41+0. The recording was divided into a) heart rate pattern (HRP) and b) periods fulfilling certain criteria of stationarity of RR-intervals, termed stationary heart rate pattern (SHRP). Within each recording, the first and the last time series from each HRP with less than 5% artifact correction were analyzed and compared. Standard deviation of normal-to-normal RR-intervals (SDNN), root mean square of successive differences (RMSSD), high frequency power (HF-power), low frequency power (LF-power), and LF-power/HF-power were performed. A multivariate mixed model was used and acceptable reliability was defined as intraclass correlation coefficient (ICC) ≥ 0.80 and a coefficient of variation (CV) ≤ 15%. Based on these results, the CV and ICC were computed if the average of two to six time series was used.
For GA 28+0 to 34+6, SDNN and RMSSD exhibited acceptable reliability (CV < 15%; ICC > 90%), whereas GA 35+0 to 41+0and 20+0 to 27+6 showed higher CVs. Spectral domain parameters also showed high CVs However, by using the mean value of two to six time series, acceptable reliability in SDNN, RMSSD and HF-power from GA 28+0 was achieved. Stationarity of RR-intervals showed high influence on reliability and SHRP was superior to HRP, whereas the length of the time series showed minor influence.
Acceptable reliability seems achievable in SDNN, RMSSD and HF-power from gestational week 28. However, stationarity of RR-intervals should be considered when selecting time series for analyses.
When determining optimal treatment regimens, patient reported outcomes including satisfaction are increasingly appreciated. It is well established that the birth experience may affect the postnatal ...attachment to the newborn and the management of subsequent pregnancies and deliveries. As we have no robust validated Danish tool to evaluate the childbirth experience exists, we aimed to perform a transcultural adaptation of the Childbirth Experience Questionnaire (CEQ) to a Danish context.
In accordance with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN), we translated the Swedish-CEQ to Danish. The Danish-CEQ was tested for content validity among 10 new mothers. In a population of women who have had their labour induced, we then assessed the electronic questionnaire for validity and reliability using factor analytical design, hypothesis testing, and internal consistency. Based on these data, we determined criterion and construct responsiveness in addition to floor and ceiling effects.
The content validation resulted in minor adjustments in two items. This improved the comprehensibility. The electronic questionnaire was completed by 377 of 495 women (76.2%). The original Swedish-CEQ was four-dimensional, however an exploratory factor analysis revealed a three-dimensional structure in our Danish population (Own capacity, Participation, and Professional support). Parous women, women who delivered vaginally, and women with a labour duration <12 hours had a higher score in each domain. The internal consistency (Cronbach's alpha) ranged between 0.75 and 0.89 and the ICC between 0.68-0.93. We found ceiling effects of 57.6% in the domain Professional support and of 25.5% in the domain Participation.
This study offers transcultural adaptation of the Swedish-CEQ to a Danish context. The 3-dimensional Danish-CEQ demonstrates construct validity and reliability. Our results revealed significant ceiling effect especially in the domain Professional support, which needs to be acknowledged when considering implementing the Danish-CEQ into trials and clinical practice.
The aim of this study was to compare the performances of two strategies for predicting intrapartum vaginal carriage of group B streptococci (GBS). One strategy was based on an antepartum culture and ...the other on an intrapartum polymerase chain reaction (PCR). We conducted a prospective observational study enrolling 902 pregnant women offered GBS screening before delivery by two strategies. The Culture-strategy was based on vaginal and rectal cultures at 35-37 weeks' gestation, whereas the PCR-strategy was based on PCR assay on intrapartum vaginal swab samples. An intrapartum vaginal culture for GBS was used as the reference standard from which the performances of the 2 strategies were evaluated. The reference standard showed a GBS-prevalence of 12%. The culture-strategy performed with a sensitivity of 82%, specificity of 91%, positive predictive value (PPV) of 55%, negative predictive value (NPV) of 98%, and Likelihood ratio (LH+) of 9.2. The PCR-strategy showed corresponding values as sensitivity of 83%, specificity of 97%, PPV of 78%, NPV of 98%, and LH+ of 27.5. We conclude that in a Danish population with a low rate of early-onset neonatal infection with GBS, the intrapartum PCR assay performs better than the antepartum culture for identification of GBS vaginal carriers during labor.
Dystocia is one of the most common causes of cesarean section in nulliparous women. Studies have described the presence of vitamin D receptors in the myometrium, but it is still unclear whether ...vitamin D affects the contractility of the smooth muscles. We therefore aimed to determine the association between the vitamin D serum level at labor and the risk of dystocia.
We conducted a case-control study between January 2012 and June 2017. Cases were primiparous women, with spontaneous onset of labor, who gave birth by cesarean section due to dystocia. Controls were primiparous women with a spontaneous vaginal delivery. We included 60 women (30 cases and 30 controls) in the analysis. The differences between cases and controls were assessed using chi-squared test for categorical variables and two-sample t-test or unequal t-test for continuous variables, as appropriate, after evaluation of whether they followed the normal distributions.
The mean serum 25-hydroxyvitamin D concentrations were 53.1nmol/l (95%CI; 45.2 to 60.9) among cases and 69.9nmol/l (95%CI; 57.5 to 82.4) among controls (P = 0.02). The mean plasma parathyroid hormone levels were 2.25 pmol/l and 2.38, respectively (P = 0.57). Even though 78% of all women reported taking a minimum of 10μg/day of vitamin D throughout pregnancy, 43% had vitamin D insufficiency, defined as serum 25-hydroxyvitamin D levels below 50nmol/l.
In a Danish group of women having a cesarean section due to dystocia, we found decreased vitamin D levels.
Introduction
Hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, are leading causes of morbidity and mortality for both mother and fetus. It has been proposed ...that vitamin D affects a number of biological processes involved in the pathogenesis of hypertensive disorders of pregnancy. Therefore, a seasonal variation in the risk of these disorders might be expected in areas such as Denmark with marked seasonal variation in sunlight exposure. In this study, we aimed to evaluate the existence of this association.
Material and methods
We used information from a cohort of 50 665 previously healthy, nulliparous women with singleton pregnancies. All women gave birth between 1989 and 2010 at Aarhus University Hospital, Denmark. Logistic regression analyses combined with the cubic spline method were used to estimate the seasonal variation for each outcome: gestational hypertension and preeclampsia, after adjusting for calendar time.
Results
Of the 50 665 women included, 8.5% were diagnosed with a hypertensive disorder of pregnancy. The overall tendency was towards increasing risk when conceiving during spring and early summer, peaking midsummer, and subsequently decreasing steadily during late summer and fall to reach the nadir by winter. Seasonal variation was found for; gestational hypertension (P = .01); preeclampsia (P = .001) and early‐onset preeclampsia (P = .014).
Conclusions
We found a seasonal variation in the risk of the hypertensive disorders of pregnancy in a large cohort of Danish nulliparous women. The highest risk was seen in women with the estimated date of conception in June and August, that is, during summer. Seasonal variation in vitamin D status may explain this association.
Plasmacytoid dendritic cells (pDCs) constitute a rare type of immune cell with multifaceted functions, but their potential use as a cell-based immunotherapy is challenged by the scarce cell numbers ...that can be extracted from blood. Here, we systematically investigate culture parameters for generating pDCs from hematopoietic stem and progenitor cells (HSPCs). Using optimized conditions combined with implementation of HSPC pre-expansion, we generate an average of 465 million HSPC-derived pDCs (HSPC-pDCs) starting from 100,000 cord blood-derived HSPCs. Furthermore, we demonstrate that such protocol allows HSPC-pDC generation from whole-blood HSPCs, and these cells display a pDC phenotype and function. Using GMP-compliant medium, we observe a remarkable loss of TLR7/9 responses, which is rescued by ascorbic acid supplementation. Ascorbic acid induces transcriptional signatures associated with pDC-specific innate immune pathways, suggesting an undescribed role of ascorbic acid for pDC functionality. This constitutes the first protocol for generating pDCs from whole blood and lays the foundation for investigating HSPC-pDCs for cell-based immunotherapy.
We aimed to investigate whether noise in delivery rooms is associated with impaired performance of obstetric teams managing major (≥1000 mL) postpartum hemorrhage.
We included video recordings of 96 ...obstetric teams managing real-life major postpartum hemorrhage. Exposure was noise defined as the occurrence of sound level pressures (SPL) above 90 dB. The outcome was high clinical performance assessed through expert ratings using the TeamOBS-PPH tool.
The 23 teams unexposed to noise had a significantly higher chance of high clinical performance than the 73 teams exposed to noise: 91.3% (95% CI; 72.0-98.9) versus 58.9% (95% CI; 46.8-70.3) (p < 0.001). The results remained significant when adjusting for the following possible confounders: team size, non-technical performance, bleeding velocity, hospital type, etiology of bleeding, event duration and time of day. Typical sources of noise above 90 dB SPL were mother or baby crying, dropping of instruments, and slamming of cupboard doors.
Noise in delivery rooms may be an independent source of impaired clinical performance.
Current guidelines regarding oxytocin stimulation are not tailored to individuals as they are based on randomised controlled trials. The objective of the study was to develop an artificial ...intelligence (AI) model for individual prediction of the risk of caesarean delivery (CD) in women with a cervical dilatation of 6 cm after oxytocin stimulation for induced labour. The model included not only variables known when labour induction was initiated but also variables describing the course of the labour induction.
Secondary analysis of data from the CONDISOX randomised controlled trial of discontinued vs. continued oxytocin infusion in the active phase of induced labour. Extreme gradient boosting (XGBoost) software was used to build the prediction model. To explain the impact of the predictors, we calculated Shapley additive explanation (SHAP) values and present a summary SHAP plot. A force plot was used to explain specifics about an individual's predictors that result in a change of the individual's risk output value from the population-based risk.
Among 1060 included women, 160 (15.1%) were delivered by CD. The XGBoost model found women who delivered vaginally were more likely to be parous, taller, to have a lower estimated birth weight, and to be stimulated with a lower amount of oxytocin. In 108 women (10% of 1060) the model favoured either continuation or discontinuation of oxytocin. For the remaining 90% of the women, the model found that continuation or discontinuation of oxytocin stimulation affected the risk difference of CD by less than 5% points.
In women undergoing labour induction, this AI model based on a secondary analysis of data from the CONDISOX trial may help predict the risk of CD and assist the mother and clinician in individual tailored management of oxytocin stimulation after reaching 6 cm of cervical dilation.
Introduction:
Fetal heart rate variability (FHRV) evaluates the fetal neurological state, which is poorly assessed by conventional prenatal surveillance including cardiotocography (CTG). Accurate ...FHRV on a beat-to-beat basis, assessed by time domain and spectral domain analyses, has shown promising results in the scope of fetal surveillance. However, accepted standards for these techniques are lacking, and the influence of fetal breathing movements and gross movements may be especially challenging. Thus, current standards for equivalent assessments in adults prescribe rest and controlled respiration. The aim of this review is to clarify the importance of fetal movements on FHRV.
Methods:
A systematic review in accordance with the PRISMA guidelines based on publications in the EMBASE, the MEDLINE, and the Cochrane Library databases was performed. Studies describing the impact of fetal movements on time domain, spectral domain and entropy analyses in healthy human fetuses were reviewed. Only studies based on fetal electrocardiography or fetal magnetocardiography were included. PROSPERO registration number: CRD42018068806.
Results:
In total, 14 observational studies were included. Fetal movement detection, signal processing, length, and selection of appropriate time series varied across studies. Despite these divergences, all studies showed an increase in overall FHRV in the moving fetus compared to the resting fetus. Especially short-term, vagal mediated indexes showed an increase during fetal breathing movements including an increase in Root Mean Square of the Successive Differences (RMSSD) and High Frequency power (HF) and a decrease in Low Frequency power/High Frequency power (LF/HF). These findings were present even in analyses restricted to one specific fetal behavioral state defined by Nijhuis. On the other hand, fetal body movements seemed to increase parameters supposed to represent the sympathetic response LF and Standard Deviation of RR-intervals from normal sinus beats (SDNN) proportionally more than parameters representing the parasympathetic response (RMSSD, HF). Results regarding entropy analyses were inconclusive.
Conclusion:
Time domain analyses as well as spectral domain analyses are affected by fetal movements. Fetal movements and especially breathing movements should be considered in these analyses of FHRV.
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