Publications by authors named "Nan van Geloven"

72 Publications

Choosing and changing the analysis scale in non-inferiority trials with a binary outcome.

Clin Trials 2021 Oct 24:17407745211053790. Epub 2021 Oct 24.

Department of Biomedical Data Sciences, Section Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.

Background: The size of the margin strongly influences the required sample size in non-inferiority and equivalence trials. What is sometimes ignored, however, is that for trials with binary outcomes, the scale of the margin - risk difference, risk ratio or odds ratio - also has a large impact on power and thus on sample size requirement. When considering several scales at the design stage of a trial, these sample size consequences should be taken into account. Sometimes, changing the scale may be needed at a later stage of a trial, for example, when the event proportion in the control arm turns out different from expected. Also after completion of a trial, a switch to another scale is sometimes made, for example, when using a regression model in a secondary analysis or when combining study results in a meta-analysis that requires unifying scales. The exact consequences of such switches are currently unknown.

Methods And Results: This article first outlines sample size consequences for different choices of analysis scale at the design stage of a trial. We add a new result on sample size requirement comparing the risk difference scale with the risk ratio scale. Then, we study two different approaches to changing the analysis scale after the trial has commenced: (1) mapping the original non-inferiority margin using the event proportion in the control arm that was anticipated at the design stage or (2) mapping the original non-inferiority margin using the observed event proportion in the control arm. We use simulations to illustrate consequences on type I and type II error rates. Methods are illustrated on the INES trial, a non-inferiority trial that compared single birth rates in subfertile couples after different fertility treatments. Our results demonstrate large differences in required sample size when choosing between risk difference, risk ratio and odds ratio scales at the design stage of non-inferiority trials. In some cases, the sample size requirement is twice as large on one scale compared with another. Changing the scale after commencing the trial using anticipated proportions mainly impacts type II error rate, whereas switching using observed proportions is not advised due to not maintaining type I error rate. Differences were more pronounced with larger margins.

Conclusions: Trialists should be aware that the analysis scale can have large impact on type I and type II error rates in non-inferiority trials.
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http://dx.doi.org/10.1177/17407745211053790DOI Listing
October 2021

Joint Modeling of Longitudinal Markers and Time-to-Event Outcomes: An Application and Tutorial in Patients After Surgical Repair of Transposition of the Great Arteries.

Circ Cardiovasc Qual Outcomes 2021 11 22;14(11):e007593. Epub 2021 Oct 22.

Department of Biomedical Data Sciences, Section Medical Statistics (H.P., R.T., N.v.G.), Leiden University Medical Center, the Netherlands.

Background: Most patients with congenital heart disease survive into adulthood; however, residual abnormalities remain and management of the patients is life-long and personalized. Patients with surgical repair of transposition of the great arteries, for example, face the risk to develop neoaortic valve regurgitation. Cardiologists update the prognosis of the patient intuitively with updated information of the cardiovascular status of the patient, for instance from echocardiographic imaging.

Methods: Usually a time-dependent version of the Cox model is used to analyze repeated measurements with a time-to-event outcome. New statistical methods have been developed with multiple advantages, of which the most prominent one being the joint model for longitudinal and time-to-event outcome. In this tutorial, the joint modeling framework is introduced and applied to patients with transposition of the great arteries after surgery with a long-term follow-up, where repeated echocardiographic values of the neoaortic root are evaluated against the risk of neoaortic valve regurgitation.

Results: The data are analyzed with the time-dependent Cox model as benchmark method, and the results are compared with a joint model, leading to different conclusions. The flexibility of the joint model is shown by adding the growth rate of the neoaortic root to the model and adding repeated values of body surface area to obtain a multimarker model. Lastly, it is demonstrated how the joint model can be used to obtain personalized dynamic predictions of the event.

Conclusions: The joint model for longitudinal and time-to-event data is an attractive method to analyze data in follow-up studies with repeated measurements. Benefits of the method include using the estimated natural trajectory of the longitudinal outcome, great flexibility through multiple extensions, and dynamic individualized predictions.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.007593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598112PMC
November 2021

Serial neurosonography in fetuses with congenital heart defects shows mild delays in cortical development.

Prenat Diagn 2021 Sep 2. Epub 2021 Sep 2.

Department of Obstetrics and Prenatal Diagnosis, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development.

Methods: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme.

Results: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses.

Conclusion: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown.
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http://dx.doi.org/10.1002/pd.6038DOI Listing
September 2021

Early diagnosis of coeliac disease in the Preventive Youth Health Care Centres in the Netherlands: study protocol of a case finding study (GLUTENSCREEN).

BMJ Paediatr Open 2021 11;5(1):e001152. Epub 2021 Aug 11.

Paediatric Gastroenterology, Leiden University Medical Center, Leiden, Zuid Holland, The Netherlands.

Introduction: Coeliac disease (CD) occurs in 1% of the population, develops early in life and is severely underdiagnosed. Undiagnosed and untreated disease is associated with short-term and long-term complications. The current healthcare approach is unable to solve the underdiagnosis of CD and timely diagnosis and treatment is only achieved by active case finding. Aim: to perform a case finding project to detect CD children who visit the Youth Health Care Centres (YHCCs) in a well-described region in the Netherlands to evaluate whether it is feasible, cost-effective and well accepted by the population.

Methods/analysis: Prospective intervention cohort study. Parents of all children aged 12 months and 4 years attending the YHCCs for a regular visit are asked whether their child has one or more CD-related symptoms from a standardised list. If so, they will be invited to participate in the case finding study. After informed consent, a point of care test (POCT) to assess CD-specific antibodies against tissue transglutaminase (TG2A) is performed onsite the YHCCs. If the POCT is positive, CD is highly suspected and the child will be referred to hospital for definitive diagnosis according to the Guideline Coeliac Disease of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition guideline.

Main Outcomes: Incidence rate of new CD diagnoses in the study region in comparison to the one in the same age diagnosed by standard of care in the rest of the Netherlands.Feasibility and cost-effectiveness of active CD case finding at the YHCCs. All costs of active case finding, diagnostics and treatment of CD and the potential short-term and long-term consequences of the disease will be calculated for the setting with and without case finding.Ethical acceptability: by questionnaires on parental and healthcare professionals' satisfaction.A statistical analysis plan was prepared and is published on the GLUTENSCREEN website (Statistical-Analysis-Plan-11-5-2021_def.pdf (glutenscreen.nl) and added as annex 1).

Ethics And Dissemination: The Medical Ethics Committee Leiden approved this study. If we prove that case finding at the YHCC is feasible, cost-effective and well accepted by the population, implementation is recommended.

Trial Registration Number: NL63291.058.17.
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http://dx.doi.org/10.1136/bmjpo-2021-001152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359518PMC
August 2021

Study protocol for a randomised controlled trial evaluating the clinical effect of antibiotic prophylaxis in children with recurrent respiratory tract infections: the Approach study.

BMJ Open 2021 07 29;11(7):e044505. Epub 2021 Jul 29.

Department of Paediatric Infectious Diseases and Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands

Introduction: Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of disease and lead to frequent doctor visits. Children with recurrent RTIs generally have no significant alterations or deficits in systemic immunity. In an attempt to treat the assumed bacterial component involved, they are often treated with prolonged courses of prophylactic antibiotics taken on a daily basis. Despite its common use, there is no evidence that this is beneficial. Studies assessing the clinical effectiveness of antibiotic prophylaxis as well as potential adverse effects and antibiotic resistance development, are therefore urgently needed.

Methods And Analysis: We present a protocol for a randomised double-blind placebo-controlled trial comparing co-trimoxazole with placebo treatment in children with recurrent RTIs. A total of 158 children (aged 6 months-10 years) with recurrent RTIs without significant comorbidity will be enrolled from a minimum of 10 Dutch hospitals. One group receives co-trimoxazole 18 mg/kg two times per day (36 mg/kg/day) and the other group receives a placebo two times per day for a period of 3 months. The main objective is to determine whether antibiotic prophylaxis is more effective than placebo to prevent/reduce respiratory symptoms in children with recurrent RTIs. Respiratory symptoms will be scored by parents on a daily basis in both study arms by the use of a mobile phone application. Our primary outcome will be the number of days with at least two respiratory symptoms during the treatment.

Ethics And Dissemination: Ethics approval was obtained from the Medical Ethics Research Committee Zuidwest Holland/LDD. A manuscript with the study results will be submitted to a peer-reviewed journal. All participants will be informed about the study results. The results of the study will inform clinical guidelines regarding the prophylactic treatment of children with recurrent RTIs.

Trial Registration Number: NL7044.
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http://dx.doi.org/10.1136/bmjopen-2020-044505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323378PMC
July 2021

Assessment of human fetal cardiac autonomic nervous system development using color tissue Doppler imaging.

Echocardiography 2021 06 21;38(6):974-981. Epub 2021 May 21.

Department of Obstetrics and Prenatal Diagnosis, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: Functional development of the fetal cardiac autonomic nervous system (cANS) plays a key role in fetal maturation and can be assessed through fetal heart rate variability (fHRV)-analysis, with each HRV parameter representing different aspects of cANS activity. Current available techniques, however, are unable to assess the fHRV parameters accurately throughout the whole pregnancy. This study aims to test the feasibility of color tissue Doppler imaging (cTDI) as a new ultrasound technique for HRV analysis. Secondly, we explored time trends of fHRV parameters using this technique.

Methods: 18 healthy singleton fetuses were examined sequentially every 8 weeks from 10 weeks GA onwards. From each examination, 3 cTDI recordings of the four-chamber view of 10 seconds were retrieved to determine accurate beat-to-beat intervals. The fHRV parameters SDNN, RMSSD, SDNN/RMSSD, and pNN10, each representing different functional aspects of the cANS, were measured, and time trends during pregnancy were explored using spline functions within a linear mixed-effects model.

Results: In total, 77% (95% Cl 66-87%) of examinations were feasible for fHRV analysis from the first trimester onwards, which is a great improvement compared to other techniques. The technique is able to determine different maturation rates of the fHRV parameters, showing that cANS function, presumably parasympathetic activity, establishes around 20 weeks GA and matures rapidly until 30 weeks GA.

Conclusions: This is the first study able to assess cANS function through fHRV analysis from the first trimester onwards. The use of cTDI to determine beat-to-beat intervals seems feasible in just 3 clips of 10 seconds, which holds promise for future clinical use in assessing fetal well-being.
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http://dx.doi.org/10.1111/echo.15094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252470PMC
June 2021

Effectiveness of a multidisciplinary clinical pathway for women with systemic lupus erythematosus and/or antiphospholipid syndrome.

Lupus Sci Med 2021 05;8(1)

Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk of developing complications during pregnancy. Therefore, clinical practice guidelines recommend that patients with SLE/APS should receive multidisciplinary counselling before getting pregnant. We investigated the clinical effectiveness of implementing a multidisciplinary clinical pathway including prepregnancy counselling of patients with SLE/APS.

Methods: A clinical pathway with specific evaluation and prepregnancy counselling for patients with SLE/APS was developed and implemented in a tertiary, academic hospital setting. Patients were prospectively managed within the clinical pathway from 2014 onwards and compared with a retrospective cohort of patients that was not managed in a clinical pathway. Primary outcome was a combined outcome of disease flares for SLE and thromboembolic events for APS. Secondary outcomes were maternal and fetal pregnancy complications.

Results: Seventy-eight patients with 112 pregnancies were included in this study. The primary combined outcome was significantly lower in the pathway cohort (adjusted OR (aOR) 0.20 (95% CI 0.06 to 0.75)) which was predominantly determined by a fivefold risk reduction of SLE flares (aOR 0.22 (95% CI 0.04 to 1.09)). Maternal and fetal pregnancy complications were not different between the cohorts (respectively, aOR 0.91 (95% CI 0.38 to 2.17) and aOR 1.26 (95% CI 0.55 to 2.88)).

Conclusions: The outcomes of this study suggest that patients with SLE/APS with a pregnancy wish benefit from a multidisciplinary clinical pathway including prepregnancy counselling.
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http://dx.doi.org/10.1136/lupus-2020-000472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103373PMC
May 2021

Evaluation of treatment, prognostic factors, and survival in 198 vulvar melanoma patients: Implications for clinical practice.

Gynecol Oncol 2021 04 26;161(1):202-210. Epub 2021 Jan 26.

Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.

Objective: To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).

Materials & Methods: This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis.

Results: The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-risk clinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy.

Conclusion: Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.018DOI Listing
April 2021

The association between flow and oxygenation and cortical development in fetuses with congenital heart defects using a brain-age prediction algorithm.

Prenat Diagn 2021 01 7;41(1):43-51. Epub 2020 Sep 7.

Department of Obstetrics and Prenatal Diagnosis, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: Presumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze fetal brain development based on hemodynamic differences, using novel brain-age prediction software.

Methods: We have performed detailed neurosonography, including acquiring 3D volumes, prospectively in cases with isolated CHD from 20 weeks onwards. An algorithm that assesses the degree of fetal brain-age automatically was used to compare CHD cases to controls. We stratified CHD cases according to flow and oxygenation profiles by lesion physiology and performed subgroup analyses.

Results: A total of 616 ultrasound volumes of 162 CHD cases and 75 controls were analyzed. Significant differences in maturation of the cortex were observed in cases with normal blood flow toward the brain (-3.8 days, 95%CI [-5.5; -2.0], P = <.001) and low (-4.0 days, 95% CI [-6.7; -1.2] P = <.05; hypoplastic left heart syndrome[HLHS]) and mixed (-4.4 days, 95%CI [-6.4; -2.5] p = <.001) oxygen saturation in the ascending aorta (TGA) and in cardiac mixing (eg, Fallot) cases.

Conclusion: The current study shows significant delay in brain-age in TGA and Fallot cases as compared to control cases. However, the small differences found in this study questions the clinical relevance.
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http://dx.doi.org/10.1002/pd.5813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891604PMC
January 2021

Neoaortic growth rate and diameter as risk factors for neoaortic valve regurgitation after arterial switch operation.

Heart 2020 12 5;106(24):1950. Epub 2020 Oct 5.

Division of Pediatric Cardiology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

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http://dx.doi.org/10.1136/heartjnl-2020-318142DOI Listing
December 2020

How long does the fertility-enhancing effect of hysterosalpingography with oil-based contrast last?

Reprod Biomed Online 2020 Dec 30;41(6):1038-1044. Epub 2020 Aug 30.

Centre for Reproductive Medicine, Amsterdam UMC, University of Amsterdam Amsterdam, the Netherlands.

Research Question: Does the fertility-enhancing effect of tubal flushing during hysterosalpingography (HSG) with oil-based contrast change over time?

Design: This was a secondary analysis of the H2Oil (long-term follow-up) study, a multicentre randomized controlled trial evaluating the effectiveness of oil-based and water-based contrast during HSG. The main outcome was ongoing pregnancy. Cox proportional hazards models for time to ongoing pregnancy were fitted over 3 years of follow-up.

Results: Data on 1107 couples were available; 550 couples had oil-based contrast and 557 water-based contrast at HSG. Ongoing pregnancy rates after 3 years were 77% and 71%, respectively. Median follow-up was 9-10 months (5th-95th percentile: <1 to 36). The hazard ratio for ongoing pregnancy for oil versus water over 3 years of follow-up was 1.26 (95% confidence interval [CI] 1.10-1.45). The scaled Schoenfeld residual plots showed a decrease in hazard ratio that was linear with log-transformed time. After including an interaction with log-transformed time, the hazard ratio immediately after HSG was 1.71 (95% CI 1.27-2.31) and reduced to no effect (hazard ratio of 1) at approximately 2 years. There was no evidence for a change in hazard ratio over time in a subgroup of women who experienced pain during HSG.

Conclusions: The hazard ratio for ongoing pregnancy of oil-based versus water-based contrast was 1.71 immediately after HSG, gradually decreasing and plateauing towards a hazard ratio of 1 (indicating no effect) after approximately 2 years. This supports the hypothesis that oil-based contrast might dislodge debris or mucus plugs from the Fallopian tubes, but this has yet to be definitively proved.
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http://dx.doi.org/10.1016/j.rbmo.2020.08.038DOI Listing
December 2020

Prediction meets causal inference: the role of treatment in clinical prediction models.

Eur J Epidemiol 2020 Jul 22;35(7):619-630. Epub 2020 May 22.

Department of Biomedical Data Sciences, Leiden University Medical Center, Zone S5-P, PO Box 9600, 2300 RC, Leiden, The Netherlands.

In this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for clinical trials, we propose a 'predictimand' framework of different questions that may be of interest when predicting risk in relation to treatment started after baseline. We provide a formal definition of the estimands matching these questions, give examples of settings in which each is useful and discuss appropriate estimators including their assumptions. We illustrate the impact of the predictimand choice in a dataset of patients with end-stage kidney disease. We argue that clearly defining the estimand is equally important in prediction research as in causal inference.
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http://dx.doi.org/10.1007/s10654-020-00636-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387325PMC
July 2020

The effect of treatment delay on time-to-recovery in the presence of unobserved heterogeneity.

Biom J 2020 07 20;62(4):1012-1024. Epub 2020 Jan 20.

Department of Biomedical Data Sciences, Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.

We study the effect of delaying treatment in the presence of (unobserved) heterogeneity. In a homogeneous population and assuming a proportional treatment effect, a treatment delay period will result in notably lower cumulative recovery percentages. We show in theoretical scenarios using frailty models that if the population is heterogeneous, the effect of a delay period is much smaller. This can be explained by the selection process that is induced by the frailty. Patient groups that start treatment later have already undergone more selection. The marginal hazard ratio for the treatment will act differently in such a more homogeneous patient group. We further discuss modeling approaches for estimating the effect of treatment delay in the presence of heterogeneity, and compare their performance in a simulation study. The conventional Cox model that fails to account for heterogeneity overestimates the effect of treatment delay. Including interaction terms between treatment and starting time of treatment or between treatment and follow up time gave no improvement. Estimating a frailty term can improve the estimation, but is sensitive to misspecification of the frailty distribution. Therefore, multiple frailty distributions should be used and the results should be compared using the Akaike Information Criterion. Non-parametric estimation of the cumulative recovery percentages can be considered if the dataset contains sufficient long term follow up for each of the delay strategies. The methods are demonstrated on a motivating application evaluating the effect of delaying the start of treatment with assisted reproductive techniques on time-to-pregnancy in couples with unexplained subfertility.
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http://dx.doi.org/10.1002/bimj.201900131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383985PMC
July 2020

Physiological-based cord clamping in very preterm infants - Randomised controlled trial on effectiveness of stabilisation.

Resuscitation 2020 02 23;147:26-33. Epub 2019 Dec 23.

Division of Neonatology, Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands.

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 (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 >90% while using FiO <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% 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.

Clinical Trial Registration: Netherlands Trial Register (NTR7194/NL7004).
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http://dx.doi.org/10.1016/j.resuscitation.2019.12.007DOI Listing
February 2020

A comparison of the beta-geometric model with landmarking for dynamic prediction of time to pregnancy.

Biom J 2020 01 18;62(1):175-190. Epub 2019 Nov 18.

Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands.

We conducted a simulation study to compare two methods that have been recently used in clinical literature for the dynamic prediction of time to pregnancy. The first is landmarking, a semi-parametric method where predictions are updated as time progresses using the patient subset still at risk at that time point. The second is the beta-geometric model that updates predictions over time from a parametric model estimated on all data and is specific to applications with a discrete time to event outcome. The beta-geometric model introduces unobserved heterogeneity by modelling the chance of an event per discrete time unit according to a beta distribution. Due to selection of patients with lower chances as time progresses, the predicted probability of an event decreases over time. Both methods were recently used to develop models predicting the chance to conceive naturally. The advantages, disadvantages and accuracy of these two methods are unknown. We simulated time-to-pregnancy data according to different scenarios. We then compared the two methods by the following out-of-sample metrics: bias and root mean squared error in the average prediction, root mean squared error in individual predictions, Brier score and c statistic. We consider different scenarios including data-generating mechanisms for which the models are misspecified. We applied the two methods on a clinical dataset comprising 4999 couples. Finally, we discuss the pros and cons of the two methods based on our results and present recommendations for use of either of the methods in different settings and (effective) sample sizes.
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http://dx.doi.org/10.1002/bimj.201900155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973003PMC
January 2020

The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study.

Br J Haematol 2020 04 15;189(1):171-181. Epub 2019 Nov 15.

Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.

In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C-reactive protein) and bleeding (WHO grading) in 88 patients with 116 on-protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05-1·46, P-value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C-reactive protein (CRP) (95% CI 1·04-1·60, P-value 0·02) after correction for morning platelet count. The 24 h post-transfusion corrected count increment (CCI ) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI We report two inexpensive and easy-to-apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients.
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http://dx.doi.org/10.1111/bjh.16291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154750PMC
April 2020

Long-term safety and efficacy of subcutaneous immunoglobulin IgPro20 in CIDP: PATH extension study.

Neurol Neuroimmunol Neuroinflamm 2019 09 3;6(5):e590. Epub 2019 Jul 3.

Department of Neurology (I.N.S.), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands; Spaarne Gasthuis (I.N.S.), Haarlem, The Netherlands; CSL Behring (O.M., M.P., B.L.D.), Marburg, Germany and King of Prussia, PA; Department of Medicine (Neurology) (V.B.), University Health Network, University of Toronto, Canada; Medical Statistics (N.G.), Department of Biomedical Data Sciences, Leiden University Medical Center, The Netherlands; Department of Neurology (H.-P.H.), Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Department of Neurology (R.A.L.), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (G.S.), Nagoya University Graduate School of Medicine, Japan; Department of Neurology (D.R.C.), Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Neurology (I.S.J.M.), Maastricht University Medical Center, The Netherlands.

Objective: To investigate the long-term safety and efficacy of weekly subcutaneous IgPro20 (Hizentra, CSL Behring) in chronic inflammatory demyelinating polyneuropathy (CIDP).

Methods: In a 48-week open-label prospective extension study to the PATH study, patients were initially started on 0.2 g/kg or on 0.4 g/kg weekly and-if clinically stable-switched to 0.2 g/kg weekly after 24 weeks. Upon CIDP relapse on the 0.2 g/kg dose, 0.4 g/kg was (re)initiated. CIDP relapse was defined as a deterioration by at least 1 point in the total adjusted Inflammatory Neuropathy Cause and Treatment score.

Results: Eighty-two patients were enrolled. Sixty-two patients initially received 0.4 g/kg, 20 patients 0.2 g/kg weekly. Seventy-two received both doses during the study. Sixty-six patients (81%) completed the 48-week study duration. Overall relapse rates were 10% in 0.4 g/kg-treated patients and 48% in 0.2 g/kg-treated patients. After dose reduction from 0.4 to 0.2 g/kg, 51% (27/53) of patients relapsed, of whom 92% (24 of 26) improved after reinitiation of the 0.4 g/kg dose. Two-thirds of patients (19/28) who completed the PATH study without relapse remained relapse-free on the 0.2 g/kg dose after dose reduction in the extension study. Sixty-two patients had adverse events (AEs) (76%), of which most were mild or moderate with no related serious AEs.

Conclusions: Subcutaneous treatment with IgPro20 provided long-term benefit at both 0.4 and 0.2 g/kg weekly doses with lower relapse rates on the higher dose. Long-term dosing should be individualized to find the most appropriate dose in a given patient.

Classification Of Evidence: This study provides Class IV evidence that for patients with CIDP, long-term treatment with SCIG beyond 24 weeks is safe and efficacious.
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http://dx.doi.org/10.1212/NXI.0000000000000590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624149PMC
September 2019

Cortical development in fetuses with congenital heart defects using an automated brain-age prediction algorithm.

Acta Obstet Gynecol Scand 2019 12 24;98(12):1595-1602. Epub 2019 Aug 24.

Department of Obstetrics and Prenatal Diagnosis, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Congenital heart defects are associated with neurodevelopmental delay. It is hypothesized that fetuses affected by congenital heart defect have altered cerebral oxygen perfusion and are therefore prone to delay in cortical maturation. The aim of this study was to determine the difference in fetal brain age between consecutive congenital heart defect cases and controls in the second and third trimester using ultrasound.

Material And Methods: Since 2014, we have included 90 isolated severe congenital heart defect cases in the Heart And Neurodevelopment (HAND)-study. Every 4 weeks, detailed neurosonography was performed in these fetuses, including the recording of a 3D volume of the fetal brain, from 20 weeks onwards. In all, 75 healthy fetuses underwent the same protocol to serve as a control group. The volumes were analyzed by automated age prediction software which determines gestational age by the assessment of cortical maturation.

Results: In total, 477 volumes were analyzed using the age prediction software (199 volumes of 90 congenital heart defect cases; 278 volumes of 75 controls). Of these, 16 (3.2%) volume recordings were excluded because of imaging quality. The age distribution was 19-33 weeks. Mixed model analysis showed that the age predicted by brain maturation was 3 days delayed compared with the control group (P = .002).

Conclusions: This study shows that fetuses with isolated cases of congenital heart defects show some delay in cortical maturation as compared with healthy control cases. The clinical relevance of this small difference is debatable. This finding was consistent throughout pregnancy and did not progress during the third trimester.
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http://dx.doi.org/10.1111/aogs.13687DOI Listing
December 2019

Progression of aortic root dilatation and aortic valve regurgitation after the arterial switch operation.

Heart 2019 11 10;105(22):1732-1740. Epub 2019 Jul 10.

Division of Pediatric Cardiology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Objective: To study neo-aortic growth and the evolution of neo-aortic valve regurgitation (AR) in patients with transposition of the great arteries (TGA) after arterial switch operation (ASO) from newborn to adulthood and to identify patients at risk.

Methods: Neo-aortic dimensions (annulus/root/sinotubular junction) and neo-aortic valve regurgitation were assessed serially in 345 patients with TGA who underwent ASO between 1977 and 2015. Linear mixed-effect models were used to assess increase of neo-aortic dimensions over time and to identify risk factors for dilatation. Risk factor analysis for AR by using time-dependent Cox regression models.

Results: After a rapid increase in the first year after ASO and proportional growth in childhood, neo-aortic dimensions continue to increase in adulthood without stabilisation. Annual diameter increase in adulthood was 0.39±0.06, 0.63±0.09 and 0.54±0.11 mm for, respectively, neo-aortic annulus, root and sinotubular junction, all significantly exceeding normal growth. AR continues to develop over time: freedom from AR ≥moderate during the first 25 years post-ASO was 69%. Risk factors for root dilatation were complex TGA anatomy (TGA-ventricular septal defect (VSD), double outlet right ventricle with subpulmonary VSD) and male gender. Risk factors for AR ≥moderate were: complex TGA anatomy and neo-aortic growth. Per millimetre increase in aortic root dimension, there was a 9% increase in the hazard of AR ≥moderate. Bicuspid pulmonary valve did not relate to the presence of root dilatation or AR.

Conclusion: After ASO, neo-aortic dilatation proceeds beyond childhood and is associated with an increase in AR incidence over time. Careful follow-up of the neo-aortic valve and root function is mandatory, especially in males and in patients with complex TGA anatomy.
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http://dx.doi.org/10.1136/heartjnl-2019-315157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855793PMC
November 2019

Effects of the FIT-HIP Intervention for Fear of Falling After Hip Fracture: A Cluster-Randomized Controlled Trial in Geriatric Rehabilitation.

J Am Med Dir Assoc 2019 07 8;20(7):857-865.e2. Epub 2019 May 8.

Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.

Objectives: Fear of falling (FoF) is common after hip fracture and can impede functional recovery because of activity restriction. The Fear of falling InTervention in HIP fracture geriatric rehabilitation (FIT-HIP intervention) was designed to target FoF and consequently to improve mobility. The aim of this study was to evaluate the effect of the FIT-HIP intervention in patients with FoF in geriatric rehabilitation (GR) after hip fracture.

Design, Setting, And Participants: This cluster-randomized controlled trial was performed in 11 post-acute GR units in the Netherlands (2016-2017). Six clusters were assigned to the intervention group, 5 to the usual care group. We included 78 patients with hip fracture and FoF (aged ≥65 years; 39 per group).

Intervention(s): The FIT-HIP intervention is a multicomponent cognitive behavioral intervention conducted by physiotherapists, embedded in usual care in GR. The FIT-HIP intervention was compared to usual care in GR.

Measurements: FoF was assessed with the Falls Efficacy Scale-International (FES-I) and mobility, with the Performance Oriented Mobility Assessment (POMA). Data were collected at baseline, discharge, and 3 and 6 months postdischarge from GR. Primary endpoints were change scores at discharge. Linear mixed models were used to evaluate the treatment effect.

Results: No significant between-group differences were observed for primary outcome measures. With the usual care group as reference, the FES-I estimated difference between mean change scores was 3.3 [95% confidence interval (CI) -1.0, 7.5, P = .13] at discharge from GR; -4.1 (95% CI -11.8, 3.6, P = .29) after 3 months; and -2.8 (95% CI -10.0, 4.4, P = .44) after 6 months. POMA estimated difference was -0.3 (95% CI -6.5, 5.8, P = .90).

Conclusion/implications: The FIT-HIP intervention was not effective in reducing FoF. Possibly FoF (shortly) after hip fracture can to some extent be appropriate. This may imply the study was not able to accurately identify and accordingly treat FoF that is maladaptive (reflective of disproportionate anxiety).
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http://dx.doi.org/10.1016/j.jamda.2019.03.009DOI Listing
July 2019

A Prospective Cohort Study on the Effects of Geriatric Rehabilitation Following Acute Exacerbations of COPD.

J Am Med Dir Assoc 2019 07 11;20(7):850-856.e2. Epub 2019 Apr 11.

Department of Public Health and Primary Care, Leiden University Medical Centre, the Netherlands.

Objectives: Older patients with chronic obstructive pulmonary disease (COPD), hospitalized for an acute exacerbation, often do not receive recommended post-acute pulmonary rehabilitation. This underuse might be related to the impaired clinical and functional status of these patients, who are more likely to present with frailty, comorbidities, and disability. Having developed and implemented a geriatric rehabilitation program for these patients (GR_COPD), the primary aim of this study was to investigate the effectiveness of this program.

Design And Intervention: A prospective cohort study with a 3-month follow-up period. Patients who declined the GR_COPD program were considered as controls.

Setting And Participants: The study was conducted at the pulmonary department of 2 hospitals. Patients were eligible when hospitalized as a result of an acute exacerbation of COPD and indicated for the GR_COPD program based on standardized criteria.

Methods: Primary outcome was defined as change in disease-specific health status measured with the clinical COPD questionnaire (CCQ), secondary outcome as the exacerbation rate ratio during follow-up. To balance potential confounders between the intervention and control group, propensity score-based weighted linear regression analyses were performed.

Results: Of the 158 included patients [78 (49.4%) male, mean age 70.8 (±8.1) years, mean forced expiratory volume in 1 second: 35.5 (±12.8) as % of predicted], 78 received the GR_COPD program. The results of the CCQ showed a significant and clinically relevant treatment effect of -0.56 points [95% confidence interval (CI) -0.89, -0.23; P = .001). Patients in the control group had 2.77 times more exacerbations compared with the intervention group (95% CI 2.13, 3.58; P < .001).

Conclusions/implications: This study shows a clinically relevant effect of the GR_COPD program on disease-specific health status and exacerbation rate. Implementation of the program for older patients with severe COPD hospitalized for an acute exacerbation is recommended.
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http://dx.doi.org/10.1016/j.jamda.2019.02.025DOI Listing
July 2019

Comparison of Two Respiratory Support Strategies for Stabilization of Very Preterm Infants at Birth: A Matched-Pairs Analysis.

Front Pediatr 2019 29;7. Epub 2019 Jan 29.

Department of Paediatrics, Leiden University Medical Center, Leiden, Netherlands.

Respiratory support for stabilizing very preterm infants at birth varies between centers. We retrospectively compared two strategies that involved either increasing continuous positive airway pressures (CPAP), or increasing oxygen supplementation. Matched-pairs of infants (<28 weeks of gestation) were born either at the Leiden University Medical Center [low-pressure: CPAP 5-8 cmHO and/or positive pressure ventilation (PPV) and fraction of inspired oxygen (FiO) 0.3-1.0; = 27], or at the University Hospital of Cologne (high-pressure: CPAP 12-35 cmHO, no PPV and FiO 0.3-0.4; = 27). Respiratory support was initiated non-invasively via facemask at both units. Infants ( = 54) were matched between centers for gestational age and birth weight, to compare physiological and short-term clinical outcomes. In the low-pressure group, 20/27 (74%) infants received 1-2 sustained inflations (20, 25 cm HO) and 22/27 (81%) received PPV (1:19-3:01 min) using pressures of 25-27 cm HO. Within 3 min of birth [median (IQR)], mean airway pressures [12 (6-15) vs. 19 (16-23) cmHO, < 0.001] and FiO [0.30 (0.28-0.31) vs. 0.22 (0.21-0.30), < 0.001] were different in low- vs. high-pressure groups, respectively. SpO and heart rates were similar. After 3 min, higher FiO levels [0.62 (0.35-0.98) vs. 0.28 (0.22-0.38), = 0.005] produced higher SpO levels [77 (50-92) vs. 53 (42-69)%, < 0.001] in the low-pressure group, but SpO/FiO and heart rates were similar. While intubation rates during admission were significantly different (70 vs. 30%, = 0.013), pneumothorax rates (4 vs. 19%, = 0.125) and the occurrence of spontaneous intestinal perforations (0 vs. 15%, = 0.125) were similar between groups. Infants (<28 weeks) can be supported non-invasively at birth with either higher or lower pressures and while higher-pressure support may require less oxygen, it does not eliminate the need for oxygen supplementation. Future studies need to examine the effect of high pressures and pressure titration in the delivery room.
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http://dx.doi.org/10.3389/fped.2019.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362425PMC
January 2019

Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies.

J Peripher Nerv Syst 2019 03 15;24(1):48-55. Epub 2019 Feb 15.

CSL Behring, Marburg, Germany, and King of Prussia, Pennsylvania.

Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was -1.0 (interquartile range -2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.].
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http://dx.doi.org/10.1111/jns.12302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594229PMC
March 2019

Restabilization treatment after intravenous immunoglobulin withdrawal in chronic inflammatory demyelinating polyneuropathy: Results from the pre-randomization phase of the Polyneuropathy And Treatment with Hizentra study.

J Peripher Nerv Syst 2019 03 1;24(1):72-79. Epub 2019 Mar 1.

Department of Neurology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.

In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal.
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http://dx.doi.org/10.1111/jns.12303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593755PMC
March 2019

Estimating the Effect of Treatment Duration Using Observational Data in Practice.

Epidemiology 2019 03;30(2):e7-e8

Section Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands, Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands Section Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands.

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http://dx.doi.org/10.1097/EDE.0000000000000943DOI Listing
March 2019

Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn.

Am J Obstet Gynecol 2018 09 11;219(3):291.e1-291.e9. Epub 2018 Jun 11.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Center for Clinical Transfusion Research, Sanquin Research, Leiden University Medical Center, Leiden, The Netherlands; Immunohematology Diagnostic Services, Sanquin Blood Supply, Amsterdam, The Netherlands.

Background: Intrauterine transfusion for severe alloimmunization in pregnancy performed <20 weeks' gestation is associated with a higher fetal death rate. Intravenous immunoglobulins may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions.

Objective: We evaluated whether maternal treatment with intravenous immunoglobulins defers the development of severe fetal anemia and its consequences in a retrospective cohort to which 12 fetal therapy centers contributed.

Study Design: We included consecutive pregnancies of alloimmunized women with a history of severe hemolytic disease and by propensity analysis compared index pregnancies treated with intravenous immunoglobulins (n = 24) with pregnancies managed without intravenous immunoglobulins (n = 28).

Results: In index pregnancies with intravenous immunoglobulin treatment, fetal anemia developed on average 15 days later compared to previous pregnancies (8% less often <20 weeks' gestation). In pregnancies without intravenous immunoglobulin treatment anemia developed 9 days earlier compared to previous pregnancies (10% more <20 weeks), an adjusted 4-day between-group difference in favor of the immunoglobulin group (95% confidence interval, -10 to +18; P = .564). In the subcohort in which immunoglobulin treatment was started <13 weeks, anemia developed 25 days later and 31% less <20 weeks' gestation (54% compared to 23%) than in the previous pregnancy. Fetal hydrops occurred in 4% of immunoglobulin-treated pregnancies and in 24% of those without intravenous immunoglobulin treatment (odds ratio, 0.03; 95% confidence interval, 0-0.5; P = .011). Exchange transfusions were given to 9% of neonates born from pregnancies with and in 37% without immunoglobulin treatment (odds ratio, 0.1; 95% confidence interval, 0-0.5; P = .009).

Conclusion: Intravenous immunoglobulin treatment in mothers pregnant with a fetus at risk for hemolytic disease seems to have a potential clinically relevant, beneficial effect on the course and severity of the disease. Confirmation in a multicenter randomized trial is needed.
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http://dx.doi.org/10.1016/j.ajog.2018.06.007DOI Listing
September 2018

Hemostatic efficacy of pathogen-inactivated vs untreated platelets: a randomized controlled trial.

Blood 2018 07 17;132(2):223-231. Epub 2018 May 17.

Center for Clinical Transfusion Research-Sanquin, Leiden, The Netherlands.

Pathogen inactivation of platelet concentrates reduces the risk for blood-borne infections. However, its effect on platelet function and hemostatic efficacy of transfusion is unclear. We conducted a randomized noninferiority trial comparing the efficacy of pathogen-inactivated platelets using riboflavin and UV B illumination technology (intervention) compared with standard plasma-stored platelets (control) for the prevention of bleeding in patients with hematologic malignancies and thrombocytopenia. The primary outcome parameter was the proportion of transfusion-treatment periods in which the patient had grade 2 or higher bleeding, as defined by World Health Organization criteria. Between November 2010 and April 2016, 469 unique patients were randomized to 567 transfusion-treatment periods (283 in the control arm, 284 in the intervention arm). There was a 3% absolute difference in grade 2 or higher bleeding in the intention-to-treat analysis: 51% of the transfusion-treatment periods in the control arm and 54% in the intervention arm (95% confidence interval [CI], -6 to 11; = .012 for noninferiority). However, in the per-protocol analysis, the difference in grade 2 or higher bleeding was 8%: 44% in the control arm and 52% in the intervention arm (95% CI -2 to 18; = .19 for noninferiority). Transfusion increment parameters were ∼50% lower in the intervention arm. There was no difference in the proportion of patients developing HLA class I alloantibodies. In conclusion, the noninferiority criterion for pathogen-inactivated platelets was met in the intention-to-treat analysis. This finding was not demonstrated in the per-protocol analysis. This trial was registered at The Netherlands National Trial Registry as #NTR2106 and at www.clinicaltrials.gov as #NCT02783313.
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http://dx.doi.org/10.1182/blood-2018-02-831289DOI Listing
July 2018

Repetitive versus standard tactile stimulation of preterm infants at birth - A randomized controlled trial.

Resuscitation 2018 06 23;127:37-43. Epub 2018 Mar 23.

Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Aim: To evaluate the direct effect of repetitive tactile stimulation on breathing effort of preterm infants at birth.

Methods: This randomized controlled trial compared the effect of repetitive stimulation on respiratory effort during the first 4 min after birth with standard stimulation based on clinical indication in preterm infants with a gestational age of 27-32 weeks. All details of the stimulation performed were noted. The main study parameter measured was respiratory minute volume, other study parameters assessed measures of respiratory effort; tidal volumes, rate of rise to maximum tidal volumes, percentage of recruitment breaths, and oxygenation of the infant.

Results: There was no significant difference in respiratory minute volume in the repetitive stimulation group when compared to the standard group. Oxygen saturation was significantly higher (87.6 ± 3.3% vs 81.7 ± 8.7%, p = .01) while the amount of FiO given during transport to the NICU was lower (28.2 (22.8-35.0)% vs 33.6 (29.4-44.1)%, p = .04). There was no significant difference in administration of positive pressure ventilation (52% vs 78%, p = .13), or the duration of ventilation (median (IQR) time 8 (0-118)s vs 35 (13-131)s, p = .23). Caregivers decided less often to administer caffeine in the delivery room to stimulate breathing in the repetitive stimulation group (10% vs 39%, p = .036).

Conclusion: Although the increase in respiratory effort during repetitive stimulation did not reach significance, oxygenation significantly improved with a lower level of FiO at transport to the NICU. Repetitive tactile stimulation could be of added value to improve breathing effort at birth.
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http://dx.doi.org/10.1016/j.resuscitation.2018.03.030DOI Listing
June 2018

Accuracy of Pulse Oximetry Screening for Critical Congenital Heart Defects after Home Birth and Early Postnatal Discharge.

J Pediatr 2018 06 23;197:29-35.e1. Epub 2018 Mar 23.

Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands.

Objective: To assess the accuracy of pulse oximetry screening for critical congenital heart defects (CCHDs) in a setting with home births and early discharge after hospital deliveries, by using an adapted protocol fitting the work patterns of community midwives.

Study Design: Pre- and postductal oxygen saturations (SpO) were measured ≥1 hour after birth and on day 2 or 3. Screenings were positive if the SpO measurement was <90% or if 2 independent measures of pre- and postductal SpO were <95% and/or the pre-/postductal difference was >3%. Positive screenings were referred for pediatric assessment. Primary outcomes were sensitivity, specificity, and false-positive rate of pulse oximetry screening for CCHD. Secondary outcome was detection of noncardiac illnesses.

Results: The prenatal detection rate of CCHDs was 73%. After we excluded these cases and symptomatic CCHDs presenting immediately after birth, 23 959 newborns were screened. Pulse oximetry screening sensitivity in the remaining cohort was 50.0% (95% CI 23.7-76.3) and specificity was 99.1% (95% CI 99.0-99.2). Pulse oximetry screening was false positive for CCHDs in 221 infants, of whom 61% (134) had noncardiac illnesses, including infections (31) and respiratory pathology (88). Pulse oximetry screening did not detect left-heart obstructive CCHDs. Including cases with prenatally detected CCHDs increased the sensitivity to 70.2% (95% CI 56.0-81.4).

Conclusion: Pulse oximetry screening adapted for perinatal care in home births and early postdelivery hospital discharge assisted the diagnosis of CCHDs before signs of cardiovascular collapse. High prenatal detection led to a moderate sensitivity of pulse oximetry screening. The screening also detected noncardiac illnesses in 0.6% of all infants, including infections and respiratory morbidity, which led to early recognition and referral for treatment.
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http://dx.doi.org/10.1016/j.jpeds.2018.01.039DOI Listing
June 2018

Surgical outcomes of laparoscopic hysterectomy with concomitant endometriosis without bowel or bladder dissection: a cohort analysis to define a case-mix variable.

Gynecol Surg 2018 16;15(1). Epub 2018 Mar 16.

1Department of Gynecology, Leiden University Medical Centre, Leiden, the Netherlands.

Background: Pelvic endometriosis is often mentioned as one of the variables influencing surgical outcomes of laparoscopic hysterectomy (LH). However, its additional surgical risks have not been well established. The aim of this study was to analyze to what extent concomitant endometriosis influences surgical outcomes of LH and to determine if it should be considered as case-mix variable.

Results: A total of 2655 LH's were analyzed, of which 397 (15.0%) with concomitant endometriosis. For blood loss and operative time, no measurable association was found for stages I ( = 106) and II ( = 103) endometriosis compared to LH without endometriosis. LH with stages III ( = 93) and IV ( = 95) endometriosis were associated with more intra-operative blood loss ( = < .001) and a prolonged operative time ( = < .001) compared to LH without endometriosis. No significant association was found between endometriosis (all stages) and complications ( = .62).

Conclusions: The findings of our study have provided numeric support for the influence of concomitant endometriosis on surgical outcomes of LH, without bowel or bladder dissection. Only stages III and IV were associated with a longer operative time and more blood loss and should thus be considered as case-mix variables in future quality measurement tools.
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http://dx.doi.org/10.1186/s10397-018-1039-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856860PMC
March 2018
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