Publications by authors named "Enrico Lopriore"

218 Publications

Persistent pulmonary hypertension in neonates with perinatal asphyxia and therapeutic hypothermia: a frequent and perilous combination.

J Matern Fetal Neonatal Med 2021 Feb 21:1-7. Epub 2021 Feb 21.

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

Objectives: (1) To investigate whether neonates with perinatal asphyxia and therapeutic hypothermia more often developed PPHN compared to a control group with perinatal asphyxia not treated with hypothermia; (2) To identify risk factors for severe PPHN during hypothermia and evaluate short-term outcome.

Methods: This single-center retrospective cohort study included (near-)term neonates with perinatal asphyxia admitted between 2004 and 2016. Neonates with perinatal asphyxia and hypothermia were compared to a historical control group without hypothermia. Primary outcome was PPHN, defined as severe hypoxemia requiring mechanical ventilation and inhaled nitric oxide, confirmed by echocardiography. Short-term adverse outcome was defined as mortality within one month and/or severe brain injury on MRI.

Results: Incidence of PPHN was 23% (26/114) in the hypothermia group and 11% (8/70) in controls. In multivariate analysis, PPHN was 2.5 times more common among neonates with hypothermia. Neonates developing PPHN during hypothermia often had higher fraction of inspired oxygen at baseline. PPHN was not associated with a higher risk of severe brain injury. However, early mortality was higher and three infants died due to severe refractory PPHN during hypothermia.

Conclusions: In this study PPHN occurred more often since the introduction of therapeutic hypothermia. This was usually reversible and did not lead to overall increased adverse outcome. However, in individual cases with PPHN deterioration occurred rapidly. In such cases the benefits of hypothermia should be weighed against the risk of a complicated, fatal course.
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http://dx.doi.org/10.1080/14767058.2021.1873941DOI Listing
February 2021

Are fetal bilirubin levels associated with the need for neonatal exchange transfusions in hemolytic disease of the fetus and newborn?

Am J Obstet Gynecol MFM 2021 Feb 17:100332. Epub 2021 Feb 17.

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

Background: Fetal bilirubin is routinely measured at our center when taking a pretransfusion blood sample at intrauterine transfusions in hemolytic disease of the fetus and newborn. However, the clinical value of fetal bilirubin assessment is not well known, and the information is rarely used. We speculated that there could be a role for this measurement in predicting the need for neonatal exchange transfusion.

Objective: To evaluate the predictive value of fetal bilirubin for exchange transfusions in severe hemolytic disease of the fetus and newborn.

Study Design: In this observational study 186 infants with Rh alloantibody mediated hemolytic disease of the fetus and newborn treated with one or more intrauterine transfusions at the Leiden University Medical Center between 2006 and June 2020 were included. Antenatal and postnatal factors were compared between infants with and without exchange transfusion treatment. The primary outcome was the fetal bilirubin level before the last intrauterine transfusion in relation to the need for exchange transfusion.

Results: In a multivariate logistic regression analysis, the fetal bilirubin level before the last intrauterine transfusions (odds ratio of 1.32; 95% confidence interval 1.09-1.61 per 1 mg/dL) and the total number of IUTs (odds ratio 0.63; 95% confidence interval 0.44-0.91 per intrauterine transfusion) were independently associated with the need for exchange transfusion. The area under the curve was determined at 0.71. A Youden index was calculated of 0.43. The corresponding fetal bilirubin level was 5 mg/dL and had a sensitivity of 79% and a specificity of 64%.

Conclusion: A high fetal bilirubin level before the last intrauterine transfusion was associated with a high likelihood of neonatal exchange transfusion.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100332DOI Listing
February 2021

Respiratory distress syndrome and bronchopulmonary dysplasia after fetal growth restriction: Lessons from a natural experiment in identical twins.

EClinicalMedicine 2021 Feb 29;32:100725. Epub 2021 Jan 29.

Neonatology, Dept. of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands.

Background: Fetal growth restriction (FGR) is thought to negatively affect lung development resulting in increased respiratory morbidity. However, research performed in singletons is often limited by a certain level of bias caused by individual differences in genetic constitution, obstetrical and maternal factors.

Methods: Respiratory morbidity was compared between the smaller and the larger twin in monochorionic twins with selective fetal growth restriction (sFGR), defined as a birth weight discordance ≥ 20%, born in our center between 2010 and 2019 in this retrospective study. Respiratory distress syndrome (RDS) was diagnosed based on the clinical picture of a neonate with respiratory failure requiring mechanical ventilation and/or surfactant, confirmed by a chest X-ray. Bronchopulmonary dysplasia (BPD) was diagnosed when the neonate required treatment with >21% oxygen for at least 28 days.

Findings: Median gestational age at birth for the 94 included pregnancies was 32.4 (IQR 30.4-34.3) weeks. Within-pair analyses showed that the prevalence of RDS was lower in the smaller twin compared to the larger twin, 19.1% (18/94) vs 34.0% (32/94), respectively ( = 0.004). The odds of RDS for the larger twin was doubled (OR 2.1 (CI95% 1.3-3.5). In contrast, the rate of BPD in the smaller twin was higher as opposed to the larger twin, 16.7% (15/90) vs 6.7% (6/89), respectively ( = 0.008), with a more than doubled odds (OR 2.5 (CI95% 1.3-4.9)).

Interpretation: Despite being genetically identical, sFGR twins have different respiratory outcomes. Adverse growth condition in the smaller twin is associated with a reduced odds of RDS at birth but a more than doubled odds of BPD, reflecting the pathophysiologic adverse effect of growth restriction on lung development.

Funding: The Dutch Heart Foundation (2017T075).
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http://dx.doi.org/10.1016/j.eclinm.2021.100725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851769PMC
February 2021

Reviewing recordings of neonatal resuscitation with parents.

Arch Dis Child Fetal Neonatal Ed 2021 Jan 29. Epub 2021 Jan 29.

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

Background: Recording of neonatal resuscitation, including video and respiratory parameters, was implemented for research and quality purposes at the neonatal intensive care unit (NICU) of the Leiden University Medical Center, and parents were offered to review the recording of their infant together with a neonatal care provider. We aimed to provide insight in parental experiences with reviewing the recording of the neonatal resuscitation of their premature infant.

Methods: This study combined participant observations during parental review of recordings with retrospective qualitative interviews with parents.

Results: Parental review of recordings of neonatal resuscitation was observed on 20 occasions, reviewing recordings of 31 children (12 singletons, 8 twins and 1 triplet), of whom 4 died during admission. Median (range) gestational age at birth was 27+5 (24+5-30+3) weeks. Subsequently, 25 parents (13 mothers and 12 fathers) were interviewed.Parents reported many positive experiences, with special emphasis on the value for getting hold of the start of their infant's life and coping with the trauma of neonatal resuscitation. Reviewing recordings of neonatal resuscitation frequently resulted in appreciation for the child, the father and the medical team. Timing and set-up of the review contributed to positive experiences. Parents considered screenshots/copies of the recording of the resuscitation of their infant as valuable keepsakes of their NICU story and reported that having the screenshots/video comforted them, especially when their child died during admission.

Conclusion: Parents consider reviewing recordings of neonatal resuscitation as valuable. These positive parental experiences could allay concerns about sharing recordings of neonatal resuscitation with parents.
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http://dx.doi.org/10.1136/archdischild-2020-320059DOI Listing
January 2021

The Effect of Single-Room Care Versus Open-Bay Care on the Incidence of Bacterial Nosocomial Infections in Pre-Term Neonates: A Retrospective Cohort Study.

Infect Dis Ther 2020 Dec 23:1-14. Epub 2020 Dec 23.

Division of Neonatology, Department of Pediatrics, Willem Alexander Children's Hospital-Leiden University Medical Center (LUMC), Leiden, The Netherlands.

Introduction: Nosocomial infections (NIs) are a major source of iatrogenic harm in neonatal intensive care units (NICUs). The influence of the infrastructure of NICUs on NIs is not well documented. This study aims to examine the effect of single-room units (SRU) versus open-bay units (OBU) on the incidence of NIs, including central-line-associated bloodstream infections (CLABSI), in preterm neonates.

Methods: All preterm neonates (< 32 weeks gestational age) admitted to our NICU were included. Two study periods were compared: one prior to (May 2015-May 2017) and one following (May 2017-May 2019) transition from OBU to SRU. Incidence density (number of infections per 1000 patient-days) and cumulative incidence (number of infections per 100 neonates) for NIs were calculated. CLABSIs were calculated per 1000 central-line days. chart analysis was performed to determine special-cause variation in quarterly CLABSI and NI rates. Multivariate competing risk regression was performed to identify independent NI risk factors.

Results: Of the 712 included infants, 164 (23%) infants acquired ≥ 1 NIs. No differences were found in incidence density (13.68 vs. 12.62,  = 0.62) or cumulative incidence of NI (23.97 vs. 22.02,  = 0.59) between OBU and SRU. CLABSIs showed a similar non-significant reduction after the move (14.00 vs. 10.59,  = 0.51). chart analysis did not identify unit transition as a potential source of special-cause variation for CLABSI and NI. Competing risks regression analysis revealed longer duration of invasive mechanical ventilation as a significant risk factor for NI (subhazards ratio: 1.03 per day on ventilation,  = 0.01).

Conclusion: Single-rooms are not associated with a significant reduction in NIs in the NICU. This study therefore does not add evidence that could support the transition to SRUs if based only on a large multimodal infection control strategy. Recommendations to build SRUs would require a wider justification, also taking into account other SRU benefits.

Supplementary Information: The online version contains supplementary material available at 10.1007/s40121-020-00380-9.
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http://dx.doi.org/10.1007/s40121-020-00380-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756131PMC
December 2020

The Effect of Single-Room Care Versus Open-Bay Care on the Incidence of Bacterial Nosocomial Infections in Pre-Term Neonates: A Retrospective Cohort Study.

Infect Dis Ther 2020 Dec 23. Epub 2020 Dec 23.

Division of Neonatology, Department of Pediatrics, Willem Alexander Children's Hospital-Leiden University Medical Center (LUMC), Leiden, The Netherlands.

Introduction: Nosocomial infections (NIs) are a major source of iatrogenic harm in neonatal intensive care units (NICUs). The influence of the infrastructure of NICUs on NIs is not well documented. This study aims to examine the effect of single-room units (SRU) versus open-bay units (OBU) on the incidence of NIs, including central-line-associated bloodstream infections (CLABSI), in preterm neonates.

Methods: All preterm neonates (< 32 weeks gestational age) admitted to our NICU were included. Two study periods were compared: one prior to (May 2015-May 2017) and one following (May 2017-May 2019) transition from OBU to SRU. Incidence density (number of infections per 1000 patient-days) and cumulative incidence (number of infections per 100 neonates) for NIs were calculated. CLABSIs were calculated per 1000 central-line days. U chart analysis was performed to determine special-cause variation in quarterly CLABSI and NI rates. Multivariate competing risk regression was performed to identify independent NI risk factors.

Results: Of the 712 included infants, 164 (23%) infants acquired ≥ 1 NIs. No differences were found in incidence density (13.68 vs. 12.62, p = 0.62) or cumulative incidence of NI (23.97 vs. 22.02, p = 0.59) between OBU and SRU. CLABSIs showed a similar non-significant reduction after the move (14.00 vs. 10.59, p = 0.51). U chart analysis did not identify unit transition as a potential source of special-cause variation for CLABSI and NI. Competing risks regression analysis revealed longer duration of invasive mechanical ventilation as a significant risk factor for NI (subhazards ratio: 1.03 per day on ventilation, p = 0.01).

Conclusion: Single-rooms are not associated with a significant reduction in NIs in the NICU. This study therefore does not add evidence that could support the transition to SRUs if based only on a large multimodal infection control strategy. Recommendations to build SRUs would require a wider justification, also taking into account other SRU benefits.
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http://dx.doi.org/10.1007/s40121-020-00380-9DOI Listing
December 2020

Changes in the Use of Fresh-Frozen Plasma Transfusions in Preterm Neonates: A Single Center Experience.

J Clin Med 2020 Nov 23;9(11). Epub 2020 Nov 23.

Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, The Netherlands.

The aim of this study was to evaluate changes in the use of fresh-frozen plasma (FFP) transfusions and the use of clotting tests in preterm neonates in our center over the past two decades. In this retrospective cohort analysis, we included all consecutive neonates with a gestational age at birth between 24 + 0 and 31 + 6 weeks admitted to our neonatal intensive care unit (NICU) between 2004 and 2019. We divided all included neonates into three consecutive time epochs according to date of birth: January 2004 to April 2009, May 2009 to August 2014 and September 2014 to December 2019. The main outcomes were the use of FFP transfusion, coagulation testing and the indications for FFP transfusion. The percentage of preterm neonates receiving FFP transfusion decreased from 5.7% (47/824) to 3.7% (30/901) to 2.0% (17/852) from the first epoch to the last epoch ( < 0.001). Additionally, the rate of neonates undergoing coagulation testing decreased from 24.3% (200/824) to 14.5% (131/901) to 8% (68/852) over the epochs ( < 0.001). Most FFP transfusions were prescribed prophylactically based on prolongation of activated partial thromboplastin time (aPTT) or prothrombin time (PT) (56%). In conclusion, both the use of FFP transfusions and the use of coagulation tests decreased significantly over the years. The majority of the FFP transfusions were administrated prophylactically for abnormal coagulation tests.
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http://dx.doi.org/10.3390/jcm9113789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700187PMC
November 2020

Benzylpenicillin Serum Concentrations in Neonates With Group B Streptococci Sepsis or Meningitis: A Descriptive Cohort Study.

Pediatr Infect Dis J 2020 Nov 10. Epub 2020 Nov 10.

From the Departments of Neonatology.

Background: Adequate dosage recommendations are imperative for successful treatment of invasive infections. We evaluated the occurrence of sub- and supratherapeutic serum and cerebrospinal fluid (CSF) concentrations of benzylpenicillin (BPEN) in neonates treated for a severe group B streptococci (GBS) sepsis and/or meningitis as well as discrepancies in dosing recommendations provided by pediatric reference sources.

Methods: Retrospective analysis of (pre)term infants treated with BPEN undergoing therapeutic drug monitoring (TDM) between May 2015 and May 2019. Outcomes included numbers of sub- and supratherapeutic concentrations, and dose adjustments, clinical evolution, and dosing recommendations from six pediatric reference sources.

Results: A total of 21 TDM samples from 8 neonates were evaluated. Among serum concentrations, 9/21 (43%) were below and 8/21 (38%) above the pre-specified therapeutic target range of 10-20 mg/L. Only 1 patient had BPEN determined in CSF whose concentration was below the lower limit of quantification. TDM identified a need for dose modification in 10/21 (48%) instances. Three of eight patients exhibited complete resolution of clinical, laboratory and radiologic signs of infection. Substantial variation in dosing recommendations (50,000-400,000 IE/kg/d) was present between reference sources.

Conclusions: Our data reveal that under current dosage recommendations, the predefined target serum or CSF concentrations of BPEN are not achieved in all children. In case of clinical failure, serum and/or CSF BPEN concentrations should be determined. Given the wide variation in concentrations and subsequent dose requirements, further exploration of the clinical and pharmacologic characteristics of BPEN in (pre)term neonates is essential to optimize therapeutic efficacy.
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http://dx.doi.org/10.1097/INF.0000000000002993DOI Listing
November 2020

Spontaneous twin anemia polycythemia sequence: diagnosis, management, and outcome in an international cohort of 249 cases.

Am J Obstet Gynecol 2021 02 27;224(2):213.e1-213.e11. Epub 2020 Jul 27.

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

Background: Twin anemia polycythemia sequence is a chronic form of unbalanced fetofetal transfusion through minuscule placental anastomoses in monochorionic twins, leading to anemia in the donor and polycythemia in the recipient. Owing to the low incidence of twin anemia polycythemia sequence, data on diagnosis, management, and outcome are limited.

Objective: This study aimed to investigate the diagnosis, management, and outcome in a large international cohort of spontaneous twin anemia polycythemia sequence.

Study Design: Data from the international twin anemia polycythemia sequence registry, retrospectively collected between 2014 and 2019, were used for this study. A total of 17 fetal therapy centers contributed to the data collection. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity.

Results: A total of 249 cases of spontaneous twin anemia polycythemia sequence were included in this study, 219 (88%) of which were diagnosed antenatally and 30 (12%) postnatally. Twin anemia polycythemia sequence was diagnosed antenatally at a median gestational age of 23.7 weeks (interquartile range, 9.7-28.8; range, 15.1-35.3). Antenatal management included laser surgery in 39% (86 of 219), expectant management in 23% (51 of 219), delivery in 16% (34 of 219), intrauterine transfusion (with partial exchange transfusion) in 12% (26 of 219), selective feticide in 8% (18 of 219), and termination of pregnancy in 1% (3 of 219) of cases. Perinatal mortality rate was 15% (72 of 493) for the total group, 22% (54 of 243) for donors, and 7% (18 of 242) for recipients (P<.001). Severe neonatal morbidity occurred in 33% (141 of 432) of twins with twin anemia polycythemia sequence and was similar for donors (32%; 63 of 196) and recipients (33%; 75 of 228) (P=.628). Independent risk factors for spontaneous perinatal mortality were donor status (odds ratio, 3.8; 95% confidence interval, 1.9-7.5; P<.001), antenatal twin anemia polycythemia sequence stage (odds ratio, 6.3; 95% confidence interval, 1.4-27.8; P=.016 [stage 2]; odds ratio, 9.6; 95% confidence interval, 2.1-45.5; P=.005 [stage 3]; odds ratio, 20.9; 95% confidence interval, 3.0-146.4; P=.002 [stage 4]), and gestational age at birth (odds ratio, 0.8; 95% confidence interval, 0.7-0.9; P=.001). Independent risk factors for severe neonatal morbidity were antenatal twin anemia polycythemia sequence stage 4 (odds ratio, 7.9; 95% confidence interval, 1.4-43.3; P=.018) and gestational age at birth (odds ratio, 1.7; 95% confidence interval, 1.5-2.1, P<.001).

Conclusion: Spontaneous twin anemia polycythemia sequence can develop at any time in pregnancy from the beginning of the second trimester to the end of the third trimester. Management for twin anemia polycythemia sequence varies considerably, with laser surgery being the most frequent intervention. Perinatal mortality and severe neonatal morbidity were high, the former especially so in the donor twins.
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http://dx.doi.org/10.1016/j.ajog.2020.07.041DOI Listing
February 2021

Increase in treatment of retinopathy of prematurity in the Netherlands from 2010 to 2017.

Acta Ophthalmol 2021 Feb 23;99(1):97-103. Epub 2020 Jul 23.

Leiden University Medical Center, Leiden, Netherlands.

Purpose: Compare patients treated for Retinopathy of Prematurity (ROP) in two consecutive periods.

Methods: Retrospective inventory of anonymized neonatal and ophthalmological data of all patients treated for ROP from 2010 to 2017 in the Netherlands, subdivided in period (P)1: 1-1-2010 to 31-3-2013 and P2: 1-4-2013 to 31-12-2016. Treatment characteristics, adherence to early treatment for ROP (ETROP) criteria, outcome of treatment and changes in neonatal parameters and policy of care were compared.

Results: Overall 196 infants were included, 57 infants (113 eyes) in P1 and 139 (275 eyes) in P2, indicating a 2.1-fold increase in ROP treatment. No differences were found in mean gestational age (GA) (25.9 ± 1.7 versus 26.0 ± 1.7 weeks, p = 0.711), mean birth weight (791 ± 311 versus 764 ± 204 grams, p = 0.967) and other neonatal risk factors for ROP. In P2, the number of premature infants born <25 weeks increased by factor 1.23 and higher oxygen saturation levels were aimed at in most centres. At treatment decision, 59.6% (P1) versus 83.5% (P2) (p = 0.263) infants were classified as Type 1 ROP (ETROP classification). Infants were treated with laser photocoagulation (98 versus 96%) and intravitreal bevacizumab (2 versus 4%). Retreatment was necessary in 10 versus 21 (p = 0.160). Retinal detachment developed in 6 versus 13 infants (p = 0.791) of which 2 versus 6 bilateral (p = 0.599).

Conclusion: In period 2, the number of infants treated according to the ETROP criteria (Type 1) increased, the number of ROP treatments, retinal detachments and retreatments doubled and the absolute number of retinal detachments increased. Neonatal data did not provide a decisive explanation, although changes in neonatal policy were reported.
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http://dx.doi.org/10.1111/aos.14501DOI Listing
February 2021

HIP (HPA-screening in pregnancy) study: protocol of a nationwide, prospective and observational study to assess incidence and natural history of fetal/neonatal alloimmune thrombocytopenia and identifying pregnancies at risk.

BMJ Open 2020 07 20;10(7):e034071. Epub 2020 Jul 20.

Department of Immunohaematology Diagnostics, Sanquin, Amsterdam, The Netherlands.

Introduction: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may lead to severe fetal or neonatal bleeding and/or perinatal death. Maternal alloantibodies, targeted against fetal human platelet antigens (HPAs), can result thrombocytopenia and bleeding complications. In pregnancies with known immunisation, fetal bleeding can be prevented by weekly maternal intravenous immunoglobulin infusions. Without population-based screening, immunisation is only detected after birth of an affected infant. Affected cases that might have been prevented, when timely identified through population-based screening. Implementation is hampered by the lack of knowledge on incidence, natural history and identification of pregnancies at high risk of bleeding. We designed a study aimed to obtain this missing knowledge.

Methods And Analysis: The HIP (HPA-screening in pregnancy) study is a nationwide, prospective and observational cohort study aimed to assess incidence and natural history of FNAIT as well as identifying pregnancies at high risk for developing bleeding complications. For logistic reasons, we invite rhesus D-negative or rhesus c-negative pregnant women, who take part in the Dutch population-based prenatal screening programme for erythrocyte immunisation, to participate in our study. Serological HPA-1a typing is performed and a luminex-based multiplex assay will be performed for the detection of anti-HPA-1a antibodies. Results will not be communicated to patients or caregivers. Clinical data of HPA-1a negative women and an HPA-1a positive control group will be collected after birth. Samples of HPA-1a immunised pregnancies with and without signs of bleeding will be compared with identify parameters for identification of pregnancies at high risk for bleeding complications.

Ethics And Dissemination: Ethical approval for this study has been obtained from the Medical Ethical Committee Leiden-The Hague-Delft (P16.002). Study enrolment began in March 2017. All pregnant women have to give informed consent for testing according to the protocol. Results of the study will be disseminated through congresses and publication in relevant peer-reviewed journals.

Trial Registration Number: NCT04067375.
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http://dx.doi.org/10.1136/bmjopen-2019-034071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375633PMC
July 2020

Evaluation of Color Difference in Placenta with Twin Anemia Polycythemia Sequence.

J Vis Exp 2020 06 17(160). Epub 2020 Jun 17.

Division of Neonatology, Department of Pediatrics, Leiden University Medical Center;

Twin anemia polycythemia sequence (TAPS) occurs in 5% of monochorionic twins and is characterized by large inter-twin hemoglobin differences. The postnatal diagnostic criteria for TAPS are based on hematologic parameters and placental characteristics. Placental examination after birth shows that color of the maternal side between placental territories of the anemic and polycythemic twins is remarkably different. The color difference in TAPS placentas is higher compared to monochorionic placentas with acute peripartum feto-fetal transfusion; thus, this is used as an additional diagnostic criterion for TAPS. Software such as ImageJ enables the computer-based measurement of color intensity in TAPS placentas. However, a detailed method for the calculation of color differences between anemic and polycythemic components of TAPS placentas has not yet been described. The protocol presented here provides a step-by-step method for analyzing color differences in the maternal side of TAPS placentas using ImageJ software.
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http://dx.doi.org/10.3791/61312DOI Listing
June 2020

Allogeneic cord blood transfusions for extremely preterm neonates: an extremely promising proof of concept.

Br J Haematol 2020 Oct 1;191(2):150-151. Epub 2020 Jul 1.

NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.

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http://dx.doi.org/10.1111/bjh.16918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689904PMC
October 2020

Post-Laser Twin Anemia Polycythemia Sequence: Diagnosis, Management, and Outcome in an International Cohort of 164 Cases.

J Clin Med 2020 Jun 5;9(6). Epub 2020 Jun 5.

Department of Obstetrics, Division of Fetal therapy, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

The aim of this study was to investigate the management and outcome in the post-laser twin anemia polycythemia sequence (TAPS). Data of the international TAPS Registry, collected between 2014 and 2019, were used for this study. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. A total of 164 post-laser TAPS pregnancies were included, of which 92% (151/164) were diagnosed antenatally and 8% (13/164) postnatally. The median number of days between laser for TTTS and detection of TAPS was 14 (IQR: 7-28, range: 1-119). Antenatal management included expectant management in 43% (62/151), intrauterine transfusion with or without partial exchange transfusion in 29% (44/151), repeated laser surgery in 15% (24/151), selective feticide in 7% (11/151), delivery in 6% (9/151), and termination of pregnancy in 1% (1/151). The median gestational age (GA) at birth was 31.7 weeks (IQR: 28.6-33.7; range: 19.0-41.3). The perinatal mortality rate was 25% (83/327) for the total group, 37% (61/164) for donors, and 14% (22/163) for recipients ( < 0.001). Severe neonatal morbidity was detected in 40% (105/263) of the cohort and was similar for donors (43%; 51/118) and recipients (37%; 54/145), = 0.568. Independent risk factors for spontaneous perinatal mortality were antenatal TAPS Stage 4 (OR = 3.4, 95%CI 1.4-26.0, = 0.015), TAPS donor status (OR = 4.2, 95%CI 2.1-8.3, < 0.001), and GA at birth (OR = 0.8, 95%CI 0.7-0.9, = 0.001). Severe neonatal morbidity was significantly associated with GA at birth (OR = 1.5, 95%CI 1.3-1.7, < 0.001). In conclusion, post-laser TAPS most often occurs within one month after laser for TTTS, but may develop up to 17 weeks after initial surgery. Management is mostly expectant, but varies greatly, highlighting the lack of consensus on the optimal treatment and heterogeneity of the condition. Perinatal outcome is poor, particularly due to the high rate of perinatal mortality in donor twins.
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http://dx.doi.org/10.3390/jcm9061759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355738PMC
June 2020

Prevalence of red-blood-cell and non-red-blood-cell-targeted autoantibodies in alloimmunized postpartum women.

Vox Sang 2020 Nov 26;115(8):783-789. Epub 2020 May 26.

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

Background And Objectives: Alloantibodies against red-blood-cell (RBC) antigens often coincide with alloantibodies against leucocytes and platelets and sometimes with autoantibodies towards various antigens. Chimerism may be one of the factors responsible for the combination of allo- and autoantibodies. Women with alloantibodies against RBC antigens causing haemolytic disease of the fetus and neonate may need to receive intrauterine transfusions. These transfusions increase not only maternal antibody formation but also fetomaternal bleeding and may enhance fetal chimerism. We determined the prevalence of and risk factors for autoantibodies against some common clinical target antigens, in alloimmunized women after IUT.

Materials And Methods: We tested for autoantibodies against RBC, anti-thyroid peroxidase, anti-extractable nuclear antigens, anti-cyclic citrullinated proteins and anti-tissue transglutaminase. Women with and without autoantibodies were compared for age; number of RBC alloantibodies, pregnancies and IUTs, and other factors that may play a role in immunization.

Results: Non-RBC-targeted autoantibodies were present in 40 of 258 tested women (15·5%, with 90% anti-TPO specificity), comparable to the prevalence reported in healthy Dutch women of these ages. Surprisingly, compared with women who had a single RBC alloantibody, a significantly higher proportion of women with multiple RBC alloantibodies had autoantibodies (5·3% and 18·4%, respectively; odds ratio 4·06, 95% CI: 1·20-13·7). Other characteristics of women with and without autoantibodies were not different.

Conclusion: Multiple RBC alloantibodies after extensive allogeneic exposure during pregnancy and presumed increased fetomaternal chimerism are not associated with (selected) autoantibodies. Lack of allo-RBC multi-responsiveness seems associated with decreased auto(-TPO) antibody formation.
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http://dx.doi.org/10.1111/vox.12941DOI Listing
November 2020

Intermittent absent and reversed umbilical artery flows in appropriately grown monochorionic diamniotic twins in relation to proximate cord insertion: A harmful combination?

Prenat Diagn 2020 09 9;40(10):1284-1289. Epub 2020 Jul 9.

Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands.

Objective: To compare the prevalence of intermittent absent or reversed end-diastolic flow (iAREDF) in the umbilical artery in appropriately grown monochorionic diamniotic (MCDA) pregnancies with and without proximate cord insertion (PCI), and to evaluate pregnancy outcome.

Methods: The prevalence of iAREDF in MCDA pregnancies with PCI (n = 11) was compared with a control group without PCI (n = 33). PCI was defined as a distance between the cord insertions below the fifth percentile. Placental sharing, number, and diameter of anastomoses were assessed by placental examination. Pregnancy outcome was evaluated.

Results: iAREDF was present in 7/11 PCI pregnancies, compared with 0/33 in the control group (P ≤ .01). All PCI pregnancies and 94% of controls had arterioarterial (AA)-anastomoses (P = .56), the diameter was larger in the PCI group, respectively 3.3 vs 2.1 mm (P = .03). Three cases with iAREDF had adverse outcome, two resulted in fetal death of which one with brain damage in the co-twin, another underwent early premature emergency section for fetal distress.

Conclusion: iAREDF occurs in a large proportion of MCDA pregnancies with PCI and is related to the diameter of the AA anastomosis. We hypothesize that iAREDF in appropriately grown MCDA twin pregnancies reflects an unstable hemodynamic balance with an increased risk for fetal deterioration. Whether outcome in these pregnancies can be improved by altered management requires further investigation.
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http://dx.doi.org/10.1002/pd.5736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539996PMC
September 2020

Fetal Diagnosis and Therapy during the COVID-19 Pandemic: Guidance on Behalf of the International Fetal Medicine and Surgery Society.

Fetal Diagn Ther 2020 6;47(9):689-698. Epub 2020 May 6.

Fetal Medicine Unit, Ontario Fetal Centre, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

The COVID-19 pandemic has stressed patients and healthcare givers alike and challenged our practice of antenatal care, including fetal diagnosis and therapy. This document aims to review relevant recent information to allow us to optimize prenatal care delivery. We discuss potential modifications to obstetric management and fetal procedures in SARS-CoV2-negative and SARS-CoV2-positive patients with fetal anomalies or disorders. Most fetal therapies are time sensitive and cannot be delayed. If personnel and resources are available, we should continue to offer procedures of proven benefit, acknowledging any fetal and maternal risks, including those to health care workers. There is, to date, minimal, unconfirmed evidence of spontaneous vertical transmission, though it may theoretically be increased with some procedures. Knowing a mother's preoperative SARS-CoV-2 status would enable us to avoid or defer certain procedures while she is contagious and to protect health care workers appropriately. Some fetal conditions may alternatively be managed neonatally. Counseling regarding fetal interventions which have a possibility of additional intra- or postoperative morbidity must be performed in the context of local resource availability. Procedures of unproven benefit should not be offered. We encourage participation in registries and trials that may help us to understand the impact of COVID-19 on pregnant women, their fetuses, and neonates.
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http://dx.doi.org/10.1159/000508254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251580PMC
September 2020

Prevalence, risk factors, and outcome of postprocedural amniotic band disruption sequence after fetoscopic laser surgery in twin-twin transfusion syndrome: a large single-center case series.

Am J Obstet Gynecol 2020 10 23;223(4):576.e1-576.e8. Epub 2020 Apr 23.

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

Background: Postprocedural amniotic band disruption sequence is a condition that is associated with intrauterine interventions, and it is characterized by a constriction of the limbs or umbilical cord by fibrous strands, leading to edema, amputation, and/or fetal demise.

Objective: To evaluate the prevalence of, risk factors for, and the outcome of postprocedural amniotic band disruption sequence after fetoscopic laser surgery in twin-twin transfusion syndrome cases.

Study Design: All consecutive cases of twin-twin transfusion syndrome treated with fetoscopic laser coagulation of the vascular anastomoses at our center between January 2002 and March 2019 were included in the study. The occurrence of postprocedural amniotic band disruption sequence in these cases was recorded, and the potential risk factors were analyzed.

Results: Postprocedural amniotic band disruption sequence was detected, at birth, in 2.2% (15/672) of twin-twin transfusion syndrome cases treated with fetoscopic laser surgery, in both the recipients (10/15, 67%) and the donors (5/15, 33%). Postprocedural amniotic band disruption sequence primarily affected the lower extremities (11/15, 73%) and, less frequently, the upper extremities (2/15, 13%), both the upper and lower extremities (1/15, 7%), or the umbilical cord (1/15, 7%). Postprocedural amniotic band disruption sequence led to the amputation of toes in 5 of 15 cases (33%) and resulted in fetal demise because of constriction of the umbilical cord in 1 case (7%). The independent risk factors identified for postprocedural amniotic band disruption sequence were lower gestational age at laser surgery (odds ratio per week, 1.43; 95% confidence interval, 1.12-1.79; P=.003) and the presence of postprocedural chorioamniotic membrane separation on antenatal ultrasound examination (odds ratio, 41.66; 95% confidence interval, 5.44-319.25; P<.001).

Conclusion: The prevalence of postprocedural amniotic band disruption sequence is low, but, when present, it may lead to severe consequences, with amputation of extremities or fetal demise occurring in more than one-third of the cases. Lower gestational age at the time of laser therapy and chorioamniotic membrane separation are independent risk factors for the postprocedural amniotic band disruption sequence.
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http://dx.doi.org/10.1016/j.ajog.2020.04.016DOI Listing
October 2020

Perioperative fetal hemodynamic changes in twin-twin transfusion syndrome and neurodevelopmental outcome at two years of age.

Prenat Diagn 2020 06 15;40(7):825-830. Epub 2020 Apr 15.

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

Objective: To investigate whether perioperative fetal hemodynamic changes in twin-to-twin transfusion syndrome (TTTS) are associated with neurodevelopmental impairment (NDI) at two years.

Methods: Doppler parameters of three sonograms (day before, first day after and 1 week after laser surgery for TTTS) were assessed for correlation with neurodevelopmental outcome at two years (2008-2016). NDI was defined as: cerebral palsy, deafness, blindness, and/or a Bayley-III cognitive/motor developmental test-score > 2SD below the mean.

Results: Long-term outcome was assessed in 492 TTTS survivors. NDI was present in 5% (24/492). After adjustment for severe cerebral injury (present in 4%), associated with NDI were: middle cerebral artery peak systolic velocity (MCA-PSV) >1.5 multiples of the median (MoM) 1 day after surgery (odds ratio [OR] 4.96; 95% confidence interval [CI]: 1.17-21.05, P = .03), a change from normal umbilical artery pulsatility index (UA-PI) presurgery to UA-PI >p95 postsurgery (OR 4.19; 95% CI: 1.04-16.87, P = .04), a change from normal to MCA-PSV >1.5MoM (OR 4.75; 95% CI: 1.43-15.77, P = .01).

Conclusion: Perioperative fetal hemodynamic changes in TTTS pregnancies treated with laser are associated with poor neurodevelopmental outcome. Prospective research on the cerebrovascular response to altered hemodynamic conditions is necessary to further understand the cerebral autoregulatory capacity of the fetus in relation to neurodevelopmental outcome.
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http://dx.doi.org/10.1002/pd.5690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383478PMC
June 2020

Epidural-Related Fever and Maternal and Neonatal Morbidity: A Systematic Review and Meta-Analysis.

Neonatology 2020 28;117(3):259-270. Epub 2020 Jan 28.

Department of Neonatology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.

Background: While epidural analgesia (EA) is associated with maternal fever during labor, the impact on the risk for maternal and/or neonatal sepsis is unknown.

Objectives: The aim of this systematic review was to investigate the effect of epidural-related intrapartum fever on maternal and neonatal outcomes.

Methods: OVID MEDLINE, OVID Embase, the Cochrane Library, Cochrane Controlled Register of Trials, and clinical trial registries were searched for randomized controlled trials (RCT) and observational cohort studies from inception to November 2018. A total of 761 studies were identified with 100 eligible for full-text review. Only articles investigating the relationship between EA and maternal fever during labor were eligible for inclusion. Study quality was assessed using the Cochrane's Risk of Bias tool and National Institute of Health Quality Assessment Tool. Two meta-analyses - one each for the RCT and observational cohort groups - were performed using the random-effects model of Mantel-Haenszel to produce summary risk ratios (RR) with 95% CI.

Results: Twelve RCTs and 16 observational cohort studies involving 579,157 parturients were included. RRs for maternal fever for the RCT and cohort analyses were 3.54 (95% CI 2.61-4.81) and 5.60 (95% CI 4.50-6.97), respectively. Meta-analyses of RR for maternal infection in both groups were infeasible given few occurrences. Meta-analysis of data from observational studies showed an increased risk for maternal antibiotic treatment in the epidural group (RR 2.60; 95% CI 1.31-5.17). For both analyses, neonates born to women with an epidural were not evaluated more often for suspected sepsis. Neither analysis reported an increased rate of neonatal bacteremia or neonatal antibiotic treatment after EA, although data precluded conclusiveness.

Conclusion: EA increases the risk of intrapartum fever and maternal antibiotic treatment. However, a definite conclusion on whether EA increases the risk for a proven maternal and/or neonatal bacteremia cannot be drawn due to the low quality of data. Further research on whether epidural-related intrapartum fever is of infectious origin or not is therefore needed.
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http://dx.doi.org/10.1159/000504805DOI Listing
January 2020

Suppression of compensatory erythropoiesis in hemolytic disease of the fetus and newborn due to intrauterine transfusions.

Am J Obstet Gynecol 2020 07 21;223(1):119.e1-119.e10. Epub 2020 Jan 21.

Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands; Department of Immunohematology Diagnostics, Sanquin, Amsterdam, the Netherlands.

Background: Infants with severe hemolytic disease of the fetus and newborn often require 1 or multiple intrauterine transfusions to treat fetal anemia. Intrauterine transfusions may have an inhibiting effect on fetal and neonatal erythropoiesis.

Objective: To quantify the effect of 1 or multiple intrauterine transfusions on the fetal erythropoiesis by assessing the fetal reticulocyte counts in a population with severe hemolytic disease of the fetus and newborn.

Study Design: This was an observational cohort study in infants admitted to the Leiden University Medical Center who received 1 or multiple intrauterine transfusions for hemolytic disease of the fetus and newborn caused by (Rh)D or Kell antibodies and were born between January 2005 and December 2018.

Results: A total of 235 patients were included, of whom 189 were patients with D-mediated hemolytic disease of the fetus and newborn and 46 with Kell-mediated hemolytic disease of the fetus and newborn. Absolute fetal reticulocyte count in D-mediated hemolytic disease of the fetus and newborn declined exponentially over the course of consecutive intrauterine transfusions, with a 62% decline after 1 intrauterine transfusion (95% confidence interval, 56-67). A similar exponential decline was observed in Kell-mediated hemolytic disease of the fetus and newborn, with 32% (95% confidence interval, 19-45) decline after 1 intrauterine transfusion. This decline was not associated with the varying gestational age at the time of the first intrauterine transfusion or the total number of intrauterine transfusions. The number of red blood cell transfusions for postnatal anemia was greater for infants with D and Kell-mediated hemolytic disease of the fetus and newborn with >2 intrauterine transfusions (median of 3 [interquartile range, 2-3] vs 2 [interquartile range, 1-3], P=.035, in D-mediated disease and median of 2 [interquartile range, 1-2] vs 1 [interquartile range, 1-1], P<.001, in Kell-mediated disease). Infants born after >2 intrauterine transfusions less often required exchange transfusion in D-mediated hemolytic disease of the fetus and newborn (19/89 [21%] vs 31/100 [31%], P=.039), compared with infants with 1-2 intrauterine transfusions.

Conclusion: Treatment with intrauterine transfusions causes an exponential decrease in fetal reticulocyte counts in both D- and Kell-mediated hemolytic disease of the fetus and newborn. Suppression of the compensatory erythropoiesis leads to prolonged postnatal anemia and an increased requirement of red blood cell transfusions after birth.
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http://dx.doi.org/10.1016/j.ajog.2020.01.028DOI Listing
July 2020

Twin-twin transfusion syndrome in the era of fetoscopic laser surgery: antenatal management, neonatal outcome and beyond.

Expert Rev Hematol 2020 03 31;13(3):259-267. Epub 2020 Jan 31.

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

: Twin-twin transfusion syndrome (TTTS) is a devastating complication of monochorionic twin pregnancy and remains a major challenge for worldwide fetal medicine specialists. In TTTS, intertwin transfusion through vascular anastomoses in the shared placenta leads to severe hemodynamic imbalance. This review summarizes the current knowledge of TTTS.: The most recent insights concerning the management of TTTS, as well as fetal and neonatal complications are described. Relevant articles were selected based on a Pubmed search using the keywords below. Understanding of the underlying pathophysiology has improved greatly as a result of placental injection studies. Advancements in antenatal management have led to increased perinatal survival and a decreased incidence of neonatal complications, including brain injury and neurodevelopmental impairment.: Further opportunities for improvement comprise technological innovations in laser procedures and the prevention of preterm rupture of membranes with subsequent prematurity. A noninvasive treatment such as high-intensity focused ultrasound (HIFU) seems to hold promise for the future treatment of TTTS. Fetal MRI studies are important to improve our understanding of fetal brain injury and should relate their findings to long-term neurodevelopment. International collaboration and centralization of care are of paramount importance to ensure the best care for our patients.
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http://dx.doi.org/10.1080/17474086.2020.1720643DOI Listing
March 2020

The Effect of Initial High vs. Low FiO on Breathing Effort in Preterm Infants at Birth: A Randomized Controlled Trial.

Front Pediatr 2019 12;7:504. Epub 2019 Dec 12.

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

Infants are currently stabilized at birth with initial low FiO which increases the risk of hypoxia and suppression of breathing in the first minutes after birth. We hypothesized that initiating stabilization at birth with a high O concentration, followed by titration, would improve breathing effort when compared to a low O concentration, followed by titration. In a bi-center randomized controlled trial, infants <30 weeks gestation were stabilized at birth with an initial O concentration of 30 or 100%, followed by oxygen titration. Primary outcome was minute volume of spontaneous breathing. We also assessed tidal volumes, mean inspiratory flow rate (MIFR) and respiratory rate with a respiratory function monitor in the first 5 min after birth, and evaluated the duration of mask ventilation in the first 10 min after birth. Pulse oximetry was used to measure heart rate and SpO values in the first 10 min. Hypoxemia was defined as SpO < 25th percentile and hyperoxemia as SpO >95%. 8-iso-prostaglandin F2α (8iPGF2α) was measured to assess oxidative stress in cord blood and 1 and 24 h after birth. Fifty-two infants were randomized and recordings were obtained in 44 infants (100% O-group: = 20, 30% O-group: = 24). Minute volumes were significantly higher in the 100% O-group (146.34 ± 112.68 mL/kg/min) compared to the 30% O-group (74.43 ± 52.19 mL/kg/min), = 0.014. Tidal volumes and MIFR were significantly higher in the 100% O-group, while the duration of mask ventilation given was significantly shorter. Oxygenation in the first 5 min after birth was significantly higher in infants in the 100% O-group [85 (64-93)%] compared to the 30% O-group [58 (46-67)%], < 0.001. The duration of hypoxemia was significantly shorter in the 100% O-group, while the duration of hyperoxemia was not different between groups. There was no difference in oxidative stress marker 8iPGF2α between the groups. Initiating stabilization of preterm infants at birth with 100% O led to higher breathing effort, improved oxygenation, and a shorter duration of mask ventilation as compared to 30% O, without increasing the risk for hyperoxia or oxidative stress. This study was registered in www.trialregister.nl, with registration number NTR6878.
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http://dx.doi.org/10.3389/fped.2019.00504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927294PMC
December 2019

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

Necrotizing enterocolitis in haemolytic disease of the newborn: a retrospective cohort study.

Vox Sang 2020 Feb 19;115(2):196-201. Epub 2019 Dec 19.

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

Background And Objectives: Necrotizing enterocolitis (NEC) is a common and often severe gastrointestinal emergency in newborn infants. While usually affecting (very) premature infants, an association between NEC and haemolytic disease of the foetus and newborn (HDFN) has been suggested. HDFN may be an additional risk factor to develop NEC. The objective of this study was to evaluate the occurrence of NEC in infants affected with moderate to severe HDFN in a large single centre cohort as compared to a broad population of infants without HDFN.

Materials And Methods: Retrospective cohort study of medical records of neonates with and without HDFN, with a gestational age at birth ≥30 weeks and ≤38 weeks, and admitted to the Leiden University Medical Center between January 2000 and December 2016.

Results: A total of 3284 patient records of infants born in the study period were reviewed and 317 cases of HDFN were identified. The incidence of NEC was significantly higher among infants with HDFN compared to infants without HDFN: 4/317 affected infants (1·3%) vs. 11/2967 affected infants (0·4%, relative risk 3·40, 95% confidence interval: 1·09-10·63).

Conclusions: We observed a higher incidence of NEC in an overall late preterm to near term population of infants with moderate to severe HDFN, compared to infants born without HDFN. The clinician taking care of an HDFN-affected infant should be cautious of this higher risk.
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http://dx.doi.org/10.1111/vox.12862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028041PMC
February 2020

Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death.

Blood 2019 12;134(26):2354-2360

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

The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 × 109/L compared with 50 × 109/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 × 109/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 × 109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. This trial was registered at www.isrctn.com as #ISRCTN87736839.
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http://dx.doi.org/10.1182/blood.2019000899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933290PMC
December 2019

Monochorionic Twins: A Delicate Balance.

J Clin Med 2019 Oct 17;8(10). Epub 2019 Oct 17.

Fetal Medicine Unit, St George's Hospital and St George's, University of London, London, UK.

Monochorionic (MC) twins are identical twins who share one placenta, with vascular anastomoses connecting the circulations of both fetuses [...].
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http://dx.doi.org/10.3390/jcm8101711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832893PMC
October 2019

Iatrogenic blood loss in extreme preterm infants due to frequent laboratory tests and procedures.

J Matern Fetal Neonatal Med 2019 Oct 6:1-6. Epub 2019 Oct 6.

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

To evaluate the cumulative amount of iatrogenic blood loss in extreme preterm infants during the first month of life. We performed an observational cohort study in 20 extreme preterm infants (gestational age <28 weeks). We recorded the amount of blood drawn for laboratory testing during the first 4 weeks of life, the number of punctures for phlebotomy and intravenous access and the amount of blood loss associated with these procedures. We compared the cumulative blood loss to the estimated total blood volume (85 ml/kg body weight) and to the total volume of red blood cell (RBC) transfusions administered during the same study period. The median cumulative iatrogenic blood loss was 24.2 ml/kg (interquartile range (IQR) 15.8-30.3 ml/kg) per patient, which equals a median of 28.5% (IQR 18.6-35.6%) of the total blood volume. Blood loss was higher in the most extreme preterm infants (30.2 ml/kg at 24 weeks versus 15.9 ml/kg at 27 weeks). The median number of punctures per infant was 47 (IQR 26-56) during the first 4 weeks of life. The median volume of RBC transfusions administered during the study period was 30 ml/kg, slightly more than the cumulative blood loss (24.2 ml/kg). Extreme preterm infants lose almost one-third of their total blood volume in the first month of life as a result of blood loss due to multiple blood draws for laboratory investigations, and procedures.
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http://dx.doi.org/10.1080/14767058.2019.1670800DOI Listing
October 2019

Long-Term Neurodevelopmental Outcome in Twin-to-Twin Transfusion Syndrome: Is there still Room for Improvement?

J Clin Med 2019 Aug 15;8(8). Epub 2019 Aug 15.

Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, J7-48, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Despite many developments in its management, twin-to-twin transfusion syndrome (TTTS) remains an important risk factor for long-term neurodevelopmental impairment (NDI). Our objective was to compare the incidence of severe NDI in a recent cohort of TTTS survivors, treated with laser surgery from 2011 to 2014, with a previous cohort treated from 2008 to 2010. Neurological, cognitive, and motor development were assessed at two years of age. We determined risk factors associated with Bayley-III scores. Severe NDI occurred in 7/241 (3%) survivors in the new cohort compared to 10/169 (6%) in the previous cohort ( = 0.189). Disease-free survival (survival without severe impairment) did not significantly differ. Low birth weight and being small for gestational age (SGA) were independently associated with lower cognitive scores (both < 0.01). Severe cerebral injury was related to decreased motor scores (B = -14.10; 95% CI -3.16, -25.04; = 0.012). Children with severe NDI were born ≥32 weeks' gestation in 53% of cases and had no evidence of cerebral injury on cranial ultrasound in 59% of cases. Our results suggest that improvement in outcome of TTTS has reached a plateau. Low birth weight, SGA, and cerebral injury are risk factors for poor neurodevelopmental outcome. Neither gestational age above 32 weeks nor the absence of cerebral injury preclude severe NDI.
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http://dx.doi.org/10.3390/jcm8081226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723379PMC
August 2019

Deferred consent for delivery room studies: the providers' perspective.

Arch Dis Child Fetal Neonatal Ed 2020 May 19;105(3):310-315. Epub 2019 Aug 19.

Division of Neonatology, Leiden University Medical Center, Leiden, Netherlands.

Objective: To gain insight into neonatal care providers' perceptions of deferred consent for delivery room (DR) studies in actual scenarios.

Methods: We conducted semistructured interviews with 46 neonatal intensive care unit (NICU) staff members of the Leiden University Medical Center (the Netherlands) and the Hospital of the University of Pennsylvania (USA). At the time interviews were conducted, both NICUs conducted the same DR studies, but differed in their consent approaches. Interviews were audio-recorded, transcribed and analysed using the qualitative data analysis software Atlas.ti V.7.0.

Results: Although providers reported to regard the prospective consent approach as the most preferable consent approach, they acknowledged that a deferred consent approach is needed for high-quality DR management. However, providers reported concerns about parental autonomy, approaching parents for consent and ethical review of study protocols that include a deferred consent approach. Providers furthermore differed in perceived appropriateness of a deferred consent approach for the studies that were being conducted at their NICUs. Providers with first-hand experience with deferred consent reported positive experiences that they attributed to appropriate communication and timing of approaching parents for consent.

Conclusion: Insight into providers' perceptions of deferred consent for DR studies in actual scenarios suggests that a deferred consent approach is considered acceptable, but that actual usage of the approach for DR studies can be improved on.
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http://dx.doi.org/10.1136/archdischild-2019-317280DOI Listing
May 2020