Publications by authors named "Kamran Yusuf"

53 Publications

Preeclampsia and postpartum mental health: mechanisms and clinical implications.

J Matern Fetal Neonatal Med 2021 Sep 19:1-7. Epub 2021 Sep 19.

Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Canada.

Preeclampsia is one of the leading causes of maternal morbidity and mortality worldwide, with the short and long-term implications for maternal health being increasingly recognized. Yet the effects of preeclampsia on mental health are often overlooked, effects which can be evident both immediately postpartum and decades later. In particular, preeclampsia has been associated with increased risk and severity of cognitive impairment, psychosocial distress, and psychiatric disorders including depression, anxiety, and post-traumatic stress disorder. While these outcomes are reported, few have proposed how the pathophysiology of preeclampsia may contribute to changes in postpartum mental health. Studies have suggested that anti-angiogenic factors and pro-inflammatory cytokines released from the preeclamptic placenta may damage the blood-brain barrier endothelium, leading to long-term structural and functional cerebral changes. These changes may contribute to subsequent impairments in mental health. In addition, the pro-inflammatory profile and patterns of cerebral damage observed in preeclampsia are similar to that of psychiatric disorders and cognitive impairment, suggesting they may share common mechanisms. Yet, there is limited evidence on how these mechanisms may interact. The purpose of this review is to summarize the evidence for these pathophysiological mechanisms and propose how they may work synergistically to affect brain structure, cognition, and postpartum mental health in preeclampsia. The role of psychosocial factors, disease severity, and psychological treatment in the mental health of preeclampsia patients will also be discussed.
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http://dx.doi.org/10.1080/14767058.2021.1978067DOI Listing
September 2021

Serum levels of TGF-β1, cytokines, angiogenic, and anti-angiogenic factors in pregnant women who smoke.

J Reprod Immunol 2021 Sep 7;147:103351. Epub 2021 Jul 7.

Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. Electronic address:

Introduction: Women who smoke during pregnancy have a reduced risk of preeclampsia. The mechanism of this association is poorly understood. Preeclampsia is an anti-angiogenic and inflammatory state. Transforming growth factor beta 1 (TGF-β1) is a multi-functional anti-inflammatory cytokine that activates membrane bound endoglin on endothelial cells causing a myriad of vascular actions including vasorelaxation. The objective of the study was to determine serum levels of cytokines, angiogenic factors, placental growth factor (PlGF), TGF-β-1 and anti-angiogenic factors, soluble endoglin (sEng) and soluble vascular endothelial growth factor 1 (sVEGFR1) in smoking and non-smoking pregnant women.

Methods: Using enzyme-linked immunosorbent and multiplex assays we prospectively analyzed serum levels of PIGF, TGF-β1, sEng, sVEGFR1 and cytokines in normotensive pregnant smokers and non-smokers. Exclusion criteria included maternal hypertension, autoimmune disorders, rupture of membranes, evidence of labor and drug use.

Results: There were 59 women in the smoking and 66 in the non-smoking group. Compared to non-smoking mothers. maternal age was lower in smoking mothers with no significant difference in other demographic variables. There was no difference in levels of cytokines, anti-angiogenic factors and PlGF between the two groups. Median TGF-β1 levels were significantly higher in the smoking group (8120 pg/mL vs 6040 pg/mL, p < 0.001) and remained significant after controlling for confounders. TGF-β1 levels correlated positively with cotinine levels in the smoking group.

Conclusions: We speculate that higher TGF-β1 levels may explain the reduced incidence of preeclampsia in mothers who smoke by being available for action on maternal endothelium even after inactivation by circulating maternal sEng.
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http://dx.doi.org/10.1016/j.jri.2021.103351DOI Listing
September 2021

Neurodevelopmental outcomes of singleton large for gestational age infants <29 weeks' gestation: a retrospective cohort study.

J Perinatol 2021 Jun 25;41(6):1313-1321. Epub 2021 May 25.

Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta, Canada.

Objective: To compare neurodevelopmental outcomes of large and appropriate for gestational age (LGA, AGA) infants <29 weeks' gestation at 18-24 months of corrected age.

Study Design: Retrospective cohort study using the Canadian Neonatal Network and Canadian Neonatal Follow-Up Network databases. Primary outcome was a composite of death or significant neurodevelopmental impairment (NDI), defined as severe cerebral palsy, Bayley III cognitive, language and motor scores of <70, need for hearing aids or cochlear implant and bilateral visual impairment. Univariate and multivariable logistic analyses were applied for outcomes.

Results: The study cohort comprised 170 LGA and 1738 AGA infants. There was no difference in significant NDI or individual components of the Bayley III between LGA and AGA groups. LGA was associated with the increased risk of death by follow-up, 44/170 (25.9%) vs. 320/1738 (18.4%) (aOR: 1.60 95% CI: 1.00-2.54).

Conclusions: Risk of NDI was similar between LGA and AGA infants.
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http://dx.doi.org/10.1038/s41372-021-01080-zDOI Listing
June 2021

Effect of enteral zinc supplementation on growth and neurodevelopment of preterm infants: a systematic review and meta-analysis.

J Perinatol 2021 May 18. Epub 2021 May 18.

Community Health Sciences, Institute of Public Health, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Objective: To evaluate effect of enteral zinc supplementation on growth and neurodevelopmental outcomes of preterm infants.

Study Design: A systematic review and meta-analysis of randomized-controlled trials (RCTs) examining growth and neurodevelopmental outcomes after zinc supplementation in preterm infants.

Results: Of eight RCTs involving 742 infants included, seven reported growth anthropometrics at 3-6 months corrected age (CA) and two reported neurodevelopmental outcomes at 6-12 months CA. Zinc supplementation was associated with increased weight z-score (weighted mean difference (WMD) = 0.50; 95% CI 0.23-0.76, heterogeneity I = 89.1%; P < 0.01), length z-score (WMD = 1.12; 95% CI 0.63-1.61, heterogeneity I = 96.0%; P < 0.01) and motor developmental score (WMD = 9.54; 95% CI 6.6-12.4 heterogeneity I = 0%; P = 0.52). There was no effect on head circumference and total developmental score. Evidence is "moderate" certainty for weight and length and "very low" certainty for neurodevelopment.

Conclusion: Zinc supplementation may enhance weight gain and linear growth in preterm infants. There is a lack of data about relationship between zinc supplementation and neurodevelopment.
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http://dx.doi.org/10.1038/s41372-021-01094-7DOI Listing
May 2021

A synthetic peptide rescues rat cortical neurons from anesthetic-induced cell death, perturbation of growth and synaptic assembly.

Sci Rep 2021 Feb 25;11(1):4567. Epub 2021 Feb 25.

University of Calgary, Calgary, T2N 4N1, Canada.

Anesthetics are deemed necessary for all major surgical procedures. However, they have also been found to exert neurotoxic effects when tested on various experimental models, but the underlying mechanisms remain unknown. Earlier studies have implicated mitochondrial fragmentation as a potential target of anesthetic-induced toxicity, although clinical strategies to protect their structure and function remain sparse. Here, we sought to determine if preserving mitochondrial networks with a non-toxic, short-life synthetic peptide-P110, would protect cortical neurons against both inhalational and intravenous anesthetic-induced neurotoxicity. This study provides the first direct and comparative account of three key anesthetics (desflurane, propofol, and ketamine) when used under identical conditions, and demonstrates their impact on neonatal, rat cortical neuronal viability, neurite outgrowth and synaptic assembly. Furthermore, we discovered that inhibiting Fis1-mediated mitochondrial fission reverses anesthetic-induced aberrations in an agent-specific manner. This study underscores the importance of designing mitigation strategies invoking mitochondria-mediated protection from anesthetic-induced toxicity in both animals and humans.
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http://dx.doi.org/10.1038/s41598-021-84168-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907385PMC
February 2021

Reply.

J Pediatr 2021 05 4;232:311-312. Epub 2021 Feb 4.

Department of Pediatrics, McMaster University, Hamilton, Canada.

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http://dx.doi.org/10.1016/j.jpeds.2021.01.062DOI Listing
May 2021

Serum levels of soluble Fas and Fas ligand in pregnant women who smoke.

Am J Reprod Immunol 2021 06 16;85(6):e13382. Epub 2020 Dec 16.

Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Problem: Cigarette smoking during pregnancy is associated with reduced incidence of preeclampsia. Mechanisms of this association are poorly understood. Cytokines, angiogenic, and anti-angiogenic factors are involved in the pathogenesis of preeclampsia. During normal pregnancy, Fas ligand (FasL) present on trophoblasts induces apoptosis of Fas bearing maternal immune cells. In preeclampsia, trophoblasts show increased apoptosis with reduced expression of FasL. We determined serum levels of cytokines, angiogenic (placental growth factor), anti-angiogenic factors (soluble endoglin, soluble fms-like tyrosine kinase-1), soluble Fas (sFas), and soluble FasL (sFasL) in smoking and non-smoking pregnant women.

Methods: Using enzyme-linked immunosorbent and multiplex assays, we prospectively analyzed serum levels of angiogenic, anti-angiogenic factors, cytokines, sFas and sFasL in normotensive smoking and non-smoking mothers. Exclusion criteria included maternal hypertension, auto-immune disorders, rupture of membranes, evidence of labor, and drug use.

Results: Of 100 women recruited to the study, 51 were in the non-smoking and 49 in the smoking group. Except for lower maternal age in the smoking group, there was no difference in gestation, BMI, gravidity, or ethnicity between the two groups. Levels of angiogenic, anti-angiogenic factors, cytokines, and sFas were similar between the two groups but sFasL levels were significantly higher in smoking group (38 pg/ml vs. 16 pg/ml, p < .001) and remained significant after controlling for confounders.

Conclusion: Our study demonstrates higher sFasL levels in pregnant women who smoke. Higher sFasL may explain the reduced incidence of preeclampsia in pregnant mothers who smoke by inducing apoptosis of immune cells which may otherwise induce trophoblast apoptosis.
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http://dx.doi.org/10.1111/aji.13382DOI Listing
June 2021

Osmolality of Medications Administered in the Neonatal Intensive Care Unit.

Can J Hosp Pharm 2020 1;73(4):288-289. Epub 2020 Oct 1.

Pharmacy Services, Alberta Health Services, Calgary, Alberta.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556401PMC
October 2020

High Early Parenteral Lipid in Very Preterm Infants: A Randomized-Controlled Trial.

J Pediatr 2021 01 13;228:16-23.e1. Epub 2020 Aug 13.

Neonatal Nutritional and Gastroenterology Program, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada; Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Objective: To determine whether high early parenteral soybean oil lipid intake in very low birth weight (VLBW) infants in the first week after birth decreases the proportion of weight loss and subsequently the incidence of extrauterine growth restriction (EUGR).

Study Design: This was a randomized controlled trial of appropriate for gestational- ge VLBW infants. Lipid intake in the control group started at 0.5-1 g/kg per day and increased daily by 0.5-1 g/kg per day till reaching 3 g/kg per day. The intervention group was started on 2 g/kg per day that increased to 3 g/kg per day the following day.

Results: Of the 176 infants assessed for eligibility, 83 were included in the trial. Infants in the intervention group were started on lipid sooner (13.8 ± 7.8 vs 17.5 ± 7.8 hour; P = .03) and had higher cumulative lipid intake in the first 7 days of age (13.5 ± 4.2 vs 10.9 ± 3.5 g/kg per day; P = .03). Infants in the intervention group had a lower percentage of weight loss (10.4 vs 12.7%; P = .02). The mean triglyceride level was higher in the intervention group (1.91 ± 0.79 vs 1.49 ± 0.54 mmol/L; P = .01), however, hypertriglyceridemia was similar between the 2 groups. The incidence of EUGR was lower in the intervention group (38.6% vs 67.6%; P = .01). Head circumference z score was higher in the intervention group (-1.09 ± 0.96 vs -1.59 ± 0.98; P = .04).

Conclusions: In VLBW infants, provision of a high early dose of parenteral lipid in the first week of age results in less weight loss and lower incidence of EUGR.

Trial Registration: Clinicaltrials.gov: NCT03594474.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.024DOI Listing
January 2021

Association of neonatal inflammatory markers and perinatal stroke subtypes.

Neurology 2020 09 29;95(9):e1163-e1173. Epub 2020 Jul 29.

From the Departments of Pediatrics (A.M., A.N.-A., S.B., K.Y., A.N., A.K.), Clinical Neurosciences (A.M., P.d.J., A.K.), and Community Health Sciences (A.N.-A.), Cumming School of Medicine, University of Calgary, Alberta, Canada.

Objective: To examine the relationship between neonatal inflammatory cytokines and perinatal stroke using a systems biology approach analyzing serum and blood-spot cytokines from 47 patients.

Methods: This was a population-based, controlled cohort study with prospective and retrospective case ascertainment. Participants were recruited through the Alberta Perinatal Stroke Project. Stroke was classified as neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or periventricular venous infarction (PVI). Biosamples were stored blood spots (retrospective) and acute serum (prospective). Controls had comparable gestational and maternal ages. Sixty-five cytokines were measured (Luminex). Hierarchical clustering analysis was performed to create heat maps. The Fisher linear discriminant analysis was used to create projection models to determine discriminatory boundaries between stroke types and controls.

Results: A total of 197 participants were analyzed (27 with NAIS, 8 with APPIS, 12 with PVI, 150 controls). Cytokines were quantifiable with quality control measures satisfied (standards testing, decay analysis). Linear discriminant analysis had high accuracy in using cytokine profiles to separate groups. Profiles in participants with PVI and controls were similar. NAIS separation was accurate (sensitivity 77%, specificity 97%). APPIS mapping was also distinguishable from NAIS (sensitivity 86%, specificity 99%). Classification tree analysis generated similar diagnostic accuracy.

Conclusions: Unique inflammatory biomarker signatures are associated with specific perinatal stroke diseases. Findings support an acquired pathophysiology and suggest the possibility that at-risk pregnancies might be identified to develop prevention strategies.

Classification Of Evidence: This study provides Class III evidence that differences in acute neonatal serum cytokine profiles can discriminate between patients with specific perinatal stroke diseases and controls.
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http://dx.doi.org/10.1212/WNL.0000000000010309DOI Listing
September 2020

Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial.

JAMA 2020 07;324(2):157-167

Department of Pediatrics, Division of Neonatology, University of British Columbia, Vancouver, Canada.

Importance: Maternal docosahexaenoic acid (DHA) supplementation may prevent bronchopulmonary dysplasia, but evidence remains inconclusive.

Objective: To determine whether maternal DHA supplementation during the neonatal period improves bronchopulmonary dysplasia-free survival in breastfed infants born before 29 weeks of gestation.

Design, Setting, And Participants: Superiority, placebo-controlled randomized clinical trial at 16 Canadian neonatal intensive care units (June 2015-April 2018 with last infant follow-up in July 2018). Lactating women who delivered before 29 weeks of gestation were enrolled within 72 hours of delivery. The trial intended to enroll 800 mothers, but was stopped earlier.

Interventions: There were 232 mothers (273 infants) assigned to oral capsules providing 1.2 g/d of DHA from randomization to 36 weeks' postmenstrual age and 229 mothers (255 infants) assigned to placebo capsules.

Main Outcomes And Measures: The primary outcome was bronchopulmonary dysplasia-free survival in infants at 36 weeks' postmenstrual age. There were 22 secondary outcomes, including mortality and bronchopulmonary dysplasia.

Results: Enrollment was stopped early due to concern for harm based on interim data from this trial and from another trial that was published during the course of this study. Among 461 mothers and their 528 infants (mean gestational age, 26.6 weeks [SD, 1.6 weeks]; 253 [47.9%] females), 375 mothers (81.3%) and 523 infants (99.1%) completed the trial. Overall, 147 of 268 infants (54.9%) in the DHA group vs 157 of 255 infants (61.6%) in the placebo group survived without bronchopulmonary dysplasia (absolute difference, -5.0% [95% CI, -11.6% to 2.6%]; relative risk, 0.91 [95% CI, 0.80 to 1.04], P = .18). Mortality occurred in 6.0% of infants in the DHA group vs 10.2% of infants in the placebo group (absolute difference, -3.9% [95% CI, -6.8% to 1.4%]; relative risk, 0.61 [95% CI, 0.33 to 1.13], P = .12). Bronchopulmonary dysplasia occurred in 41.7% of surviving infants in the DHA group vs 31.4% in the placebo group (absolute difference, 11.5% [95% CI, 2.3% to 23.2%]; relative risk, 1.36 [95% CI, 1.07 to 1.73], P = .01). Of 22 prespecified secondary outcomes, 19 were not significantly different.

Conclusions And Relevance: Among breastfed preterm infants born before 29 weeks of gestation, maternal docosahexaenoic acid supplementation during the neonatal period did not significantly improve bronchopulmonary dysplasia-free survival at 36 weeks' postmenstrual age compared with placebo. Study interpretation is limited by early trial termination.

Trial Registration: ClinicalTrials.gov Identifier: NCT02371460.
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http://dx.doi.org/10.1001/jama.2020.8896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361648PMC
July 2020

Haematoma complicating subcutaneous fat necrosis of the newborn: a rare complication following therapeutic hypothermia.

BMJ Case Rep 2020 Jun 11;13(6). Epub 2020 Jun 11.

Pediatrics-Neonatology, University of Calgary, Calgary, Alberta, Canada.

A term, large for gestational age male newborn, was admitted to the neonatal intensive care unit with meconium aspiration syndrome and severe hypoxic-ischaemic encephalopathy. The baby was treated with therapeutic hypothermia using a total body cooling blanket. After 48 hours, the baby developed tender, indurated subcutaneous nodules consistent with subcutaneous fat necrosis (SCFN). The lesions started initially over the back but gradually spread to cover both shoulders, upper arms, chest area and both thighs. On day 19 of life, multiple small nodules on the back softened and coalesced to form one sizeable fluctuant swelling over the thoracolumbar area. Over a few hours, the swelling rapidly progressed to a large, tense mass with sloughing of the gangrenous overlying skin. This unusual complication of SCFN required surgical intervention for evacuation and debridement of the haematoma followed by graft repair of the skin defect.
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http://dx.doi.org/10.1136/bcr-2020-234360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295416PMC
June 2020

Physiological Basis of Neonatal Aerodigestive Difficulties in Chronic Lung Disease.

Clin Perinatol 2020 06 12;47(2):277-299. Epub 2020 Mar 12.

Neonatal Intensive Care Unit, Alberta Health Services, Cumming School of Medicine, Alberta Children's Hospital, 28 Oki Drive Northwest, Calgary, Alberta T3B 6A8, Canada.

In the United States, preterm birth rates have steadily increased since 2014. Despite the recent advances in neonatal-perinatal care, more than 40% of very low-birth-weight infants develop chronic lung disease (CLD) and almost 25% have feeding difficulties resulting in delayed achievement of full oral feeds and longer hospital stay. Establishment of full oral feeds, a major challenge for preterm infants, becomes magnified among those on respiratory support and/or with CLD. The strategies to minimize aerodigestive disorders include supporting nonnutritive sucking, developing infant-directed feeding protocols, sensory oromotor stimulation, and early introduction of oral feeds.
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http://dx.doi.org/10.1016/j.clp.2020.03.001DOI Listing
June 2020

Neonatal coning secondary to hypoxic ischaemic encephalopathy: A case study and literature review.

Paediatr Child Health 2021 Apr-May;26(2):e67-e69. Epub 2019 Nov 25.

Division of Neonatology, Department of Pediatrics, Hospital for Sick Children, School of Medicine, University of Toronto, Toronto, Ontario.

Introduction: Brain herniation is an extremely rare complication of hypoxic ischaemic encephalopathy (HIE) in the neonatal period with only a single report described. We report a 2-day-old term infant with severe HIE, who developed diffuse brain oedema and herniation.

Case Presentation And Description: A term female infant delivered by vacuum, required therapeutic hypothermia for severe encephalopathy. At 36 hours of age, a marked change in neurological status was noted with signs of brainstem involvement. A head Computed Tomography Scan showed uncal and tonsillar herniation.

Conclusion: Vigilance in monitoring neonatal neurological status during therapeutic hypothermia is imperative for early brain herniation detection.
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http://dx.doi.org/10.1093/pch/pxz138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962716PMC
November 2019

Fetal Doppler Assessment in Neonatal Care: Analysis of Fetal Doppler Abnormalities and Neonatal Outcomes.

Neoreviews 2019 10;20(10):e575-e583

Section of Neonatology, Department of Pediatrics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada.

Fetal Doppler ultrasonography provides an effective and noninvasive approach to identify circulatory abnormalities in the maternal-fetal circulation. It is invaluable to assess the hemodynamic status of the fetus under a wide range of physiologic, infectious, and abnormal anatomic conditions. Findings from these studies are often used to make clinical decisions, including whether to proceed with urgent delivery of the fetus. In this review, we focus on key literature describing the main uses of Doppler ultrasonography in neonatal medicine, including how abnormal findings may be implicated in immediate and long-term outcomes. Our review highlights the importance of fetal Doppler examination as an effective intrauterine management strategy, and its full potential is more likely to be realized when considered in context with other available clinical information.
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http://dx.doi.org/10.1542/neo.20-10-e575DOI Listing
October 2019

Respiratory outcomes of late preterm infants of mothers with early and late onset preeclampsia.

J Perinatol 2020 01 24;40(1):39-45. Epub 2019 Sep 24.

Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Objective: To study the effect of early and late onset preeclampsia (EOPE, LOPE, respectively) on outcomes of late preterm infants.

Study Design: Cohort study of late preterm infants admitted to a tertiary care NICU from January 2014-July 2015. Outcomes of late preterm infants of EOPE mothers were compared with the next late preterm infant of a LOPE mother and the next two late preterm infants of normotensive non-PE mothers. Primary outcome comprised use of continuous positive airway pressure, mechanical ventilation and/or surfactant in the 24 h after birth.

Results: Compared to normotensives (n = 131), adjusted odds ratio (AORs) of the primary outcome was higher in the EOPE (n = 64) and LOPE (n = 65) groups but reached statistical significance only in the EOPE group, AORs 12.9, 95% CI 3.5-37 and 2.7, 95% CI 0.95-8.1, respectively.

Conclusions: Compared to late preterm infants of normotensive and LOPE mothers, infants of mothers with EOPE have significantly higher respiratory morbidity.
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http://dx.doi.org/10.1038/s41372-019-0497-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222144PMC
January 2020

Early total enteral feeding in stable preterm infants: a systematic review and meta-analysis.

J Matern Fetal Neonatal Med 2021 May 9;34(9):1479-1486. Epub 2019 Jul 9.

Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Objective: To evaluate safety and feasibility of early total enteral feeding (ETEF) in stable preterm infants.

Study Design: Systematic review and meta-analysis of randomized trials comparing incidence of necrotizing enterocolitis (NEC) and feeding intolerance between ETEF and slow rates of enteral feed advancement.

Results: Four trials involving 393 very low birth weight (VLBW) infants with birth weight >1000-1200 g were included. Meta-analyses did not show statistical difference in risks for NEC (RR 0.87, 95% CI 0.19-3.98) and feeding intolerance (RR 0.78, 95% CI 0.39-1.59). ETEF resulted in lower risk of late-onset sepsis (RR: 0.43, 95% CI: 0.30-0.61). Length of hospital stay was reduced in ETEF (mean difference -1.31 days, 95% CI: -1.54 to -1.07).

Conclusions: ETEF appears to be safe and feasible in stable VLBW infants with birth weight >1000-1200 g. A large randomized trial is needed to confirm benefits.
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http://dx.doi.org/10.1080/14767058.2019.1637848DOI Listing
May 2021

Outcomes of singleton small for gestational age preterm infants exposed to maternal hypertension: a retrospective cohort study.

Pediatr Res 2019 08 13;86(2):269-275. Epub 2019 May 13.

Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Background: Hypertensive disorders of pregnancy (HDP) are a major cause of small for gestational age (SGA). Preterm SGA infants have higher rates of adverse outcomes than appropriate for gestational age infants. However, the outcomes are not well established in the setting of HDP.

Methods: Retrospective population-based study using the Canadian Neonatal Network database from January 1, 2010 to December 31, 2016 of SGA infants <33 weeks gestation. Using multivariable models, we determined the adjusted odds ratios (AORs) with 95% confidence intervals (CI) for mortality, bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage (IVH), severe retinopathy of prematurity, necrotizing enterocolitis, late-onset sepsis, and patent ductus arteriosus (PDA) in infants of HDP mothers and compared them to infants of non-HDP mothers.

Results: Of the 2081 eligible SGA infants, 1317 (63%) were born to HDP mothers and had lower odds of mortality (AOR 0.57, 95% CI 0.39-0.83) and BPD (AOR 0.69, 95% CI 0.53-0.90). Sub-group analysis demonstrated decreased mortality in 26-28 and 29-32 weeks gestation groups, decreased BPD in 29-32 weeks gestation group, and decreased PDA in <26 weeks gestation group.

Conclusion: Preterm SGA infants of HDP mothers have lower odds of mortality and BPD compared to infants of non-HDP mothers.
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http://dx.doi.org/10.1038/s41390-019-0416-6DOI Listing
August 2019

Neonatal transport services, a cross-sectional study.

J Matern Fetal Neonatal Med 2021 Mar 21;34(5):774-779. Epub 2019 May 21.

Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Canada.

To understand the process and challenges facing neonatal transport in Canada and to delineate their composition and working. An online questionnaire was sent to all neonatal transport team directors/coordinators in Canada. The questionnaire covered different aspects of transport and was pilot tested prior to finalization. The responses were anonymous to the investigators. All sixteen neonatal transport teams in Canada surveyed. Fifteen teams responded. Dedicated team as a model was adopted by 12 teams (80%). A combined Neonatal/pediatrics team, where the team could be assembled by either neonatal or pediatrics intensive care staff, adopted by two (13%). Team members were cross-trained in about quarter of the teams (four teams out of 15) with respiratory therapists and registered nurses performing each other's roles. Neonatal Resuscitation Program was mandatory for all teams that responded (15 teams) to become certified as a neonatal transport team member. Nine teams use a central dispatch phone call system. As the first to comprehensively describe the status of neonatal transport in Canada, our study shows that neonatal transport teams have similarities as well as differences. Regionalization and differences in referral practices, geography, provincial laws, and manpower are the main reasons why teams may have their individual variations in policies, protocols, and logistics. Our data can be utilized by health professionals and policy makers to improve neonatal transport logistics within their health care systems resulting in better outcomes of transported neonates.
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http://dx.doi.org/10.1080/14767058.2019.1618823DOI Listing
March 2021

CD-34 and VE-cadherin endothelial progenitor cells in preeclampsia and normotensive pregnancies.

Pregnancy Hypertens 2019 Apr 23;16:42-47. Epub 2019 Feb 23.

Section of Neonatology, Department of Pediatrics, Cumming School of Medicine, University of Calgary, Alberta, Canada. Electronic address:

Objective: The objective of our study was to determine levels of endothelial progenitor cells (EPCs) in preeclampsia and normotensive pregnant women.

Study Design: Prospective cohort study of women with preeclampsia and normotensive pregnancies. EPCs were estimated by flow cytometry. Multiple linear regression was used to assess the association of EPCs with preeclampsia adjusting for maternal age, body mass index (BMI), gestation and ethnicity.

Main Outcome Measure: Levels of EPCs in preeclampsia and normotensive pregnancies, with CD-34 and vascular endothelial (VE)-cadherin as markers of EPCs. VE-cadherin is an endothelial cell adhesion molecule used to delineate endothelial lineage of EPCs.

Results: There were thirty women in the preeclampsia group and thirty-three in the normotensive group. The two groups were similar except for the BMI and blood pressures, which were higher in preeclampsia. On multiple linear regression, EPCs numbers were significantly higher by 29 (95% confidence interval 11.7-46.6, p = 0.001) in preeclampsia compared to the normotensive group. There was significant positive correlation between EPCs and systolic blood pressure in preeclampsia (Spearman correlation coefficient 0.39, p = 0.03).

Conclusion: Although widely used in cardiovascular disease other than preeclampsia, this is the first study using VE-cadherin as a marker of endothelial lineage to define EPCs in preeclampsia. Our results suggest the higher number of EPCs in preeclampsia may be a response of the bone marrow to endothelial injury.
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http://dx.doi.org/10.1016/j.preghy.2019.02.007DOI Listing
April 2019

Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants.

Pediatrics 2019 01 5;143(1). Epub 2018 Dec 5.

Maternal-Infant Care Research Center, Mount Sinai Hospital, Toronto, Ontario, Canada.

Background: Although caffeine use for apnea of prematurity is well studied, the long-term safety and benefit of routine early caffeine administration has not been explored. Our objective was to determine the association between early (within 2 days of birth) versus late caffeine exposure and neurodevelopmental outcomes in preterm infants.

Methods: Infants of <29 weeks' gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network units and then assessed at Canadian Neonatal Follow-up Network centers were studied. Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months' corrected age.

Results: Of 2108 neonates who were eligible, 1545 were in the early-caffeine group and 563 were in the late-caffeine group. Rates of bronchopulmonary dysplasia, patent ductus arteriosus, and severe neurologic injury were lower in the early-caffeine group than in the late-caffeine group. Significant neurodevelopmental impairment (adjusted odds ratio 0.68 [95% confidence interval 0.50-0.94]) and odds of Bayley Scales of Infant and Toddler Development, Third Edition cognitive scores of <85 (adjusted odds ratio 0.67 [95% confidence interval 0.47-0.95]) were lower in the early-caffeine group than in the late-caffeine group. Propensity score-based matched-pair analyses revealed lower odds of cerebral palsy and hearing impairment only.

Conclusions: Early caffeine therapy is associated with better neurodevelopmental outcomes compared with late caffeine therapy in preterm infants born at <29 weeks' gestation.
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http://dx.doi.org/10.1542/peds.2018-1348DOI Listing
January 2019

Dexmedetomidine Use in a Tertiary Care NICU: A Descriptive Study.

Ann Pharmacother 2019 05 3;53(5):464-470. Epub 2018 Dec 3.

2 Department of Peditrics, University of Calgary, Calgary, AB, Canada.

Background: Continuous infusions of dexmedetomidine are increasingly used for sedation in critically ill pediatric patients. Emerging data suggest potential benefits when used for sedation in neonates, including reduced sedative requirements and earlier enteral feeds.

Objective: To describe the use, adverse effects, and signs of withdrawal in a cohort of neonates receiving dexmedetomidine, the majority of whom were receiving concomitant opioids.

Methods: This was a retrospective, descriptive review of 38 neonates receiving dexmedetomidine in a medical surgical neonatal intensive care unit, including data on duration of use, dose, adverse effects, weaning, and signs of withdrawal.

Results: Dexmedetomidine was used for a median of 183 hours, at a median maximum dose of 0.5 µg/kg/h. Premature infants were started on dexmedetomidine at a later chronological age than term infants (41 vs 9 days, P = 0.004). Of 18 patients receiving an opioid infusion at the time of dexmedetomidine initiation, 67% had a dose reduction in opioids by 24 hours. The majority (89%) of neonates had at least 1 potentially related adverse effect during the dexmedetomidine infusion, though no discontinuations were needed as a result. In all, 80% of patients had their dexmedetomidine gradually weaned off, and 71% had at least 1 sign of withdrawal.

Conclusions And Relevance: In this cohort, dexmedetomidine was often used in a postsurgical setting, with concomitant opioids, over prolonged periods. These factors appear to affect and likely confound the rates of adverse effects and withdrawal signs from dexmedetomidine. Clinicians considering the use of dexmedetomidine in a similar population can draw guidance from our data.
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http://dx.doi.org/10.1177/1060028018812089DOI Listing
May 2019

Evolution of empiric vancomycin dosing in a neonatal population.

J Perinatol 2018 12 19;38(12):1702-1707. Epub 2018 Oct 19.

Alberta Health Services, Pharmacy Services, Calgary, AB, Canada.

Background: In 2014, we assessed the effectiveness of our neonatal vancomycin empirical dosing regimen (15-45 mg/kg/day) which led to development of a revised regimen (20-60 mg/kg/day).

Objective: To validate the revised empirical vancomycin dosage regimen in achieving target troughs.

Methods: The primary outcome of this multicenter retrospective before-and-after cohort study was the proportion of neonates in the present cohort achieving trough levels below, at or above target (<10, 10-20 and >20 mg/L). Secondary outcomes included difference between cohorts (historical and present) in mean troughs and proportion of patients achieving target levels.

Results: Out of 118 participants, 63 (53.39%) achieved target troughs, 44 (37.29%) had below target troughs and 11 (9.32%) reached above target levels. Mean trough levels and proportion of patients achieving target levels were higher in the present versus historical cohort (p < 0.01 for all comparisons).

Conclusions: The revised empiric dosing regimen was more effective in achieving target serum trough concentrations.
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http://dx.doi.org/10.1038/s41372-018-0251-3DOI Listing
December 2018

The Impact of Prenatal Diagnosis of Selected Central Nervous System Anomalies for Prenatal Counselling Based on Significant Pregnancy Morbidity and Neonatal Outcomes.

J Obstet Gynaecol Can 2019 Feb 10;41(2):166-173.e1. Epub 2018 Oct 10.

Department of Obstetrics & Gynecology, Cumming School of Medicine, University of Calgary, Calgary, AB; Department of Obstetrics & Gynecology, Saint John Regional Hospital, Horizon Health Network, Saint John, NB. Electronic address:

Background & Objectives: Prenatal screening and diagnostic imaging advances have led to an increased detection of CNS anomalies, including ventriculomegaly/congenital hydrocephalus (HCP), Dandy-Walker malformation (DWM), and myelomeningocele (MMC). Data on pregnancy outcomes and the impact of prenatal diagnosis on neonatal outcomes is limited. Our study aimed to provide data on obstetric and neonatal outcomes following prenatal diagnosis of one of three CNS anomalies.

Methods: A retrospective search of two databases in Alberta, Canada and NICU chart review of cases between 2001 and 2011was completed. Primary outcomes for each group were pregnancy outcome (live birth, stillbirth, and termination) and detection rate. Secondary outcomes were live and total birth prevalence, mode of delivery, GA at delivery, and length of NICU stay for inborn versus outborn patients.

Results: Prenatal detection rates were 91.6% (HCP), 83.4% (DWM), and 92.9 % (MMC). Termination rates were 30.2% (DWM), 34.2% (HCP), and 48.5% (MMC). Median GA (weeks, range) at diagnosis were 22 (17-38), 20 (12-37), and 20.5 (18-34) for HCP, DWM, and MMC, respectively. Rate of Caesarean section for fetal indication was 50.0%, 44.4%, and 42.9% for HCP, DWM, and MMC, respectively. Median NICU length of stay was longer for outborn patients than inborn patients and were as follows: (range) 33.0 (21-38) versus 8.5 (1-49) d (HCP), and 29 (29-57) versus 14 (2-75) d (DWM).

Conclusion: This study provides termination rates, obstetric interventions, and NICU length of stay for prenatally-identified CNS anomalies. Collectively, this study assists prenatal counselling women with a fetus affected by a described CNS anomaly.
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http://dx.doi.org/10.1016/j.jogc.2018.03.130DOI Listing
February 2019

Neonatal outcomes of extremely preterm infants exposed to maternal hypertension and cigarette smoking.

J Perinatol 2018 08 8;38(8):1051-1059. Epub 2018 May 8.

Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Objective: To study the outcomes of extremely preterm infants of hypertensive mothers who smoke.

Study Design: This retrospective cohort study included infants born between 2003 and 2012 at <29 weeks' gestation and admitted to neonatal intensive care units participating in the Canadian Neonatal Network. Infants were divided into four mutually exclusive groups. Infants of hypertensive mothers who smoked; infants of hypertensive, non-smoking mothers; infants of normotensive mothers who smoked; and infants of normotensive, non-smoking mothers. Using infants of normotensive, non-smoking mothers as the reference group, neonatal outcomes were compared between the groups. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariate regression analysis.

Results: Of the 12,307 eligible infants, 172 had hypertensive mothers who smoked, 1689 had hypertensive non-smoking mothers, 1535 had normotensive mothers who smoked, and 8911 had normotensive non-smoking mothers. Compared to infants of normotensive non-smoking mothers, infants of hypertensive mothers, regardless of smoking status, had higher odds of developing bronchopulmonary dysplasia (AORs of smokers 1.62; 95% CI 1.12-2.35 and of non-smokers 1.43; 95% CI 1.24-1.64). There was no difference in the odds of mortality and retinopathy of prematurity stage ≥3 between the groups. Infants of hypertensive, non-smoking mothers had decreased odds of intraventricular hemorrhage >grade 2 and higher odds of necrotizing enterocolitis. There was decreased odds of hypertension if the mother was a smoker (AOR 0.71; 95% CI 0.59-0.85).

Conclusion: Maternal hypertension is associated with increased rates of bronchopulmonary dysplasia, irrespective of smoking status.
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http://dx.doi.org/10.1038/s41372-018-0111-1DOI Listing
August 2018

Neonatal Thyrotoxicosis with Tricuspid Valve Regurgitation and Hydrops in a Preterm Infant Born to a Mother with Graves' Disease.

AJP Rep 2018 Apr 4;8(2):e85-e88. Epub 2018 May 4.

Section of Neonatology, Department of Pediatrics, University of Calgary, Cumming School of Medicine, Alberta, Canada.

Neonatal hyperthyroidism is rare disorder due to the passage of thyroid receptor antibodies (TRBs) from the mother to the fetus. Neonatal thyrotoxicosis can present in several ways and if unrecognized, can be fatal. We present a preterm neonate who developed fetal hydrops and tricuspid regurgitation in utero. The mother had a history of treated Grave's disease. The infant responded to maternal treatment antenatally and postnatal anti-thyroid treatment, with resolution of both the tricuspid regurgitation and hydrops. To our knowledge, this is the first case report of tricuspid regurgitation associated with fetal and neonatal thyrotoxicosis. Our case also highlights the importance of obtaining a detailed and accurate history in a mother with previous Grave's disease, even if treated.
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http://dx.doi.org/10.1055/s-0038-1645879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935506PMC
April 2018

Effectiveness of Injectable Ibuprofen Salts and Indomethacin to Treat Patent Ductus Arteriosus in Preterm Infants: Observational Cohort Study.

Can J Hosp Pharm 2018 Jan-Feb;71(1):22-28. Epub 2018 Mar 7.

, MD, is with the Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, Alberta.

Background: There is no injectable ibuprofen product marketed to treat patent ductus arteriosus (PDA) in newborns in Canada. The authors' institution has used ibuprofen arginine in the past. In the absence of published evidence supporting use of this salt form of ibuprofen for neonatal PDA, a retrospective analysis was undertaken.

Objective: To compare the effectiveness and adverse effects of ibuprofen arginine, ibuprofen tromethamine, and indomethacin in the treatment of PDA.

Methods: This retrospective observational cohort study, for patients admitted between 2009 and 2015, included preterm infants with symptomatic PDA who received at least one dose of injectable indomethacin, ibuprofen tromethamine, or ibuprofen arginine. Three effectiveness end points were analyzed: closure after one course of treatment, repeat medical treatment, and surgical ligation. The secondary end points included acute kidney injury, necrotizing enterocolitis, chronic lung disease, and time to full enteral feeding.

Results: A total of 179 infants were included. There were no differences among groups in terms of closure after one course of treatment (37/54 [69%] with indomethacin, 42/70 [60%] with ibuprofen tromethamine, and 28/55 [51%] with ibuprofen arginine; = 0.21) or surgical ligation (10/54 [19%] with indomethacin, 13/70 [19%] with ibuprofen tromethamine, and 12/55 [22%] with ibuprofen arginine; = 0.88). However, there was a difference regarding use of a repeat course of treatment, ibuprofen arginine having the highest rate (8/54 [15%] with indomethacin, 18/70 [26%] with ibuprofen tromethamine, and 20/55 [36%] with ibuprofen arginine; = 0.04). After adjustment for gestational age, the association between ibuprofen arginine and increased use of a repeat course of treatment remained significant. The groups did not differ with respect to adverse effects.

Conclusion: These results highlight the potential for differences in effectiveness among various salt forms of injectable ibuprofen and indomethacin. Because of the small sample size and retrospective methodology, confirmation of the present results through a larger prospective study is needed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842047PMC
March 2018

Pre-eclampsia and the risk of retinopathy of prematurity in preterm infants with birth weight <1500 g and/or <31 weeks' gestation.

BMJ Open Ophthalmol 2017 19;1(1):e000049. Epub 2017 Jun 19.

Department of Pediatrics, University of Calgary Cumming School of Medicine, Calgary, Canada.

Objective: To evaluate the relationship between pre-eclampsia and development of retinopathy of prematurity (ROP) in infants with birth weight of <1500 g and/or gestation <31 weeks.

Methods: A retrospective cohort study comprising infants born to mothers with pre-eclampsia between January 2007 and June 2010 at a single tertiary care centre. Their ROP outcome was compared with infants born to the next two normotensive mothers with a ±1 week gestational age difference. Pearson χ test was used for categorical variables and Mann-Whitney U test was used for continuous variables. Multivariable regression was used to estimate the OR of ROP with prenatal pre-eclampsia exposure and adjust for confounders.

Results: Of the 97 infants in the pre-eclampsia group, 27 (27%) developed ROP and of the 185 infants in the normotensive group, 50 (27%) developed ROP. On multivariable regression modelling, pre-eclampsia was not a risk factor for the development of ROP (OR 1.4, 95% CI 0.46 to 4.1). Gestational age, intrauterine growth restriction and blood transfusion were significant risk factors for the development of ROP.

Conclusions: In our cohort, pre-eclampsia was not a significant risk factor for the development of ROP. Intrauterine growth restricted infants of pre-eclamptic and normotensive mothers were at higher risk of ROP.
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http://dx.doi.org/10.1136/bmjophth-2016-000049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721629PMC
June 2017

Elective transfers of preterm neonates to regional centres on non-invasive respiratory support is cost effective and increases tertiary care bed capacity.

Acta Paediatr 2018 Jan 25;107(1):52-56. Epub 2017 Sep 25.

Section of Neonatology, Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Aim: Managing capacity at regional facilities caring for sick neonates is increasingly challenging. This study estimated the clinical and economic impact of the elective transfer of stable infants requiring nasal continuous positive airway pressure (NCPAP) from level three to level two neonatal intensive care units (NICUs) within an established clinical network of five NICUs.

Methods: We retrospectively analysed the records of 99 stable infants transferred on NCPAP between two level three NICUs and three level two NICUs in Calgary, Canada, between June 2014 and May 2016.

Results: The median gestational age and weight at birth were 28 weeks and 955 g, and the median corrected gestational age and weight at transfer were 33 weeks and 1597 g, respectively. This resulted in cost savings of $2.65 million Canadian dollars during the two-year study period, and 848 level three NICU days were freed up for potentially sick neonates. There were no adverse events associated with the transfers.

Conclusion: The elective transfer of stable neonates on NCPAP from level three to level two NICUs within an established clinical network led to substantial cost savings, was safe and increased the bed capacity at the two level three NICUs.
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http://dx.doi.org/10.1111/apa.14059DOI Listing
January 2018

Intravenous immunoglobulin in the management of a rare cause of hemolytic disease of the newborn: Anti-SARA antibodies.

J Neonatal Perinatal Med 2017 ;10(3):329-332

Section of Neonatology, University of Calgary, Calgary, AB, Canada.

Hemolytic disease of newborn (HDN) is a condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta and attack the fetal red blood cells. HDN can occur due to Rh and ABO incompatibilities between the mother and the fetus as well as due to other allo-immune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNS (M, N, S, and s) systems. Role of intravenous immunoglobulin in management of HDN is not clear.SARA red blood cell antigen, first discovered in 1990 is a low frequency antigen. We report, a multiparous female whose pregnancy was complicated by HDN due to anti-SARA antibodies requiring both exchange transfusion and intravenous immunoglobulin. The response was sustained after intravenous immunoglobulin (IVIG) rather than after exchange transfusion.
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http://dx.doi.org/10.3233/NPM-16131DOI Listing
January 2018
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