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Fulltext Subcutaneous fat necrosis and hypercalcaemia following therapeutic hypothermia in an infant with birth asphyxia

Reyhanah Mohd Rashid, Wan Nurulhuda, Synn, Joyce Hong Soo, Wu, Loo Ling, Cheah, Fook Choe

Malaysian Journal of Paediatrics and Child Health, 2016;22(101):0-0.
MyJurnal

Subcutaneous fat necrosis is a recognised complication of hypothermia. There appears to be a resurgence in this condition when therapeutic hypothermia emerges as a standard of care for asphyxiated infants. The TOBY trial reported an incidence of 0.1% for 1239 infants cooled.(Copied from article)
Cephalhematoma infected by Escherichia coli presenting as an extensive scalp abscess

Wong CS, Cheah FC

J Pediatr Surg, 2012 Dec;47(12):2336-40.
PMID: 23217901 DOI: 10.1016/j.jpedsurg.2012.09.029

Cephalhematoma is normally a self-limiting condition affecting 1%-2% of live births, especially following instrumental forceps delivery. The sub-periosteal bleed is characteristically limited by the cranial sutures. Although benign in most instances, this condition may, in a small proportion of cases, be complicated by hyperbilirubinemia or scalp infection. We describe a case of cephalhematoma in a newborn infant infected with Escherichia coli resulting in an extensive deep seated scalp abscess. The infection was also systemic causing E. coli septicemia and initial assessment assumed local extension including bone and meningeal to cause skull osteomyelitis and meningitis respectively. Further investigations and multiple-modality imaging with ultrasound, CT scan and bone scintigraphy outlined the involvement as limited to the scalp, resulting in a shorter antibiotic treatment period and earlier discharge from hospital. The infant recovered well with parenteral antibiotics, saucerization of the abscess and a later skin grafting procedure.
Practical Implementation of Quality Nutritional Care to Preterm Infants in Developing Countries

Cheah FC, Tan TL

World Rev Nutr Diet, 2021;122:340-356.
PMID: 34352769 DOI: 10.1159/000514761
Favism and glucose-6-phosphate dehydrogenase deficiency

Winterbourn CC, Cheah FC

N Engl J Med, 2018 03 15;378(11):1067-8.
PMID: 29542310 DOI: 10.1056/NEJMc1801271

Comment on: Luzzatto L, Arese P. Favism and Glucose-6-Phosphate Dehydrogenase Deficiency.
N Engl J Med. 2018 Jan 4;378(1):60-71. Review. PubMed PMID: 29298156.
Thromboembolism and anticoagulation management in the preterm infant

Rajagopal R, Cheah FC, Monagle P

Semin Fetal Neonatal Med, 2016 Feb;21(1):50-6.
PMID: 26553525 DOI: 10.1016/j.siny.2015.10.005

The incidence of preterm thromboembolism has been increasing due to advances in diagnostic imaging which allow better detection of thrombi in sick preterm infants. At the same time, improvement in neonatal intensive care unit supportive care has increased the number of surviving and living preterm infants with thromboembolic risk factors. Disruption in the fine balance of hemostasis with potential risk factors, specifically septicemia and indwelling catheters, increase the occurrence of thromboembolic events. Treatment strategies in preterm infants are challenging due to limited data.
Fulltext Editorial: Research Model Innovations in Advancing Neonatal Care

Cheah FC, Tan GC, Shi Y

Front Pediatr, 2021;9:711409.
PMID: 34222156 DOI: 10.3389/fped.2021.711409
Fulltext The expectant management of a rare neonatal disease: transient neonatal myasthenia gravis

Masra F, Ishak S, Cheah FC

Turk J Pediatr, 2023;65(2):321-325.
PMID: 37114697 DOI: 10.24953/turkjped.2022.717

BACKGROUND: Transient neonatal myasthenia gravis (TNMG) is an acquired disease which occurs in 10 to 20% of infants born to a mother with myasthenia gravis. Even though it is a self-limiting disorder, it may potentially be life-threatening if prompt diagnosis is not made, and expedient supportive respiratory management is not initiated when required.
CASE: Here we describe three infants with TNMG. Two of them developed symptoms of TNMG within 24 hours of life, but one developed symptoms at 43 hours of life. One of the patients had an atypical form of TNMG with contracture and hypotonia. The other two infants survived a typical form of TNMG with hypotonia and poor sucking. All cases resolved spontaneously by one to two weeks of life with conservative management.
CONCLUSIONS: Infants born to mothers with myasthenia gravis need to be monitored closely for symptoms of TNMG for the first 48 to 72 hours of life. However, the majority of infants with TNMG traverse a benign course and resolve spontaneously with expectant care.
Fulltext Simulation-Based Education in the Training of Newborn Care Providers-A Malaysian Perspective

Pong KM, Teo JT, Cheah FC

Front Pediatr, 2021;9:619035.
PMID: 33643974 DOI: 10.3389/fped.2021.619035

Simulation-based education (SBE) is increasingly used as an education tool to improve learning for healthcare providers. In newborn care practice, SBE is used in the Neonatal Resuscitation Program (NRP) and training in procedural skills. The NRP is a mandatory course in Malaysia for all house officers (interns) and medical officers (residents) during their pediatric rotation. Almost 30,000 of NRP providers have been trained over the last 5 years. The recent establishment of the Allied Healthcare Center of Excellence (AHCoE), an organization dedicated to promoting SBE, and Malaysian Society for Simulation in Healthcare (MaSSH) aims to enhance the integration of SBE into the healthcare training curriculum and set up a local healthcare simulation educator training program. Our experience in implementing SBE necessitated that we made several important choices. As there was no strong evidence to favor high-fidelity over low-fidelity simulation, and because simulation centers can be very costly to set up with limited resources, we chose SBE mainly in the form of low-fidelity and in situ simulation. We also identified an important developmental goal to train Malaysian instructors on structured debriefing, a critical activity for learning in SBE. Currently, debriefing is often carried out in our centers at an ad hoc basis because of time limitation and the lack of personnel trained. Finally, we aim to implement SBE further in Malaysia, with two axes: (1) the credentialing and recertification of physicians and nurses, and (2) the education of lay caregivers of high-risk infants before discharge from the neonatal intensive care unit.
Glucose-6-phosphate dehydrogenase (G6PD)-deficient infants: Enzyme activity and gene variants as risk factors for phototherapy in the first week of life

Wong FL, Ithnin A, Othman A, Cheah FC

J Paediatr Child Health, 2017 Jul;53(7):705-710.
PMID: 28376293 DOI: 10.1111/jpc.13509

AIM: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a recognised cause of severe neonatal hyperbilirubinaemia, and identifying which infants are at risk could optimise care and resources. In this study, we determined if G6PD enzyme activity (EA) and certain gene variants were associated with neonatal hyperbilirubinaemia requiring phototherapy during the first week after birth.
METHODS: Newborn infants with G6PD deficiency and a group with normal results obtained by the fluorescent spot test were selected for analyses of G6PD EA and the 10 commonly encountered G6PD mutations in this region, relating these with whether the infants required phototherapy before discharge from the hospital in the first week.
RESULTS: A total of 222 infants with mean gestation and birth weight of 38.3 ± 1.8 weeks and 3.02 ± 0.48 kg, respectively, were enrolled. Of these, n = 121 were deficient with EA ≤6.76 U/g Hb, and approximately half (43%) received phototherapy in the first week after birth. The mean EA level was 3.7 U/g Hb. The EA had good accuracy in predicting phototherapy use, with area under the receiver-operating-characteristic curve of 0.81 ± 0.05. Infants on phototherapy more commonly displayed World Health Organization Class II mutations (<10% residual EA). Logistic regression analysis showed that deficiency in EA and mutation at c.1388G>A (adjusted odds ratio, 1.5 and 5.7; 95% confidence interval: 1.31-1.76 and 1.30-25.0, respectively) were independent risk factors for phototherapy.
CONCLUSION: Low G6PD EA (<6.76 U/g Hb) and the G6PD gene variant, c.1388G>A, are risk factors for the need of phototherapy in newborn infants during the first week after birth.
Study site: Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Fulltext Nutritional practices and growth of preterm infants in two neonatal units in the UK and Malaysia: a prospective exploratory study

Abdul Hamid H, Szatkowski L, Budge H, Cheah FC, Ojha S

BMJ Paediatr Open, 2021;5(1):e001153.
PMID: 34514178 DOI: 10.1136/bmjpo-2021-001153

Objective: To explore differences in nutritional practices and growth outcomes among preterm infants in neonatal units in Malaysia and the UK.
Design: Prospective exploratory study of infants born at <34 weeks gestational age (GA).
Setting: Two neonatal units, one in Malaysia and one in the UK (May 2019 to March 2020).
Methods: Data collected from birth until discharge and compared between units.
Results: From 100 infants included, median GA (IQR) was 31 (30-33) and mean±SD birth weight was 1549±444 g. There were more small-for-gestational age infants in Malaysian unit: 12/50 (24%) vs UK: 3/50 (6%), p=0.012 and more morbidities. More Malaysian infants received breast milk (Malaysia: 49 (98%) vs UK: 38 (76%), p=0.001), fortified breast milk (Malaysia: 43 (86%) vs UK: 13 (26%), p<0.001) and exclusive breast milk at discharge (Malaysia: 26 (52%) vs UK: 16 (32%), p=0.043). There was higher parenteral nutrition use among Malaysian infants (40/50 (80%)) vs UK (19/50 (38%)) (p<0.001) with higher protein intake (mean±SD Malaysia: 3.0±0.5 vs UK: 2.7±0.6 g/kg/d, p=0.004) in weeks 1-4 and smaller cumulative protein deficits (mean±SD Malaysia: 11.4±6.1 vs UK: 15.4±8.0 g/kg, p=0.006). There were no significant differences in short-term growth between units and more than half of the infants in both units had ≥1.28 changes in weight-for-age Z-score at discharge (p=0.841).
Conclusions: An exploratory comparison of practices showed differences in patient characteristics and nutritional practices which impacted growth. Future studies with larger sample sizes and detailed analysis of maternal characteristics and infants' outcomes are needed for improving care of preterm infants in all settings.
Insulin-like growth factor-1 receptor expression in the placentae of diabetic and normal pregnancies

Hayati AR, Cheah FC, Tan AE, Tan GC

Early Hum Dev, 2007 Jan;83(1):41-6.
PMID: 16750336 DOI: 10.1016/j.earlhumdev.2006.04.002

BACKGROUND: Septal hypertrophic cardiomyopathy (sHCM) is a characteristic anomaly of the infant of diabetic mother (IDM). Insulin-like growth factor-1 (IGF-1) has been identified as a mediator of tissue overgrowth and we have previously shown that maternal IGF-1 levels were significantly elevated among neonates with asymmetrical sHCM. IGF-1 does not cross the placenta; it exerts physiologic action through binding to the IGF-1 receptor (IGF-1R). Localisation and expression of IGF-1R in term diabetic pregnancies are largely unclear. We have studied IGF-1R in the placentae of diabetic and normal pregnancies and this receptor expression in association with neonates with sHCM.
METHODS: IGF-1R localization and expression in the placentae of six diabetic pregnancies associated with neonatal sHCM were compared with six each of randomly selected diabetic and normal pregnancies without neonatal sHCM by immunohistochemistry. The staining for IGF-1R in the deciduas, cytotrophoblasts, syncytiotrophoblasts and villous endothelium for these 18 samples were assessed and scored by two pathologists who were blinded to the respective diagnoses.
RESULTS: Placental IGF-1R staining was negative in the villous endothelium for all three groups. IGF-1R staining was present in deciduas, cytotrophoblasts and syncytiotrophoblasts but the staining was weaker in the entire group of infants with sHCM compared to those without sHCM.
CONCLUSIONS: IGF-1R is localized in all cell types of the placenta except in villous endothelium. Weaker placental IGF-1R staining in the placentae of diabetic pregnancies associated with sHCM suggests reduced expression of IGF-1R. This may be a down-regulatory response to elevated maternal IGF with neonatal sHCM outcome.
Fulltext Increased basal oxidation of peroxiredoxin 2 and limited peroxiredoxin recycling in glucose-6-phosphate dehydrogenase-deficient erythrocytes from newborn infants

Cheah FC, Peskin AV, Wong FL, Ithnin A, Othman A, Winterbourn CC

FASEB J, 2014 Jul;28(7):3205-10.
PMID: 24636884 DOI: 10.1096/fj.14-250050

Erythrocytes require glucose-6-phosphate dehydrogenase (G6PD) to generate NADPH and protect themselves against hemolytic anemia induced by oxidative stress. Peroxiredoxin 2 (Prx2) is a major antioxidant enzyme that requires NADPH to recycle its oxidized (disulfide-bonded) form. Our aims were to determine whether Prx2 is more highly oxidized in G6PD-deficient erythrocytes and whether these cells are able to recycle oxidized Prx2 after oxidant challenge. Blood was obtained from 61 Malaysian neonates with G6PD deficiency (average 33% normal activity) and 86 controls. Prx2 redox state was analyzed by Western blotting under nonreducing conditions. Prx2 in freshly isolated blood was predominantly reduced in both groups, but the median level of oxidation was significantly higher (8 vs 3%) and the range greater for the G6PD-deficient population. When treated with reagent H2O2, the G6PD-deficient erythrocytes were severely compromised in their ability to recycle oxidized Prx2, with only 27 or 4% reduction after 1 h treatment with 0.1 or 1 mM H2O2 respectively, compared with >97% reduction in control erythrocytes. The accumulation of oxidized Prx2 in oxidatively stressed erythrocytes with common G6PD variants suggests that impaired antioxidant activity of Prx2 could contribute to the hemolysis and other complications associated with the condition.-Cheah, F.-C., Peskin, A. V., Wong, F.-L., Ithnin, A., Othman, A., Winterbourn, C. C. Increased basal oxidation of peroxiredoxin 2 and limited peroxiredoxin recycling in glucose-6-phosphate dehydrogenase deficient erythrocytes from newborn infants.
Bacteria in expressed breastmilk from mothers of premature infants and maternal hygienic status

Dahaban NM, Romli MF, Roslan NR, Kong SS, Cheah FC

Breastfeed Med, 2013 Aug;8(4):422-3.
PMID: 23398139 DOI: 10.1089/bfm.2012.0109
Comparison of serum cardiac troponin T and creatine kinase MB isoenzyme mass concentrations in asphyxiated term infants during the first 48 h of life

Boo NY, Hafidz H, Nawawi HM, Cheah FC, Fadzil YJ, Abdul-Aziz BB, et al.

J Paediatr Child Health, 2005 Jul;41(7):331-7.
PMID: 16014136

This prospective study aimed to compare serum creatine kinase MB isoenzyme (CK-MB) mass concentrations and cardiac troponin T (cTnT) concentrations during the first 48 h of life in asphyxiated term infants.
Fulltext CRISPR Gene-Editing Models Geared Toward Therapy for Hereditary and Developmental Neurological Disorders

Wong PK, Cheah FC, Syafruddin SE, Mohtar MA, Azmi N, Ng PY, et al.

Front Pediatr, 2021;9:592571.
PMID: 33791256 DOI: 10.3389/fped.2021.592571

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down syndrome. We also discuss how CRISPR can be used to generate research models to examine the effects of genetic variation and caffeine therapy on the developing brain. Several drawbacks of CRISPR may preclude its use at the clinics, particularly the vulnerability of neuronal cells to the adverse effect of gene editing, and the inefficiency of CRISPR delivery into the brain. In concluding the review, we offer some suggestions for enhancing the gene-editing efficacy of CRISPR and how it may be morphed into safe and effective therapy for HNDs and other brain disorders.
Intrauterine Gardnerella vaginalis Infection Results in Fetal Growth Restriction and Alveolar Septal Hypertrophy in a Rabbit Model

Cheah FC, Lai CH, Tan GC, Swaminathan A, Wong KK, Wong YP, et al.

Front Pediatr, 2020;8:593802.
PMID: 33553066 DOI: 10.3389/fped.2020.593802

Background:Gardnerella vaginalis (GV) is most frequently associated with bacterial vaginosis and is the second most common etiology causing intrauterine infection after Ureaplasma urealyticum. Intrauterine GV infection adversely affects pregnancy outcomes, resulting in preterm birth, fetal growth restriction, and neonatal pneumonia. The knowledge of how GV exerts its effects is limited. We developed an in vivo animal model to study its effects on fetal development. Materials and Methods: A survival mini-laparotomy was conducted on New Zealand rabbits on gestational day 21 (28 weeks of human pregnancy). In each dam, fetuses in the right uterine horn received intra-amniotic 0.5 × 102 colony-forming units of GV injections each, while their littermate controls in the left horn received sterile saline injections. A second laparotomy was performed seven days later. Assessment of the fetal pups, histopathology of the placenta and histomorphometric examination of the fetal lung tissues was done. Results: Three dams with a combined total of 12 fetuses were exposed to intra-amniotic GV, and 9 fetuses were unexposed. The weights of fetuses, placenta, and fetal lung were significantly lower in the GV group than the saline-inoculated control group [mean gross weight, GV (19.8 ± 3.8 g) vs. control (27.9 ± 1.7 g), p < 0.001; mean placenta weight, GV (5.5 ± 1.0 g) vs. control (6.5 ± 0.7 g), p = 0.027; mean fetal lung weight, GV (0.59 ± 0.11 g) vs. control (0.91 ± 0.08 g), p = 0.002. There was a two-fold increase in the multinucleated syncytiotrophoblasts in the placenta of the GV group than their littermate controls (82.9 ± 14.9 vs. 41.6 ± 13.4, p < 0.001). The mean alveolar septae of GV fetuses was significantly thicker than the control (14.8 ± 2.8 μm vs. 12.4 ± 3.8 μm, p = 0.007). Correspondingly, the proliferative index in the interalveolar septum was 1.8-fold higher in the GV group than controls (24.9 ± 6.6% vs. 14.2 ± 2.9%, p = 0.011). The number of alveoli and alveolar surface area did not vary between groups. Discussion: Low-dose intra-amniotic GV injection induces fetal growth restriction, increased placental multinucleated syncytiotrophoblasts and fetal lung re-modeling characterized by alveolar septal hypertrophy with cellular proliferative changes. Conclusion: This intra-amniotic model could be utilized in future studies to elucidate the acute and chronic effects of GV intrauterine infections.
Nutritional therapies in the neonatal intensive care unit and post-natal growth outcomes of preterm very low birthweight Asian infants

Lee LY, Lee J, Niduvaje K, Seah SS, Atmawidjaja RW, Cheah FC

J Paediatr Child Health, 2020 Mar;56(3):400-407.
PMID: 31618507 DOI: 10.1111/jpc.14634

AIM: A collaborative study was conducted between two Southeast Asian university hospitals to compare the nutritional intervention and growth outcomes and evaluate the extent of post-natal growth faltering (PNGF) among very low birthweight (VLBW) infants.
METHODS: Data of all infants admitted during the 2011-2012 period to the two hospitals at Singapore (SG) and Malaysia (MY) were pooled and analysed.
RESULTS: Of the 236 infants, SG infants received lower total protein and energy intake than MY infants (2.69 vs. 3.54 g/kg/day and 92.4 vs. 128.9 kcal/kg/day respectively; P -2 SDS (55 vs. 16%; P = 0.001). The greater use of a diuretic in SG to treat haemodynamically significant patent ductus arteriosus (hsPDA) may have contributed to the higher PNGF rate. Mean growth velocity of at least 15 g/kg/day was attained by VLBW infants only from Day 14 and by ELBW infants only from Day 28 post-natally. Overall, severe PNGF rates (z-score change >-2 SDS at 36 weeks' corrected age) were 28.8 and 36.5% for VLBW and ELBW infants, respectively.
CONCLUSIONS: Being very preterm, ELBW with hsPDA and receiving insufficient protein and energy were risk factors for severe PNGF. Increasing protein and energy content, augmenting fortification of breast milk and concentrating feed volumes, especially if there is an hsPDA, may curb severe PNGF among these infants.
Umbilical artery resistance index in diabetic pregnancies: the associations with fetal outcome and neonatal septal hypertrophic cardiomyopathy

Tan AE, Norizah WM, Rahman HA, Aziz BA, Cheah FC

J Obstet Gynaecol Res, 2005 Aug;31(4):296-301.
PMID: 16018775 DOI: 10.1111/j.1447-0756.2005.00291.x

Aim: To determine the incidence of an abnormal umbilical artery resistance index (UARI) in diabetic pregnancies and the relation to fetal outcome and the development of neonatal septal hypertrophic cardiomyopathy.

Methods: A case-control study with subjects comprising 50 randomly selected diabetic mothers and a matched control group of 50 non-diabetic pregnancies. Doppler studies of the UARI were carried out at least once per week, beginning from 36 weeks' gestation for both groups. Within 48 h post delivery, echocardiograms were carried out on the newborn infants to identify those with hypertrophic cardiomyopathy, particularly asymmetrical septal hypertrophy.

Results: The numbers of patients with abnormal UARI were similar in both the diabetic and control groups. A higher proportion of operative deliveries for intrapartum fetal distress was seen in patients with an abnormal UARI in the diabetic group. However, the groups did not differ in the numbers of infants who were small for gestational age, who had low Apgar scores or umbilical artery acidosis, and who required admission to the special care nursery. Six infants of diabetic mothers (12%) had septal hypertrophy, but none of these were associated with abnormal antenatal UARI.

Conclusion: Diabetic pregnancy is not associated with a significantly higher incidence of abnormal UARI on Doppler study than non-diabetic pregnancy. UARI is not a useful single indicator by which to predict subsequent fetal outcome or the development of neonatal septal hypertrophic cardiomyopathy in diabetic pregnancies.
Fulltext Maternal and umbilical cord blood polymorphonuclear leukocytes showed moderate oxidative burst at phagocytosis of Gardnerella vaginalis

Swaminathan A, Abd Aziz NH, Ayub NA, Wong KK, Cheah FC

BMC Res Notes, 2021 Nov 22;14(1):420.
PMID: 34809696 DOI: 10.1186/s13104-021-05842-y

OBJECTIVE: Pregnant women with bacterial vaginosis due to Gardnerella vaginalis (GV) infection presents with a wide-ranging disease symptomatology. We speculate this may be due to interaction that varies between host immune response and the pathogen. We studied the oxidative burst in polymorphonuclear leukocytes (PMNL)s from maternal blood (MB) and cord blood (CB) upon phagocytosis of GV and compared against E. coli and Group B Streptococcus (GBS).
RESULTS: The PHAGOBURST™ assay detects fluorescence from oxidized dihydrorhodamine during oxidative burst. The average percentage of PMNL showing oxidative burst was almost two-fold greater with GBS (99.5%) and E. coli (98.2%) than GV (56.9%) (p
Recommended Nutrient Intake Levels for Preterm Infants

Koletzko B, Wieczorek S, Cheah FC, Domellöf M, van Goudoever JB, Poindexter BB, et al.

World Rev Nutr Diet, 2021;122:191-197.
PMID: 34352778 DOI: 10.1159/000514772

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