Clinical and neurodevelopmental outcome of newborns with ...scripties.umcg.eldoc.ub.rug.nl/.../root/geneeskunde/2017/WoudaE/WoudaE.pdf · Introductie: Icterus neonatorum is een van

REPORT RESEARCH CLERKSHIP

Clinical and neurodevelopmental outcome of newborns with excessively high levels of serum bilirubin in a marginalized population along the Thai-Myanmar border: a matched case-control study

Eva Wouda [email protected], s1965085

Report Research Clerkship – Eva Wouda, S1965085 Abstract 28 mei. 17

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Abstract English Introduction: Neonatal hyperbilirubinemia (NH) is the most common condition that requires medical attention in newborns. In some infants serum bilirubin (SBR) levels rise excessively and cause acute bilirubin encephalopathy (ABE) leading to death or lifelong neurological impairment. This study aimed to describe the clinical and neurodevelopmental outcome in infants with NH born in a limited-resource setting along the Thai-Myanmar border, without immediate access to exchange transfusion, but with phototherapy facilities. Methods: The study consisted of a description of 132 cases; neonates > 28 weeks of gestational age hospitalized between 2009 and 2014 who had two consecutive high SBR measurements that would justify exchange transfusion, or a rapid rise in SBR with neurological signs. Additionally, follow-up information of 39 two to eight year-old survivors was compared to 39 matched controls with no to moderately raised SBR levels. Neurodevelopmental outcome was evaluated with the Griffiths Mental Development Scale (GMDS) and expressed as centile. Results: Neonatal mortality among cases was 11%, all neonatal deaths occurred in ABE cases. At follow-up three cases (7.7%) showed severe clinical and neurological impairment, with untestable GMDS-scores. Overall, cases had significantly poorer neurodevelopmental scores on ‘Hearing and Language’ and ‘Practical Reasoning’ subscales and poorer summarizing scores (Median Percentile 10 (IQR <1 – 42) compared to Median Percentile 30.5 (IQR 4 - 67); p=0.013) Conclusion: In this setting with constrained exchange transfusion possibilities, 89% of infants with excessively high SBR levels survive the neonatal period. Survivors have an increased risk of neurodevelopmental delay compared to matched controls who had no to moderately raised SBR levels. Overall, GMDS-scores were low in this marginalized population where stunting prevalence is high and pre-school activities rarely available. Systematic follow-up of cases and attention for prevention of confounding factors might decrease the overall risk of neurodevelopmental delay.

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Nederlands Introductie: Icterus neonatorum is een van de meest voorkomende zorgbehoevende aandoeningen in de neonaat. Vaak gaat het om een goedaardig geelzien, maar in sommige gevallen stijgt de serumbilirubine waarde zodanig dat het tot neurotoxiciteit leidt; acuut (Acute Bilirubin Encephalopathy, ABE), dan wel chronisch (kernicterus) met levenslange beperking. Het doel van de studie is het beschrijven van de lange termijn gevolgen van ernstige hyperbilirubinemie bij kinderen behandeld in klinieken voor migranten en vluchtelingen op de Thai-Burmese grens, waar fototherapie wel, maar wisseltransfusie niet (direct) voorhanden is. Methoden: De studie bestaat uit een beschrijving van 132 cases, neonaten van > 28 weken zwangerschapsduur, opgenomen tussen 2009 en 2014 met zeer hoge serumbilirubine waarden (SBR) die voor wisseltransfusie in aanmerking zouden komen. Daarnaast werd eenmalig follow-up onderzoek van 39 twee tot acht jaar oude cases vergeleken met 39 controle-patiënten die geen tot matig-verhoogde serumbilirubine waarden hadden. De neuro-ontwikkeling werd getest middels de Griffiths Mental Development Scale (GMDS) scores. Resultaten: Er was een neonatale mortaliteit van 10.7%, bij alle overlijdens was ABE gerapporteerd. Bij follow-up hadden drie cases (7,7%) een ernstige neurologische beperking, en extreem lage GMDS-scores. Over het geheel waren cases waren achter in de ontwikkeling in vergelijking met controles op het gebied van ‘Hearing and Language’ en ‘Practical Reasoning’ en wat betreft samenvattende scores (Mediane Percentielscore 10 (IQR <1 – 42) tegenover Mediane Percentielscore 30,5 (IQR 4 - 67); p=0,013). Conclusie: In deze setting, met beperkte toegang tot wisseltransfusie, overleeft 89% van de neonaten met zeer ernstige hyperbilirubinemie de acute periode. Cases waren achter in de ontwikkeling vergeleken met controles die geen tot matig-verhoogde bilirubinewaarden hadden. In totaal zijn de GMDS-scores laag in deze gemarginaliseerde populatie met hoge prevalentie van groeiachterstanden en nauwelijks voorschoolse activiteiten voorhanden. Systematische follow-up van cases en aandacht voor preventie van co-factoren zou het risico op ontwikkelingsachterstand kunnen verkleinen.

Report Research Clerkship – Eva Wouda, S1965085 Table of contents 28 mei. 17

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Table of contents

Abstract ..................................................................................................................................................................................................... 2

Background ............................................................................................................................................................................................... 5

Research question ..................................................................................................................................................................................... 7

Methods..................................................................................................................................................................................................... 8

Study design ......................................................................................................................................................................................... 8

Participants .......................................................................................................................................................................................... 8

Data sources ......................................................................................................................................................................................... 8

Case selection ...................................................................................................................................................................................... 9

Variables .............................................................................................................................................................................................. 9

Bias .................................................................................................................................................................................................... 11

Statistical methods ............................................................................................................................................................................. 11

Results ..................................................................................................................................................................................................... 12

Neonatal period .................................................................................................................................................................................. 12

Long term outcome ............................................................................................................................................................................ 17

Discussion ............................................................................................................................................................................................... 19

Acknowledgements ................................................................................................................................................................................. 22

Literature ................................................................................................................................................................................................. 23

Appendices .............................................................................................................................................................................................. 25

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Background Neonatal jaundice Jaundice, the yellow discolouration of eyes and skin is caused by the accumulation of bilirubin. Jaundice in the neonate, or neonatal hyperbilirubinemia (NH), is usually caused by unconjugated hyperbilirubinemia. It occurs in 60% to 80% of all neonates worldwide and is usually benign. [1], [2] Physiologic factors that cause unconjugated NH in the neonate are (i) immaturity of the bilirubin metabolism process (including a lower activity of the enzyme that metabolises bilirubin in the liver; uridine diphosphogluconurate glucuronosyltransferase (UGT)), (ii) shortened life span of red blood cells and increased turnover, and (iii) an increase in the entero-hepatic circulation of bilirubin. The so-called physiologic jaundice presents after 24 to 72 hours of life and total serum bilirubin (SBR) levels should not exceed 13 mg/dl (222 µmol/L) within the first 72 hours of life and the fraction of conjugated bilirubin should not exceed 50%. [2], [3] Causative mechanisms of pathologic unconjugated NH are blood group incompatibilities (ABO or Rh factor), birth trauma, polycythaemia and blood anomalies such as glucose-6-phosphate-dehydrogenase (G6PD) deficiency. Preterm neonates are susceptible to pathologic jaundice as the physiologic factors are prominent. Additionally, comorbid sepsis, certain agents in breast milk yet to be defined (‘breast milk jaundice’) and maternal diabetes are increasing the risk of developing pathologic NH. [4] Treatment Phototherapy is the keystone of the treatment of NH and represents a cheap, effective and safe way to reduce unconjugated bilirubin levels. When a faster removal of large amounts of bilirubin from the blood is necessary, exchange transfusion (ET) can be performed. It is the only alternative in the treatment of NH and should be used as a last resource. Although it is effective, reducing serum bilirubin levels by approximately 50 percent of the starting level, serious adverse events such as sepsis, electrolyte imbalances, necrotizing enterocolitis and procedure-related death need to be taken into account. [2], [5]–[7] Most jaundice-related research until now included neonates treated following the American Academy of Pediatrics (AAP) guideline for neonates over 35 weeks of gestational age in which SBR levels higher than 25 or 30 mg/dL (428 or 513 µmol/L) are considered to be extreme or hazardous respectively. [8], [9] In the UK, a guideline was designed by the National Institute for Health and Clinical Excellence (NICE) with dynamic treatment thresholds based on age of gestation ranging from 23 to >38 weeks and age of the neonate from birth to 14 days of life (Appendix I). [2], [3] Outcomes after using these dynamic treatment thresholds remain unknown. Moreover, little is known about the course and outcome of hyperbilirubinemia starting in newborns less than 72 hours of age. [10]–[12] Bilirubin toxicity Normally the lipid-soluble unconjugated bilirubin binds to albumin in the plasma. In the situation of pathologic jaundice high amounts of unconjugated bilirubin lead to increased amounts of neurotoxic unbound bilirubin, that can pass the blood brain barrier. In the acute phase this can cause ‘Acute Bilirubin Encephalopathy’ (ABE). Symptoms range from mild and reversible (sleepiness, decreased tone, abnormal cry), to severe (irritability, lethargy, convulsions, opisthotonus, paralysis of the upward gaze and apnoea) with increased risk of permanent damage. [13]–[16]

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Kernicterus, or chronic bilirubin encephalopathy, was named after the yellow staining of the basal ganglia found in autopsy of neonates that died from severe hyperbilirubinemia. [16]–[18] Classic kernicterus is characterized by a triad of symptoms including hearing loss or deafness, neuromotor symptoms as dystonia, hypertonia and athetosis, impaired eye movement (paresis of upward gaze) and/or enamel dysplasia of the teeth. [18] Diminished IQ, speech or language delay, attention deficit/hyperactivity disorder (ADHD) and autism have been researched as subtle disabilities following NH, but more carefully designed research is needed to disentangle the role of hyperbilirubinemia and important confounding factors in neonates at risk of subtle neurodevelopmental impairment. [19]–[21] Predictors of bilirubin toxicity are high SBR levels, age and gestational age, presence of haemolyis and sepsis, and disorders of bilirubin binding to albumin. These factors and their interactions need to be researched further to get a better insight in the onset and progress of ABE and kernicterus. [7], [17], [21]–[29]

Kernicterus as public health concern There is lack of information on the global incidence and prevalence of NH and kernicterus. The best approach to these numbers was published by Bhutani et al. [30], who based the prevalence on national risks of underlying pathology of NH worldwide. Prevalence of severe NH, related mortality and kernicterus were estimated at 350/100,000, at 85/100,000 and at 56/100,000 live births respectively. Low- and middle income countries bear the highest burden; two third of deaths related to excessive NH occurred in Sub-Saharan Africa and South Asia. [30]–[35] Infants who survived the neonatal period after being exposed to extreme NH had a 80 to 97% risk of abnormal neurodevelopment at long term follow-up. [27], [30], [33], [36] Worldwide, Rhesus disease is generally mentioned as the most important cause of NH [30]; but the incidence is low among Asians. [37], [38] In Myanmar, its prevalence has been estimated at 8/1000 live births. [24] Factors that contribute to the high burden of NH in Asia include failure of early recognition and treatment of NH, higher proportions of neonates with low birth weight, neonatal infections, higher prevalence of glucose-6-phosphate-dehydrogenase (G6PD) deficiency, and a poor identification of blood group incompatibilities. [35], [39] Difficulty to visually recognise jaundice in the newborn, in particular when premature, difficult access to high quality medical care for phototherapy and exchange transfusion, a lower overall education level and a lack of disease-related knowledge of caretakers are influencing these factors. [40], [41] Jaundice along the Thai-Myanmar border The Shoklo Malaria Research Unit (SMRU) has been providing free maternal and obstetric care for migrants and refugees living along the Thai-Myanmar border since 1986. In 2008 the SMRU Special Care Baby Unit (SCBU) was set up to provide intensive care for neonates in a resource constrained setting. Jaundice was one of the main admission diagnoses at the SCBU while evaluating the impact of the 4 first years of SCBU set in the refugee population. G6PD-deficiency was a common problem (incidence of 7.2% at routine newborn screening in the SMRU clinic) and almost half of the G6PD-deficient neonates were admitted to the SCBU for phototherapy. [42] Neonates presenting with hyperbilirubinemia are treated with phototherapy and supportive measures following a guideline adjusted from the UK NICE guideline on neonatal jaundice, see Appendix II. They cannot receive exchange transfusion on site and have to be referred to a Thai general hospital, a 30 minutes to over one-hour drive from the clinics. Referral is agreed on a case-by-case situation. Therefore, severely jaundiced babies are mostly treated in the SCBU and only few have received exchange transfusion. At discharge from the SCBU,

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survivors are not requested to come for further follow-up on evaluating their clinical status or neurodevelopment. The aim of this study is to describe the group of neonates who had excessively high SBR levels that would justify exchange transfusion (but were treated with phototherapy) and to compare the long-term clinical and neurodevelopmental outcome of survivors to those with no to moderately raised SBR levels.

Research question Primary objective Describing the long term clinical and neurodevelopmental outcome of survivors of NH with excessively high SBR levels that would justify exchange transfusion compared to survivors of NH with no to moderately raised SBR levels. Secondary objectives Describing the neonatal period of neonates with excessively high SBR levels that would justify exchange transfusion with regards to:

i. The mortality rate; ii. The proportion of common risk factors of NH: G6PD deficiency, ABO

incompatibility, polycythaemia, birth trauma, neonatalsepsis, and prematurity; iii. The proportion of neonates with clinical signs of ABE and risk factors among them; iv. The course of SBR and its outcome.

It was hypothesized that mortality rate would be high among the neonates with excessively high SBR levels that would justify exchange transfusion. Survivors could have a compromised clinical condition and/or a delayed neurodevelopment, compared to those with no to moderately raised SBR levels. Ethical approval This observational study involved human subjects, but no invasive procedures were done. The study protocol was approved by the Tak Province Border Community Ethics Advisory Board (T-CAB) representing the local community (TCAB-01/REV/2016, 30th July 2016). The protocol was officially approved as a minimal risk protocol at Oxford Tropical Research Ethics Committee (OxTREC) of the University of Oxford (OXTREC 5113-16, 31st August 2016) as well as by the Ethics Committee of the Faculty of Tropical Medicine (FTMEC) of the Mahidol University (TMEC 16-071, 18th October 2016). This trial is registered in www.clinicaltrials.gov with reference NCT02927093.

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Methods Study design The study consisted of a matched case-control series for the evaluation of the long term clinical and neurodevelopmental outcome of survivors of excessively high SBR levels that would justify exchange transfusion compared to those with no to moderately raised SBR levels. A retrospective review of clinical charts of neonates with these excessively high SBR levels was added. Participants Study participants were singleton, live born neonates with a gestational age of at least 28 weeks, hospitalized for phototherapy between 1st January 2009 and 31st December 2014 in the SMRU Special Care Baby Units (SCBU). Exclusion criteria were twins, gestational age below 28 weeks and major congenital malformations (i.e. chromosomal malformations or congenital heart defects). Participants were included from three sites: Mae La refugee camp clinic (January 2009-December 2014), and the clinics for the migrant population Wang Pha and Maw Ker Thai where SBR measurements were implemented later (January 2011-December 2014). See Figure 1.

Figure 1. Geographical map of the area on the Thai-Myanmar border that is covered by the Shoklo Malaria Research Unit (SMRU) clinics. (Credit: D Parker, SMRU). Data sources Variables available for the present project were extracted from several sources. Pregnancy information was extracted from the ‘ANC Database’, which contains information on all women who attended SMRU antenatal care. Information about the admission to the SCBU was extracted from the computerized ‘SCBU database’ since 2009 which included delivery history, reason for admission, major events during hospitalization, laboratory results, final diagnosis and outcome. Clinical diagnoses in this database represent the clinical judgement of


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attending doctors or medics following the local consensus-based SMRU neonatal guidelines. Inconsistencies in variables relevant for this study were cross-checked with the original paper SCBU summary sheets and SCBU charts. The ‘SCBU Database’ was searched for all neonates who had a clinical diagnosis of ‘jaundice’ or ‘kernicterus’ and/or were recorded as ‘yes’ for receiving phototherapy. Medical charts and summary sheets of these neonates were checked to confirm the diagnosis of NH and subsequently added to a ‘SBR Database’ in which time and result of all SBR measurements, haematocrit (hct) results, start and stop times of phototherapy, daily weight, use of intravenous fluids and/or antibiotics, oxygen therapy and feeding type were entered. Case selection A formula based on the treatment threshold graphs from the UK clinical guideline on neonatal jaundice was computerized in STATA. Cases with two consecutive SBR measurements above the ET treatment threshold were selected through the program, as well as cases with a rapid rise in the SBR trajectory and one SBR measurement above the ET treatment threshold. Selected cases were cross-checked for confirming eligibility using medical charts and originally drawn SBR trajectories. Cases were eligible when they had; i. Two consecutive SBR measurements above the ET treatment threshold; ii. SBR levels rising faster than 8.5 µmol/L per hour in combination with

a. ABE signs; or b. at least one SBR above the exchange transfusion threshold; or c. a referral for exchange transfusion.

iii. Charts with a clinical diagnosis of kernicterus were reviewed to confirm whether these were eligible or not.

All cases who survived the neonatal period were traced using the parents address that was collected at the Antenatal Care and the help of the local community. Found cases were matched to one control each by site, sex, gestational age, season of birth. Matching was computerized. Controls were eligible when they had; i. No SBR above the severe treatment threshold at any time point; and ii. No reported abnormal neurological signs that could indicate ABE (i.e. convulsions,

abnormal cry or tone) For those cases without control the program was run again keeping sex as a matched variable but modifying the other criteria: first by removing site, then extending the ‘season of birth period’ and the range of gestational age. A one-time appointment was organised at the nearest clinic between November 2016 and March 2017. Transportation costs were compensated and a present was given to the child. Variables Maternal and birth variables The following maternal demographics were collected: age, ethnicity, gravida, parity, weight and height, smoking and literacy. Birth variables were: type of delivery, date and time of birth, birth weight, APGAR score, presence of meconium, resuscitation at birth, congenital abnormality. Birth weight was recorded as missing if the weight was measured later than 72 hours after birth. Small-for-gestational age (SGA) was defined as birth weight below the 10th percentile calculated with the Intergrowth-21st newborn size application tool (https://intergrowth21.tghn.org). Resuscitation was defined as the provision of at least five inflation breaths; provision of oxygen and suction only were not considered resuscitation. Newborns were screened for


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congenital abnormality by the nursing staff. Those with presumed abnormalities were re-assessed and categorized by one of the researchers (RMG). The variable ‘Poor start to life’ was defined as an APGAR score of less than 7 at five minutes and/or clinical suspicion of meconium aspiration and/or resuscitation at birth. Neonatal variables Estimated gestational age (EGA) was based on a first trimester ultrasound. [43] SMRU follows the WHO guideline for prematurity. The more commonly used cut-off in jaundice-related literature of 35 weeks of gestation was used in this paper. [8], [11], [13], [36], [44] Presence of sepsis was defined as a full course antibiotic treatment (at least five days of IV gentamycin and IV amoxicillin) combined with either a clinical diagnosis of (early or late onset) sepsis recorded on the SCBU summary sheet or clinical signs of sepsis in the chart confirmed by two investigators. Probable ABO-incompatibility was defined as ABO-incompatibility of mothers with blood group “O” and neonates with blood group “A” or “B”. [45] Rh incompatibility was considered absent, as the prevalence of the Rh-negative blood group is considered to be less than 2% for this Asian population. [24], [37], [38] The G6PD Fluorescent Test as performed in the SMRU lab was used for G6PD-deficiency diagnosis. [46] Polycythaemia was defined as the presence of two consecutive haematocrit values >0.70, or clinical diagnosis of polycythaemia recorded on the SCBU summary sheet. Birth trauma was defined as any visible bruising after birth recorded in the chart or clinical diagnosis of birth trauma recorded on the SCBU summary sheet. Neonatal outcome was categorised as alive, death, referral to another hospital. Causes of death were manually collected from the neonatal mortality sheets and two investigators went through the charts to report a primary cause of death. SBR levels Peak SBR was defined as the maximum SBR reached while above the ET threshold. For cases selected by inclusion criteria (ii), maximum SBR reached while above severe or moderate threshold were given. Time of the peak SBR and time of start and stop phototherapy were extracted from the ‘SBR database’. Age at peak SBR was calculated by subtracting date and time of birth from date and time of SBR measurement. To enable comparison with the majority of literature that uses the AAP guidelines, cases with EGA > 35 weeks and a peak SBR occurring after 72 hours of life were grouped severe (above 342 µmol/L or 20.0 mg/dl), extreme (above 428 µmol/L or 25.0 mg/dl) and hazardous (above 513 µmol/L or 30.0 mg/dl). [8], [9] ABE signs and exchange transfusion Charts were manually searched by the main investigator for the presence of neurological symptoms and for treatment with exchange transfusion. Type of cry and eye movement were never mentioned in the charts and therefore a simplified ABE definition was used. Presence of neurological signs was recorded as ‘yes’ when at least two of the following symptoms were mentioned in the chart: ‘look quiet’, ‘baby sleepy’, ‘less sucking’, ‘irritable’, ‘lethargic’, ‘floppy’, ‘hypotonic’, ‘rigid’, ‘apnoea’, ‘seizure’. A second review was done by the co-investigator when neurological symptoms were present. Disagreements between the two investigators were discussed and a final consensus was made. Date, and if available, time of symptoms were recorded. Neurological symptoms occurring within two days before or after the peak SBR were recorded as ABE. Neurological symptoms and ABE were recorded as unknown in referred neonates.


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Clinical and neurological outcome measures Clinical and neurological examination of the children was completed on a standardized case report form (CRF). ‘Unwell-being’ was defined as more than one hospitalization per year or presence of a chronic disease. Growth z-scores were calculated using WHO Child Growth Standards (http://www.who.int/childgrowth/en/). The Griffiths Mental Development Scales-Extended revised (GMDS-ER) was used to assess the neuro-cognitive development. All test items were scored as pass or fail on six subscales: Locomotor, Personal-Social, Hearing and Language, Eye and Hand-coordination and Practical Reasoning. Raw scores of the six subscales and a summarizing general quotient were calculated manually, as recommended by the GMDS-ER Administration Manual. Subsequently percentiles, z-scores and age equivalent scores for each subscale as well as the summarizing general quotient were manually obtained from the GMDS-ER Analysis Manual. Visual function was assessed with the Cardiff cards, visual acuity was recorded in logmar and visual contrast was recorded in percentage. All tests were performed by local staff trained in clinical neurological examination and neurodevelopmental testing. Staff at different sites is trained in the same manner and regularly quality-controlled. Two third of follow-up appointments were supervised by one of the researchers. Prevention of bias Case finding was computerized. Eligibility was checked by critically reviewing the charts using pre-defined definition of ABE signs. To reduce confounding bias the controls were matched to cases. A list was given out to the staff with all potential controls matched to the cases. Every first found potential control was used. Cases were seen independently from their controls. The testers only recorded pass or fail of the test items. Scoring was done separately, by one of the investigators. Obtaining percentiles, z-scores and age equivalent scores was done separately from calculating total raw scores. In case of doubt of pass or fail single test items were discussed by at least two investigators. Benefit of the doubt was given in any occasion, regardless of being case or control. Results were not assessed nor compared until all patients were seen. Statistical methods Statistical analysis was performed using IBM SPSS Statistics version 24.0.0.1. The mean and standard deviation were calculated for continuous normally distributed data, and the median with range or Inter Quartile Range for non-normally distributed data. Categorical data were presented with their proportion. Variables were compared using Fisher’s Exact test, Mann-Whitney U or Kruskal-Wallis tests as appropriate. Odds-Ratios (OR) and 95% Confidence Intervals (95%CI) were presented. Adjusted Odds-Ratios (AOR) and 95% Confidence Intervals (95%CI) were derived from multinomial logistic regression. Long-term outcome was analysed in a data file for matched case-control studies (https://www.ibm.com/support/knowledgecenter/en/). Both categorical and continuous data were analysed by multinomial logistic regression.

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Results Participants Between 2009 and 2014 there were 12,948 live births > 28 weeks of gestation at the three SMRU antenatal clinics; of those 2,980 (23%) were hospitalized in the SCBUs. A total of 1,946 (65%) neonates were treated with phototherapy. 132 neonates fulfilled the criteria for cases, see Figure 2. There were 14 neonatal deaths, 79 were lost to follow-up; leaving 39 cases available for follow-up. The baseline characteristics of the 39 cases found were similar to those not found for follow up. Data not shown.

Figure 2. Flowchart of case-selection. 132 neonates met the inclusion criteria. Thirty-nine were found for follow-up. Controls were 29 neonates with moderately raised SBR levels, and ten with no jaundice. Neonatal period Characteristics of cases Detailed individual case characteristics are presented in Appendix III. The majority of cases was included from the clinic in the refugee camp (94 cases, 71.2%). There were 77 (58.3%) boys. Median EGA at birth was 37 weeks + 3 days (range: 29+4 – 41+0). There were 39 cases with gestational age below 35 weeks of gestation (29.5%). Median birth weight was 2.515 kg (range: 1.130 – 2.720, n=127) and 18.2% (24/127) were born small-for-gestational age. The majority was born from normal vaginal delivery (116/132; 87.9%). Thirteen cases had a traumatic presentation (9.9%; nine breech and one face presentation, three vacuum extraction). Sixteen (1.1%) were classified as having a poor start to life. Median age of mothers was 23 years (range: 15-44). There were 61/132 primigravid (46%). See Table 1.


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Age at admission to SCBU ranged from birth to 18 days (median 1 day) and cases were hospitalized median 6.5 days (range <1 – 70). Peak SBR was reached at a median 96 hours of life (13 – 440h). Peak SBR was 424 µmol/L (median = 24.8 mg/dl) with the lowest peak at 135 µmol/L (7.9 mg/dl) and the highest reaching 1147 µmol/L (67 mg/dl). All cases received phototherapy treatment, which lasted a median 75 hours (range 2 –412). Phototherapy treatment was for most started in the first 72 hours of life (81/132; 61.4%); amongst them 22 cases started before 24 hours of age (22/132; 16.7%). Six cases were referred. Four successfully received exchange transfusion; one was referred with rising SBR levels and was lost to follow-up; and one was referred with high SBR levels and vomiting and died in the referral hospital with sepsis as most likely primary cause of death. For common risk factors of NH, see also Table 1. Probable ABO-incompatibility was found in 24/129 (18.2%) of cases. One third (38/132; 28.8%) of the cases were G6PD deficient. Polycythaemia was reported in 10 cases (7.6%) and 6 had birth trauma (4.5%). One third of cases was preterm < 35 weeks EGA (39/132; 29.5%). Thirty-eight were clinically diagnosed with sepsis (28.8%); the onset of sepsis was after the onset of NH in 4 charts, but sepsis could have been an etiologic factor for the other 34.

Characteristics of cases Total (n=132) General Year of admission

2009 2010 2011 2012 2013 2014

22 (16.7%) 27 (20.5%) 12 (9.1%) 26 (19.7%) 27 (20.5%) 18 (13.6%)

Site Refugee camp Migrant clinics

94 (71.2%) 38 (28.8%)

Sex (male) 77 (58.3%) EGA median (min-max) 37+3 (29+4 - 41) Normal vaginal delivery 116 (87.9%) Poor start to life 16 (12.1%) Maternal age median (min-max) 23 (15 - 44) Primigravid 61 (46.2%) Neonatal Period Age at admission in days median (min-max) 1 (<1 - 18) Peak SBR µmol/ml median (min-max) 424 (135 - 1147) Timing of peak SBR (hours) median (min-max) 96 (13 - 440) Timing of peak SBR < 72 hours of life 44 (33.3%) Duration of admission (days) median (min-max) 7 (<1 - 70) Duration of phototherapy (hours) median (min-max) 2 (2 - 412) Received exchange transfusion 4 (3.1%) Risk factors Probable ABO-incompatibility 24 (18.2%) (n=129) G6PD-deficiency 38 (28.8%) Polycythaemia 10 (7.6%) Birth trauma 6 (4.5%) Gestational age < 35 weeks 39 (29.5%) Neonatal sepsis 34 (25.8%)

Table 1. Characteristics of cases. Data are presented in count (%) unless stated otherwise.


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Mortality The neonatal mortality rate was 10.7% (14/131, one missing). All charts of neonates had reported ABE signs prior to death. After review of the charts the most likely primary causes of deaths were ABE (6 cases), very preterm (<32 weeks, 2 cases), prematurity (EGA 33+1 and 32+3, 2 cases), NEC (1 case), sepsis (3 cases). Two children were known to have died after the neonatal period (1 sepsis, 1 unknown cause); see case no. 53 and case no. 125 in Appendix III. More than half of the neonatal deaths occurred in 2009 and 2010, see Figure 3. Odds of death were reduced by 3.5 (95%CI: 1.1 – 11.0) between 2009/2010 and 2011 and later.

Figure 3. Stacked bar chart of death and alive neonates at discharge from SCBU. Filled bars represent mortality rate among the total of included cases. Numbers of death and alive neonates displayed in table. ABE and associated factors Presence of neurological symptoms around the peak SBR were defined as ABE and were found in 37/126 cases (29.4%, 6 missing). Factors associated with ABE were compared between those with and those without ABE. See Figure 4. Odds of prematurity and diagnosis of sepsis were significantly higher in the group with ABE than in the group without ABE in univariable analysis. As prematurity and neonatal sepsis were related they could not be put together in a regression model. When adjusting for all other factors in separate models prematurity had an AOR 5.4 (1.6 - 17.8) p=0.006 and sepsis AOR 2.9 (1.1 - 7.5) p=0.032. G6PD-deficiency was not associated with ABE in this study group. All neonatal deaths occurred among cases with ABE. No deaths occurred in the non ABE group.

0%

20%

40%

60%

80%

100%

2009 2010 2011 2012 2013 2014

Alive 16 24 11 22 26 18

Deaths 6 3 1 3 1 0

Mortality among cases


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Figure 4. Odds Ratio and 95% confidence interval of factors associated with ABE. Factors with an Odds Ratio >1 were more common in ABE. Course of SBR Peak SBR occurred in the first 72 hours of life for 44 cases; and in the first 24 hours for 4 cases. Cases with an early peak SBR (<72 hours of life, 44/132) and cases with a later peak SBR were at similar risks of both death, OR 3.2 (95%CI 0.7 – 15.2) p=0.143, and ABE, OR 0.9 (95%CI 0.4 - 2.0) p=0.835. To enable comparison with the majority of literature that uses the AAP guideline, cases with a peak SBR after 72 hours and EGA >35 weeks (57/132) were grouped by severity and outcome was compared. See Figure 5. Twelve had a peak SBR above 342 µmol/L (20.0 mg/dl – severe); 28 had a peak SBR above 428 µmol/L (25.0 mg/dl – extreme); and 12 a peak SBR above 513 µmol/L (30.0 mg/dl – hazardous). Mortality and the risk of ABE increased with severity category (numbers were to small to reach significant levels).


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Figure 5. Mortality risk and proportion of ABE according to the timing of SBR, severity category and prematurity. Excluded cases were referrals as ABE was unknown, cases that had ABE by definition. Mortality (*) and risk of ABE (∆) increased significantly over the severity groups that include all gestational ages. Numbers in gestational age groups were too small to reach significant levels.


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Long term outcome Thirty-nine cases were found. Each case was matched to one control by sex, age and location (refugees versus migrants). A gestational age difference of ± 4 weeks was reached for 32 case/control pairs. A third (5/13) of cases born < 35 weeks EGA were matched within a wider EGA range (± 8 weeks); these were older than 60 months (5 years) at time of the visit. Ten controls did not require phototherapy; 29 had moderate jaundice requiring phototherapy for a median of 24 hours (12 – 61). There were no major differences in general characteristics between cases and controls, apart from a longer duration of SCBU hospitalization, see Table 2.

Characteristics Cases (n=39) Controls (n=39) Matching criteria Male 21 (53.8%) 21 (53.8%) Age in months 51 (23.0 - 96.5) 52 (24.0 – 97.0) Neonatal characteristics EGA at date of birth median (min-max) 37+3 (29+5 - 40+4) 39+5 (32+3 - 42+2) Normal vaginal delivery 32 (82.1%) 36 (92.3%) Poor start to life or oxygen administration

10 (25.6%) 8 (21.1%)

Days of stay at SCBU median (min-max) 8 (3 - 70) 4 (1 - 25) Mother characteristics Maternal age median (min-max) 24 (17 - 43) 24 (16 - 42) Illiteracy 10 (34.5%) (n=29) 4 (11.8%) (n=34) Smoking 8 (20.5%) 4 (10.3%) Position in family First born 21 (53.8%) 20 (51.3%) Second or third born 12 (30.8%) 12 (30.8%) Fourth born and up 6 (15.4%) 7 (17.9%)

Table 2. Characteristics of cases and controls agreed to participate to the study (39 pairs). Data shown in count and percent, unless stated otherwise. In case of missing data, count was shown in brackets. Clinical outcome Long term outcome for cases and controls is presented in Table 3. Median age at time of follow-up was 52 months (4.3 years). None of the participants were acutely ill, but 21/77 reported frequent hospitalizations (>1/year) or a chronic disease (unwell-being). There was a high proportion chronic malnutrition: 25/78 were stunted (46.2% of cases and 20.5% of controls) and 4/78 had a low BMI. The cardio-respiratory and abdominal examination was overall normal. Half of the participants had damaged teeth. The visual examination included the presence of abnormal eye movements or fixed gaze, and a visual contrast and acuity test. Vision was reported as abnormal in 16 children (10 cases and 6 controls) consisting mostly of abnormal acuity tests (13/16). None of the children wore glasses. Eye movement was abnormal in four cases and none of the controls.

LONG TERM OUTCOME Cases (n=39) Controls (n=39) P-value OR (95% CI) Clinical outcome Unwell-being (1 missing) 13 (34.2%) (n=38) 8 (20.5%) 0.144 2.2 (0.8 – 6.3) Stunting (height/age < -2 SD) 17 (43.6%) 8 (20.5%) 0.058 2.5 (1.0 – 6.4) Low bmi (BMI/age < -2 SD) 3 (7.7%) 1 (2.6%) 0.341 3.0 (0.3 – 28.8) Teeth abnormal 19 (51.4%) (n=37) 21 (55.3%) 0.819 1.1 (0.5 – 2.7) Vision abnormal 10 (25.6%) 6 (15.4%) 0.220 0.4 (0.1 – 1.7) Neurological exam abnormal 4 (10.3%) 0 0.019 NA Neurodevelopment Maternal perception of child’s development: mother has worries

8 (20.5%) 2 (5.1%) 0.080 0.3 (0.1 – 1.2)


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GMDS summarizing score General percentile score median (IQR) 10 (<1 - 42) 30.5 (4 - 67) 0.013 0.97 (0.95 - 0.99) Scoring below the 10th percentile 18 (47.4%) 11 (28.9%) 0.067 3.3 (0.9 - 12.1)

GMDS subscales Locomotion median (IQR) 18 (4 - 58) 46 (13 - 65) 0.090 0.99 (0.97 - 1.00) Personal and social median (IQR) 25 (8 - 64) 46 (20 - 72) 0.148 0.99 (0.97 - 1.00) Hearing and language median (IQR) 11 (<1 - 33) 27 (4 - 62) 0.023 0.97 (0.95 - 1.00) Eye and hand co-ordination median (IQR) 14 (3 - 46) 29 (5 - 44) 0.335 0.99 (0.97 - 1.01) Performance median (IQR) 4 (<1 - 40) 15 (3 - 69) 0.074 0.98 (0.95 - 1.00) Practical reasoning median (IQR) 10.5 (1 - 47) 50 (10 - 67) 0.018 0.98 (0.95 - 1.00)

Table 3. Long term outcome of two to eight years old cases and controls who agreed to participate in the study (n=78). Data shown in count (%), unless stated otherwise. Missing data was shown in brackets if applicable. P-values and Odds Ratios derived from matched case control analysis. Neurological outcome Four cases had an abnormal neurological exam; see Appendix III and IV (No. 47, 74, 107, 111). One case was compatible with kernicterus, two had severe neurological impairment of other kind, and one had mild neurological impairment. Neurodevelopmental outcome Mothers of cases were more worried about their child’s development than mothers of controls (not reaching significant level). Percentile scores of each subscale and the summarizing General Quotient were compared between the cases and the controls, see Table 3. Overall, cases performed less well than controls in all subscales, and significant differences were observed in the subscales ‘Hearing and Language’ and ‘Practical Reasoning’. Median percentile of the General Quotient score was also significantly lower (10 vs 30.5, p = 0.013). The analysis was repeated after removing the four neurologically impaired cases and their respective controls from this analysis; median percentile scores of the subscale ‘Practical Reasoning’ and the General Quotient remained significantly different. Data not shown. Factors known to potentially influence the child’s development for which information was available, i.e. stunting, unwell-being, EGA < 35 weeks, were added into a multinomial regression. Odds of cases having a lower General Quotient Percentile score remained significant regardless of the other factors, AOR: 0.96 (0.93 - 0.99) p=0.017. Results were similar after excluding the four impaired cases from analysis.

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Discussion This study presented the characteristics of 132 neonates who had excessively high SBR levels that would justify exchange transfusion (but were treated with phototherapy) in a constraint-resource setting along the Thai-Myanmar border over a 6-year period. The long term outcome of survivors was compared to that of children born in the same environment and matched for sex, age and gestational age at birth. To our knowledge this is the first report describing the neonatal period and the long term outcome of severe NH this area. Key Results Mortality among cases was 10.7%, Acute Bilirubin Encephalopathy occurred among 29.4%. Important risk factors for NH in this study were prematurity, G6PD-deficiency and comorbid neonatal sepsis. Presence of both prematurity and sepsis were significantly associated with the development of ABE. At long term, 10% of cases had an abnormal neurological exam, of which one was compatible with kernicterus. Cases had a delayed neurodevelopment compared to controls, independent of being stunted, often unwell or being born premature. Limitations There are limitations to this study. The description of the neonatal period was retrospective and derived from clinical charts where only limited variables were routinely collected. There was no systematic reporting of clinical signs and neurological symptoms using the BIND scoring system and therefore ABE as presented in this study might be underestimated. [15] Limited laboratory and radiological exams were available, therefore diagnoses of sepsis and kernicterus were clinically-based only and might have been overestimated. Neonatal outcome was known up to discharge from the SCBU, and not all cases could be traced, due to the mobile nature of this population. The clinical, neurological and developmental examination of found children was a one-off appointment and a small number of all possible confounding factors associated to neurodevelopmental outcome were collected. Matching on prematurity was difficult as virtually none of the preterms hospitalized in the SCBU had moderate jaundice without complications and thus the effect of this important confounder of neurodevelopment could only be estimated with regression analysis. The overall poor results in the neurodevelopmental tests should be considered with caution. Neurodevelopmental tests are usually performed by specialists working at tertiary hospitals while these tests were performed by locally trained and regularly quality controlled staff fluent in local languages (Karen and Burmese). And despite the Griffiths Mental Development Scales being validated for worldwide use, cultural and environmental factors in this marginalized population of migrant workers and refugees could have influenced the overall poor test outcome. For example, none of the participants knew how to skip a rope and none of them knew their birthday. There is very little exposure to picture-books or brick toys, and little stimulation to learn the colours, to count or to draw, likely affecting scores of children younger than four years old. Although information on school going was not systematically collected, those available tell us that school was either started late or that children were over-aged for their class [own observation: 7/14; 50% of children of 5 years and older was in kindergarten or nursery] and scores of those younger than 4 years old were worse than scores of older children [own observation: 17/30 (57%) < 4-year old compared to 12/46 (26%) older kids scored below the 10th centile]. Nevertheless, cases and their matched controls came from the same environment, faced the same difficulties in doing the test, and each item passed or failed were recorded as such by the staff unaware of the final scoring. Therefore, the significant differences observed in this


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relatively small study group might indicate that severe NH plays a role in delaying neurodevelopment. Interpretation Characteristics and risk factors The characteristics of this case-series are very similar to those found in other low and middle income countries: mothers were mostly primigravid and there was a high prevalence of premature neonates. Diagnosis of sepsis was frequent, but the prevalence was much higher than that reported worldwide, and even higher than in other developing countries; a finding however to consider with caution as only a clinical diagnosis was available. [47]–[50] G6PD-deficiency was frequently observed (in a third of the cases) as well as ABO-incompatibility. Rates of ABO-incompatibility and G6PD-deficiency were comparable to those of other studies in Asia. [24], [25], [51] Rh disease was not tested but believed to be absent in this Rhesus positive population. [37], [38] Mortality Mortality among cases is comparable to numbers reported in other low- and middle income countries. [30] The majority of severe NH and of deaths occurred in 2009 and 2010, during the early stage of SCBU set up. After 2011 systematic guidelines were introduced for the care of jaundiced neonates, early diagnosis and treatment were promoted and mortality decreased. Thus in this setting where exchange transfusion is still only occasionally accessible, it is possible to reduce mortality among severe NH to a minimum with improving skills of clinical staff, a more systematic approach in diagnosis of jaundice and an effective treatment with LED phototherapy. ABE and associated factors Literature describes a large heterogeneity of researched NH populations and a large variation in ABE risk; from none to two third of severe NH cases. [23], [24], [31], [32], [49], [50], [52] In this study, that included preterm neonates, one third of cases had ABE. Risk of ABE and death increased with increasing severity of SBR levels. Preterm neonates were at greater risk of ABE. Studies on NH in preterm neonates are scarce and long term outcome is even less known. [53], [54] The high numbers of ABE among preterm neonates occurred even though the UK guidelines, which based severity thresholds on gestational ages as low as 28 weeks, were used. A better understanding of the risks in preterm neonates and a more aggressive management might be necessary to reduce ABE and associated mortality rate further. Long term follow-up of those who survive might help to better evaluate their long-term risks. [53] In the Netherlands, guidelines have been designed with treatment threshold graphs based on birth weight instead of gestational age, with generally lower treatment thresholds than the UK guidelines. Assessing NH in preterms based on these guidelines might lead to a better outcome in this group. [55], [56] Neonatal sepsis was also associated with the presence of ABE. Despite the retrospective character of the study and the difficulty of separating the influence and causality of hyperbilirubinemia, sepsis and prematurity on the development of neurological symptoms the findings are similar to those previously reported in the literature. [23], [27] G6PD-deficiency was not a significant risk factor for developing ABE; even though G6PD-deficiency is a proven risk factor of developing hyperbilirubinemia and one third of the severe jaundice cases in this study were G6PD deficient. The staff awareness of the risk encountered if a neonate was G6PD deficiency and the availability of a tool diagnosing G6PD-deficiency might have improved outcome of deficient cases. [41], [46], [57]


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An early appearance of the peak SBR, frequently observed in this setting, was not associated with an increased risk of ABE nor with an excess mortality. This is an encouraging finding with regards to the use of guidelines with treatment thresholds adjusted not only for gestational age but also for the timing of appearance of the jaundice. Neurological signs were reported in all charts of dead cases and in most, these were described the day prior to or the day of their death. This suggests that once a severely jaundiced neonate shows neurological symptoms serious enough to be observed and reported in the chart, an irreversible phase of ABE might have started and therefore death becomes very hard to prevent. Thus in presence of neurological symptoms additional attention should be paid – whether these symptoms are associated with NH, sepsis or prematurity. [58] Reporting clinical signs using a system such as the BIND score [15] was not set up but might be a tool to consider in order to capture clinical signs at an early stage that might otherwise be overlooked. Outcome The proportion of neurological impairment among the 39 found cases was high (10%), although only one case fitted the criteria of kernicterus (2.6%). Abnormality in vision was frequently reported. However, these were not the characteristic kernicterus-related abnormalities, but were related to acuity mostly and were similar for cases and controls. Typical staining of the teeth reported in the literature as a sign of kernicterus was difficult to distinguish from general staining and carries that were present in half of the study participants. [18], [59] Neurodevelopment was poorer in cases than in controls considering the summarizing scores and scores on ‘Hearing and Language’ and ‘Practical Reasoning’. The risk of lower summarizing scores in cases remained significant after adjusting for stunting, prematurity and unwell-being suggesting that regardless of these important confounding factors severe NH presents a risk of neurodevelopmental impairment. The lower scores on the ‘Hearing and Language’ scale are congruent with literature, as hearing loss is one of the kernicterus sequelae. [16], [60] Scoring poorly on ‘Hearing and Language’ affects the scores in the ‘Practical Reasoning’ scale as most of the items of this scale are based on a verbal response. Delay in intellect was therefore difficult to estimate. Shapiro [18] stated that intellect is usually normal in children with kernicterus and, although one might encounter difficulty to assess them, the use of humour may in fact show that these children are not necessarily mentally retarded. Our results are supporting this statement by showing no difference on the ‘Personal-Social’ subscale and a relatively good ‘Personal-Social’ development of the child diagnosed with kernicterus. Generalisability Results of the neonatal description of cases can well extrapolated to comparable limited-resource settings with access to phototherapy, but no (immediate) access to exchange transfusion. Important etiologic factors of NH slightly differ; for example, G6PD-deficiency is important in Asia and Rh-disease in other parts of the world. [61] However, prematurity and sepsis are important comorbid factors in all low and middle income countries (LMIC), and caution should be exercised anywhere in the world in the presence of NH and these comorbidities. [58] Absolute neurodevelopmental scores should not be extrapolated or compared to those measured in other settings, since they derive from a specific setting as described in the limitations. However, the significant differences between cases and matched controls are considered valid also outside of this specific setting as matching and regression analyses

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adjusted for known - and likely also for unknown - confounding and environmental factors of neurodevelopment.

Conclusion In conclusion, this matched case-control study showed that neonates with excessively high SBR levels have a higher risk of long term impaired neurodevelopment compared to their controls with only moderately raised SBR levels. In an already compromised environment it is recommended to follow up survivors of NH with excessively high SBR levels and prevent them from developing other preventable risk factors for neurodevelopment such as stunting and anaemia. Further prospective research is needed to disentangle the precise role of these and other confounding factors such as prematurity on neurodevelopment in this limited resource setting.

Acknowledgements I would like to thank my supervisor Verena Carrara, colleague and PhD student Laurence Thielemans, and all the doctors, study medics and baby testing teams at the three clinical sites, especially Mue Chae Darakamon. A special thanks to all the mothers and children who were willing to join in the study. Thanks to Stepping Stones physiotherapy for treating one of the disabled study participants. The main part of the study was funded by SMRU, supported by Wellcome trust (UK). Kilroy Foundation, Holland Scholarship and Marco Polo fund provided extra funds for personal and study-related expenses.

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Report Research Clerkship – Eva Wouda, S1965085 Appendices 28 mei. 17

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Appendices Appendix I. Example of a neonatal jaundice treatment threshold graph for assessing whether to treat neonatal jaundice by phototherapy or exchange transfusion from the Full Clinical Guideline on Neonatal Jaundice by the UK, 2010. [2]


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Appendix II. Example of a SMRU phototherapy chart (Version 3, 19th August 2011) adapted from the NICE threshold graphs to fit a setting without exchange transfusion: the exchange transfusion line has been deleted and a severe line has been identified as a threshold 50 µmol/L below the exchange transfusion line from 72 hours of life onwards and a slope measured between 0 and 72 hours. Intensive phototherapy, and close monitoring of the clinical condition of the newborn is required once the severe threshold is reached.


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Appendix III. Presentation of Case Series. Clinic was replaced by a number; 1 and 2 were migrant clinics and 3 refugee camp clinic. Mother characteristics: SK=Sgaw-Karen, PK=Poe-Karen, BM=Burmese Muslim, B=Burman, O=Other, m=mixed. Type of case included: 1=two SBR above ET, 2=rise and one above ET, 3=rise and ABE-symptoms, 4=rise and referred for ET but ever above ET, 5=clinical kernicterus. ABE signs: ABE=ABE signs present within 2 days around the peak, no=no ABE signs around the peak. Discharge from SCBU represent the outcome of the neonatal period. Primary cause of death: most likely primary cause of death as found by reviewing clinical charts and mortality sheets by the main investigator and co-investigator (paediatrician). Follow-up is presented if available: neurological exam normal or abnormal and summarizing neurodevelopment percentile score in brackets (General Quotient). ABO-incompatibility: no=no ABO-incompatibility, yes= mother “O” with infant “A” or “B”, unk=unknown. Weightloss: weightloss at start of phototherapy compared to the birth weight in percentage; negative percentages are weight gain.


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Appendix IV Neurologically abnormal cases.

NO. GENERAL PEAK SBR, ABE, ET

EXAMINATION NEURODEVELOPMENT

111 3yo male Hazardous ABE yes ET no

Fixed upward gaze, neurological findings compatible with cerebral palsy.

3 weeks of age; no locomotor development at all, ability to smile, grasp a ring and search for sound with eyes.

107 3.5yo male <72h of life with rapid rise ET yes ABE unk

Paralysis of up- and downward gaze and preference to the right side, dystonia and staining of the teeth, possible hearing loss on the left side; all compatible with a diagnosis of kernicterus.

3 months of age. ‘Personal-Social’ and ‘Hearing and Language’ at 5 months. Poorer development on the other scales. Ability to lift chin when prone, show emotions, be attentive to other people, babble, look at pictures, grasp and hold objects.

47 6yo male <72h of life ABE yes ET no

Strabismus and inability to follow a target horizontally, bilateral partially repaired talipes, a history of prematurity, neonatal seizures and some dysmorphic features.

2 years of age.

74 4yo girl

<72h of life ABE yes ET no

Repaired cleft palate, severe chronic malnutrition. External strabismus of both sides and decreased muscle strength.

2 years of age. Language scores (at 15 months) worse than other scales. Other scales (at around 2.5-year) low due to inability to speak.

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