Kasai-operatie

Beoordeeld: 22-05-2024

Uitgangsvraag

Welke strategieën voor vroege detectie van neonatale cholestase leiden tot betere uitkomsten voor kinderen met biliaire atresie?

Clinical question

What are the effects of strategies for early detection of neonatal cholestasis on long term outcomes of children with biliary atresia?

Aanbeveling

Implementeer screening met behulp van de ontlastingskleurenkaart voor alle neonaten voor vroege herkenning van cholestatische ziekte en om de kans op transplantatie-vrije overleving bij kinderen met biliaire atresie te vergroten.

Implementeer geen meting van het directe bilirubine voor alle neonaten, maar richt dit onderzoek op neonaten met ontkleurde ontlasting of persisterende geelzucht.

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

Na het op een rij zetten van de beschikbaar medische literatuur werd duidelijk dat twee strategieën voor vroege herkenning van neonatale cholestase uitgebreid geëvalueerd zijn. Het gaat om (1) het toevoegen van de ontlasting kleurenkaart aan het Child Health Booklet voor het herkennen van ontkleurde ontlasting, en (2) het meten van de directe bilirubinefractie bij kinderen die 3 weken na de geboorte nog geel zijn. Het belang van vroege detectie en vroege behandeling is in een recente systematische review nog weer bevestigd (Hoshino, 2023). Voor het schrijven van de overwegingen en aanbevelingen besloot de richtlijn commissie uitgangsvraag 3 daarom toe te spitsen op deze twee strategieën.

De ontlastingskleurenkaart helpt ouders en zorgverleners ontkleurde ontlasting te herkennen en maakt het mogelijk gele baby’s met een verhoogde kans op galgangatresie te identificeren. Introductie van een screeningsprogramma met de ontlasting kleurenkaart leidt tot het op jongere leeftijd uitvoeren van de Kasai operatie, een betere klaring van het bilirubine na de operatie en een langere overleving met de eigen lever [zie ook module 1: Ontlastingskleurenkaart].

Harpavat et al toonde aan dat het meten van de directe bilirubinefractie op de leeftijd van twee weken bij baby’s die in de eerste 60 uur na de geboorte een verhoogd totaal bilirubine hadden ook een geschikte strategie is voor de vroege herkenning van cholestatische leverziekte. Ook deze screeningsmethode leidde tot het op jongere leeftijd uitvoeren van de Kasai operatie en een betere klaring van bilirubine na de operatie. Een verschil in overleving met de eigen lever werd niet aangetoond.

De ondersteunende bewijskracht van beide strategieën is erg laag door de inclusie van observationele studies met kleine patiënten aantallen, maar het directe verband tussen het toepassen van deze strategieën en de behandeling stroomafwaarts en de lange termijn uitkomsten zijn cruciaal voor besluitvorming omtrent onze aanbevelingen.

Het herkennen van ontkleurde ontlasting blijkt zowel voor ouders, jeugdartsen als huisartsen moeilijk te zijn (Witt, 2016). Gebruik van de ontlasting kleurenkaart vergemakkelijkt het onderscheid tussen ontkleurde en normaalgekleurde ontlasting. Het printen van ontlasting kleurenkaarten en het toevoegen aan het Nederlandse groeiboekje is een goedkope, niet-invasieve en eenvoudig toepasbare interventie die de behandeluitkomsten van kinderen met galgangatresie kan verbeteren (Mogul, 2015; Masucci, 2019). Een mogelijk bijkomend voordeel van een dergelijk screeningsprogramma is dat het besef van de ernst van neonatale cholestase en de noodzaak tot snelle verwijzing naar een kinderarts onder huisartsen en binnen de jeugdgezondheidszorg zal toenemen.

In de Verenigde Staten wordt implementatie van de ontlasting kleurenkaart bemoeilijkt door het gedecentraliseerde gezondheidszorgsysteem en het niet-bestaan van een standaard check-up op de leeftijd van 1 maand bij jeugdgezondheidszorg. Veel baby’s in de VS worden wel op de leeftijd van twee weken gezien wanneer een hielprik screening wordt gedaan. Deze screening kan dan worden gecombineerd met het meten van de directe bilirubinefractie (Rabbani, 2021).

De ontlasting kleurenkaart is een eenvoudig, niet-invasief hulpmiddel om ouders ontkleurde ontlasting te laten herkennen. Zorgprofessionals dienen bij het vermoeden op ontkleurde ontlasting de gele baby onmiddellijk te verwijzen voor aanvullende diagnostiek. In een dergelijk geval moet een expectatief beleid als een medische fout worden beschouwd. Er zijn enkele andere aandoeningen die ontkleurde ontlasting kunnen veroorzaken (zie tabel 4 van module 2), maar de kans op een obstructieve geelzucht is zeer hoog. Dit advies komt echter niet in plaats van het meten van de directe bilirubinefractie bij kinderen die 3 weken na de geboorte nog geel zijn.

Kinderen met galgangatresie die in een kleurenkaart screeningsprogramma werden geïdentificeerd ondergingen de Kasai operatie op een jongere leeftijd dan een historische controlegroep. Het mediane verschil tussen de cohorten varieerde van 3 tot 25 dagen. Het aandeel kinderen dat voor de leeftijd van 60 dagen kon worden geopereerd was ook groter in het kleurenkaart screenings programma: het mediane verschil bedroeg 5 tot 17%.

Een intra-operatief cholangiogram wordt beschouwd als de referentietest voor het vaststellen van galgangatresie en wordt gepland nadat een obstructieve cholangiopathie is vastgesteld in een leverbiopt.

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Voor kinderen met biliaire atresie en hun verzorgers is vroegtijdige herkenning en behandeling cruciaal. Vroegtijdige herkenning kan zorgen voor het op jongere leeftijd uitvoeren van de Kasai-operatie, een betere klaring van het bilirubine na de operatie en een langere overleving met de eigen lever. Screening met de ontlastingskleurenkaart is niet belastend voor het kind en wordt ook geaccepteerd door de meeste ouders. Het is daarbij wel belangrijk dat ouders duidelijke informatie krijgen over hoe ze de ontlastingkleurenkaart moeten gebruiken, zoals bijvoorbeeld de ontlasting bij daglicht bekijken. De informatie moet op passende en begrijpelijke wijze worden gedeeld met ouders en ook te begrijpen zijn voor laaggeletterde ouders. Bilirubinemeting gebeurt middels bloedprik, en kan een pijnlijke procedure zijn voor het kind.

Kosten (middelenbeslag)

De kosteneffectiviteit van de meting van de directe bilirubinefractie wordt nog onderzocht.

Aanvaardbaarheid, haalbaarheid en implementatie

Zie module 1 Ontlastingskleurenkaart en module 2 Diagnostische pathway.

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Ondanks de zwakke bewijskracht van de beschikbare data meent de richtlijn commissie dat de impact van het gebruik van de ontlasting kleurenkaart op het sneller identificeren van een klein aantal risicopatiënten in voldoende mate opweegt tegen het nadeel (bloedafname) voor een grote groep gele baby’s die geen cholestase blijkt te hebben, en tegen het nadeel (ongerustheid) voor een grote groep ouders.

Onderbouwing

Achtergrond

Een van de oorzaken van neonatale cholestase is galgangatresie, een aangeboren afwijking die de galafvloed naar de dunne darm belemmert. De chirurgische behandeling van galgangatresie is het aanleggen van een portoenterostomie volgens Kasai, waardoor de galafvloed hersteld kan worden en de geelzucht verdwijnt. Hoe korter de Kasai-operatie na de geboorte kan worden uitgevoerd, hoe groter de kans dat een kind zijn peutertijd doorkomt zonder levertransplantatie. In deze module evalueren we welke strategieën succesvol zijn gebleken in het vervroegen van het tijdstip van de Kasai-operatie. Vroege herkenning van neonatale cholestase door het screenen van de “population at risk” is naar verwachting een van de effectieve strategieën, maar de vraag is of het “number-needed-to-screen” acceptabel zal zijn.

Bij baby’s in de leeftijdscategorie van 3 weken of ouder wordt de gele kleur meestal veroorzaakt door een borstvoeding geassocieerde indirecte hyperbilirubinemie. Borstvoedingsicterus is een ongevaarlijk verschijnsel dat spontaan zal verdwijnen. Slechts een klein deel van de gele baby’s heeft cholestase (met directe hyperbilirubinemie als gevolg). Deze vorm van icterus is pathologisch en vereist onmiddellijke evaluatie. Directe hyperbilirubinemie heeft tal van oorzaken, maar de aanwezigheid van ontkleurde ontlasting maakt de diagnose galgangatresie waarschijnlijker. Tijdige chirurgisch correctie verbetert het behandelresultaat van kinderen met galgalgangatresie, zowel op korte termijn (het verdwijnen van de gele kleur) als op lange termijn (het overleven met eigen lever).

Borstvoeding geassocieerde indirecte hyperbilirubinemie met normaalgekleurde ontlasting komt veel voor. Twee weken na de geboorte is ongeveer 14% van de baby’s nog geel (Kelly, 1995). Vier weken na de geboorte is nog slechts 2.5% van de kinderen geel. De aanwezigheid van ontkleurde ontlasting en/of van icterus op de leeftijd van 3 weken moet kan goed wijzen op het bestaan van galgangatresie of een andere vorm van neonatale cholestase. Noch bij borstgevoede, noch bij fles-gevoede zuigelingen is met het blote oog of transcutane bilimeter te bepalen of de geelzucht berust op verhoogd ongeconjugeerd of geconjugeerd bilirubine. Ook is bij kinderen met galgangatresie op jonge leeftijd nog niet altijd sprake van ontkleurde ontlasting. In Nederland krijgt ongeveer 1 op de 19.000 levendgeborenen de diagnose galgangatresie, wat neerkomt op circa 10 nieuwe patiënten per jaar (Nomden, 2021).

Conclusies

Very Low Grade	Native liver survival Adding the Stool Color Card to the Child Health Booklet may improve early recognition of biliary atresia, may shorten the time to Kasai hepatoportoenterostomy and consequently improves native liver survival, but the evidence is very uncertain. Sources: Lien ( 2011), Zheng ( 2020), Lee (2016), Gu ( 2017)

Very Low Grade	Native liver survival The evidence is very uncertain about the effect of screening newborns with direct bilirubin on transplant-free survival Infants with biliary atresia, who are detected early by measuring the direct bilirubin fraction in newborns who had increased levels of total bilirubin within the first 60 hours of birth, may have a better native liver survival after Kasai operation, but the evidence is very uncertain. Source: Harpavat (2020)
Very Low Grade	Native liver survival National centralization of surgical care for children with biliary atresia may improve native liver survival, but the evidence is very uncertain. Sources: Davenport (2004), Hukkinen (2018)

Very Low Grade	Age at Kasai portoenterostomy Adding the Stool Color Card to the Child Health Booklet may improve early recognition of biliary atresia and may shorten the time to Kasai hepatoportoenterostomy, but the evidence is very uncertain. Sources: Reyes-Cerecedo (2018), Lien (2011), Zheng (2020) Tseng (2011), Lee (2016), Hsaio (2008), Gu (2017).

Very Low Grade	Age of Kasai Screening for biliary atresia using direct bilirubin measurements may improve early recognition and shorten the time to Kasai portoenterostomy, but the evidence is very uncertain. Measuring the direct bilirubin fraction in newborns who had increased levels of total bilirubin within the first 60 hours of birth may assist in early recognition of biliary atresia and consequently younger age at Kasai operation, but the evidence is very uncertain. Sources: Harpavat (2020)

Very Low Grade	Age of Kasai National centralization of surgical care for children with biliary atresia may decrease the age at Kasai portoenterostomy, but the evidence is very uncertain. Sources: Hukkinen (2018), Davenport (2004)

Very Low Grade	Clearance of jaundice Infants with biliary atresia who are detected early with the Stool Color Card may have a better decrease of blood bilirubin levels after Kasai operation, but the evidence is very uncertain. Adding the Stool Color Card to the Child Health Booklet may improve early recognition of biliary atresia, may shorten the time to Kasai hepatoportoenterostomy, and may improve clearance of jaundice, but the evidence is very uncertain. Sources: Lien ( 2011), Zheng (2020), Hsaio ( 2008 )

Very Low Grade	Clearance of jaundice Infants with biliary atresia who are detected early by measuring the direct bilirubin fraction in newborns who had increased levels of total bilirubin within the first 60 hours of birth may have a better decrease of blood bilirubin levels after Kasai operation, but the evidence is very uncertain. Screening for biliary atresia using direct bilirubin measurements may improve early recognition, may shorten the time to Kasai hepatoportoenterostomy and to postoperative normalization of direct bilirubin, but the evidence is very uncertain. Source: Harpavat ( 2020)
Very Low Grade	Clearance of jaundice National centralization of surgical care for children with biliary atresia may increase the clearance of jaundice after a Kasai operation, but the evidence is very uncertain. Sources: Hukkinen (2018), Davenport (2004)

Samenvatting literatuur

The systematic literature search resulted in 551 hits. After reading title and abstract 13 titles were included by both authors and no consensus was made about 69 articles. Based on title and abstract the third reviewer excluded 45 out of 69 studies. Twenty-seven full text articles were read, and in the final analysis 10 studies were included.

Results

Ten papers that studied strategies for early detection of neonatal cholestasis and compared outcomes with a historic or control cohort were included in the final analysis. The evidence table-lists the characteristics of the 10 studies. The assessment of the risk of bias is summarized in the risk of bias table.

Description of studies

Stool color card

Reyes-Cerecedo (2018) described a study performed in Mexico. The objective of the study was to determine the impact of the SCC implementation by comparing the reference time of patients seen in two specialized hospitals, as well as the age at when Kasai surgery was performed in children with BA. To measure the impact of the implementation of the SCC, children were divided into two groups: the first consisted of patients referred from January 2010 to December 2012 (first period), to whom the SCC was not granted; the second group was those referred from January 2013 to June 2015 (second period), to whom the SCC was granted. In Mexico, as of January 2013, the SCC was added to the National Health Card (NHC) to carry screening of children with BA. All children with BA were included, 59 patients in total. In the period without SCC 27 patients were diagnosed with BA, afterwards 32 patients. Prevalence in the population is not known.

Lien (2011) performed a retrospective cohort study in which they aimed to compare the outcome of the BA patients after Kasai operation before versus after the launch of

the infant stool color card screening program in Taiwan, which was introduced in 2004. This study is a follow up study of the pilot study of Chen et al (2006). The stool color card was handed out into the child health booklet. The historical control cohort (cohort A) was derived from the 96 cases diagnosed as BA at the National Taiwan University Hospital from January 1990 to December 2000, patients without Kasai or shorter follow up then 3 months were excluded. Cohort B were patients included in the pilot study, described by Chen et al which included 28 patients with BA who underwent HPE. Seventy-four BA patients were enrolled in cohort C, which represented the nationwide screening data in Taiwan. Jaundice-free was defined as total serum bilirubin <2.0 mg/dL (34 µmol/L). The prevalence could not be calculated, total number of children who were born in these periods are not described. They calculated jaundice-free rates at 3 months after Kasai operation, 3- and 5-year survival rate with native liver, 3- and 5-year jaundice-free survival rates with native liver, and 3-year and 5-year overall survival rates between different cohorts.

Zheng (2020) performed a cohort study in China. Children with BA (diagnosed by cholangiogram) born in Shenzhen who underwent HPE were included. Cohort A was a history cohort, patients in cohort B received a stool color card (SCC) attached to the health handbook for mothers and children. This card also included instructions about the stool and card, information about BA and contact information. A total of 118 patient were diagnosed by cholangiography. In cohort A 34 patient (<2015) and in cohort B 57 children (>2015) were included. All HPE were performed by the same surgical group. All patients underwent follow-up visits through phone calls and outpatient clinic visits for 1–5 years after being discharged from the hospital. No loss of follow up is reported. In this cohort it is not known how many children are born in this period and how many other diagnoses are made.

Another retrospective cohort study was described by Tseng (2011). In this historic cohort between 1996 and 2008, comparison was made before and after introduction of SCC. They searched Taiwan’s National Health Insurance Research Database (NHIRD) for patients’ medical charts from 1996 to 2008. All medical charts were reviewed based on International Classification of diseases Codes. The overall incidence was 1.48 per 10 000 live births during the study period. Prevalence of BA was 0.013%. In total 472 patients were diagnosed with BA, 440 underwent HPE, 32 had a liver transplant directly. No native liver survival/ clearance of jaundice was reported. Furthermore, this study, because of its retrospective design, could not report the proportion of infants with biliary atresia who were diagnosed by stool card screening.

Lee (2016) performed a population-based cohort study in which BA cases were identified during 1997 to 2010 in Taiwan. The aim of this study was to examine whether the implementation of the SCC screening program can improve BA case outcomes. The objectives of this study were to assess the hospitalization, LT, and mortality rates of BA cases before and after the launch of this screening program, and (2) to examine the association between the hospitalization rate and

survival outcomes. The data set was generated from the claims data of the National Health Insurance system. They used a cohort without (before 2004) and with introduction of the SCC. The BA cases from every 2 years were grouped into one period, resulting in a total of 7 periods. A total of 513 BA cases were identified, incidence of BA ranged between 0.12 and 0.19 per 1000 live births.

Hsaio (2008) performed a cohort study in Taiwan with neonates born between January

2004 and December 2005. In this study they aimed to publish results of the first national screening program. Stool color cards were integrated into the child health booklet, which every child in Taiwan receives. On this card contact information for consultation was printed, and each guardian was instructed to contact the registry center within 24 hours of discovery and identification of abnormal stools. The study groups were divided in three historic cohorts: one the long-term participation group, included infants born in the 95 collaborating hospitals or clinics covering the northern, central, southern, and eastern parts of Taiwan and who participated in the pilot study of infant stool color card from March 2002 to December 2003. The other group, the new participation group, included those born in hospitals or clinics where the infant stool card had just been introduced at the beginning of January 2004. A third historic cohort was formed by retrospectively reviewing medical records of infants with BA admitted to the hospital from January 1976 to December 2000. Patients who were lost to follow up before one year of age were excluded. Jaundice free status was defined as total serum bilirubin < 2 mg/dl (34 μmol/l) with normal stool with SCC 3 months after hepatoportoenterostomy according to Kasai (HPE). The diagnostic criteria of BA in this study had to meet either the radiological evidence of BA in operative cholangiography or the characteristic operative and histological findings of BA after laparotomy, when operative cholangiography had not been performed. Data was compared with the total numbers of children born and with the total number of BA, because of contact with all pediatric gastroenterologists. Prevalence in this cohort with BA was 75/422273 (0,017%).

Gu (2017) included children with BA and open Kasai in Japan between August 1994 and March 2011. The aim of the study was to explore the association between use of SCC and native liver survival. As described above (Gu 2015) SCC was provided by caregivers in Tochigi Prefecture and parents were instructed to use them from birth until the first month postnatal health checkup.

Children with no open HPE, children born outside August 1994–March 2011 or who used the SCC were excluded of the control cohort, existing of children with BA born outside Tochigi Prefecture. The total number of children who were included in this study was 148 (34 in SCC cohort, non-SCC cohort 114). Patient characteristics showed no difference in sexes or type BA. This study did not collect data on deceased patients in the control group (SCC non-users) because their caregivers withdrew from membership of the associations for BA patients. The other limitation of this study was that other factors that may have affected outcomes, such as clearance of jaundice and pathological data was not taken in conclusion. Since this is the same cohort as Gu et al (205) prevalence in this study is 0.013%.

Serum bilirubin screening

Harpavat (2020) described a screening study to determine the diagnostic yield of newborn direct bilirubin measurements for biliary atresia and a pre-post study to evaluate the association of screening implementation with clinical outcomes. The prescreening group included patients treated between January 2008 and June 2011 at 14 south Texas hospitals. In the post study infants born in these same hospitals between January 2015 and June 2018 were included. Total bilirubin was before 2015 measured in the first 60 hours of life to screen for the need for phototherapy. The screening from January 2015 onwards followed a 2-stage prospective direct bilirubin testing strategy. In stage 1, all infants were tested via heel stick within the first 60 hours of life as part of routine clinical assessment for hyperbilirubinemia. The infants who had values below upper limit of normal were considered to have negative screening results in stage 1 and were not tested further. The infants who had values above this upper limit were considered to have positive screening results in stage 1 and underwent repeat testing in stage 2 at or before the 2-week well-child visit as part of standard clinical care. Biliary atresia was excluded if direct bilirubin levels had normalized, icterus was absent by 3 months per report from the parents or clinicians, or an alternative diagnosis was made. Infants with negative screening results in stage 1 were followed up indirectly by monitoring admissions at 3 pediatric hepatology centers in the region.

The prespecified primary outcome was the age infants underwent the Kasai portoenterostomy for treatment of biliary atresia. Prevalence of BA was 0.006% (7/124385).

Centralization

Hukkinen (2018) described a cohort study of BA patients born between 1987 and 2016 with at least a 4-month follow-up after primary operation. They aimed to evaluate the effect of centralization on BA outcomes after more than a decade of follow-up and compare the outcomes with those obtained in Helsinki before centralization. Since 2005 all BA patients were tertiary referred to the Helsinki University Children’s Hospital. Before this centralization medical care of BA patients was not standardized in Finland, with different use (and dosage of) ursodeoxycholic acid, trimethoprim-sulfadiazine, dexamethasone and feeding protocols. Clearance of jaundice was defined as serum total bilirubin (https://www.sciencedirect.com/topics/medicine-and-dentistry/bilirubin) <20 μmol/L at any time point postoperatively. Bilirubin levels were recorded at 3 and 6 months after HPE, as well as at last follow-up. Total 63 patients (cohort A 25, cohort B 36) were diagnosed with BA, but two patients were excluded because they died because of other congenital morbidities. The incidence of BA was 1:18600. Age of HPE was significantly earlier in cohort B (54 (28-79) vs 73 (53-101) days, p 0.016. No other patient characteristics were significantly different.

Davenport (2004) described in a cohort study in England and Wales the implementation of centralization to three designated centers where both Kasai, and if necessary, liver transplantation is performed. They aimed to assess the early outcomes resulting from change in policy. In the historic cohort patients were treated in 15 pediatric surgical centers between 1993-1995. In the intervention group they identified all cases with BA between January 1999 and June 2002. Diagnosis of BA was confirmed within each center by a combination of operative and histological findings. Children with anomalies and cystic biliary atresia were excluded in analysis of the effect of age at HPE. No incidence could me calculated based on the study data. Three indicators were assessed: native liver survival and true survival estimates, median time to HPE and percentage of clearance of jaundice, defined as bilirubin < 20 mol/l post HPE within 6 months.

Results

Stool color card

Seven studies described intervention for early detection of biliary atresia with stool color card.

Native liver survival was described in 4 studies (Lien , Zheng , Lee , Gu ). Lien et al showed a 5-years native liver survival significant improvement in 5-years native liver survival from 38% without SCC to 64% with SCC screening. This improvement was not significant for 3 years native liver survival. Zheng reported native liver survival at 2 years post Kasai, which showed an improvement from 44 to 53%, which was not significant. Lee showed native liver survival of 32% without SCC screening and 56% with SCC screening. In this study it is not clear at which age this native liver survival is reported. At last Gu calculated a probability of NLS at 5, 10, and 12.5 years, without and with SCC which were respectively 53%, 44%, 37% and 88%, 77%, and 49%, with statistically significance.

All seven studies reported age at Kasai-operation (Reyes-Cerecedo (2018), Lien (2011), Zheng (2020), Tseng (2011), Lee et al (2016), Hsaio (2008) and Gu et al (2017)). Age at Kasai improved in all studies, but only two showed statistically significance (Zheng et al, Gu et al). More studies showed no significant difference in the timing of operation before 60 days of life (Lee , Tseng , Lien ) in groups screened with stool color card in comparison with groups of children who were not screened.

Clearance of jaundice was reported in 3 out of seven studies (Lien , Zheng , Hsaio ). In Lien et al clearance of jaundice, defined at 3 months post Kasai improved significantly from 35 % without SCC to 61% with SCC. In Zheng , clearance of jaundice was defined as total bilirubin <20 mmol/L within 6 months of the Kasai-operation and improved from 47% without SCC till 54%, but this was not significant.

Hsaio defined COJ as bilirubin < 34 μmol/l with normal stool 3 months after Kasai and showed improved significantly from 37% to 60% with SCC.

Due to large heterogeneity of the study populations, no meta-analysis was performed.

Screening with serum bilirubin.

Only one study is included in this analysis. Harpavat showed improvement of one-year native liver survival from 71 to 95%. This was not significant, because the small number of patients in this study. The study showed a significant reduction in age of Kasai from 56 days before implementation of screening to 36 days after implementation. Clearance of jaundice at 90 days after Kasai improved also significantly from 42% to 79%.

Centralization

Two studies described implementation of centralization (Hukkinen (2018) and Davenport (2004)).

Both studies reported native liver survival. Hukkinen showed a significantly higher native liver survival 5 years post Kasai-operation, 38 and 70% respectively. Davenport et al also showed a significant result between centers with less than 5 cases/year and more than 5 cases/year in the historic cohort (5 years native liver survival: 14 vs 61% respectively), but no significant improvement after centralization in 3 centres; 4 years native liver survival 51%. Age of Kasai improved in Hukkinen et a. from 73 days before centralization to 54 days after centralization. Davenport showed no difference in age of Kasai before and after centralization, which was 53 vs 54 days.

Both studies also reported clearance of jaundice. Hukkinen defined this as < 20umol/l at any time post Kasai and showed a significant improvement from 42 to 80%. Davenport showed an improvement from 62% (> 5 cases/year) and 44% (<5 cases/year) to 57% after centralization, but this was not significant.

Due to large heterogeneity of the study populations, no meta-analysis was performed.

Table 1: Effect of screening methods on native liver survival, age at Kasai procedure, and jaundice clearance

Study	Number of BA patients	Prevalence (95% CI)	Native liver survival	Age Kasai	Clearance of jaundice	Mortality
*Stool color card*
Reyes-Cerecedo (2018)	57	Not reported	Not reported	Age Kasai (median (range) in days) Group with SCC 82 (28-116) Group without SCC 90 days (63-11) p = 0.4	Not reported	Not reported
Lien (2011)	191	Not reported	NLS (3 years) Cohort A 46/89 (52, 95% CI 41-62%) Cohort B+C 63/102 (62%, 95% CI 52-71%)) P 0.16 NLS (5 years) Cohort A 33/88 (38%, 95% CI 28-48%) Cohort B 18/28(64%, 95% CI 46-79%) P=0.01	Age Kasai (number before <60 days) Cohort A 44/89 (49%, 95% CI 39-60%) Cohort B+ C 67/102 (66%, 95 % CI 56-74%) P=0.02 Specific age not reported	COJ (3 months after Kasai operation) Cohort A 31/89 (35%, 95% CI 26-45%) Cohort B+C 62/102 (61%, 95% CI 51-70%) P <0.001	3-year overall survival Cohort A 91/102 (89%, 95% CI 82-94%) P <0.001 Cohort B 57/89 (64.0%, 96% CI 54-73%) OR 4.64 (2.17-9.94) 5-year overall survival Cohort A: 25/28 (89%, 95% CI 73-96%) Cohort B: 49/88 (56%, 95% CI) P <0.001 OR 6.63 (1.86-23.60) P 0.003
Zheng (2020)	N 118	Not reported (total number children born in period not known)	2-year native NLS (2 years) Cohort A A 15/34 (44%, 95 CI 27-61%) Cohort B 30/57 (53%, 95% CI 40-65%) P < 0.05	Age Kasai (days) mean±SD Cohort A: 81±12 Cohort B: 56±15 P < 0.05	COJ (total bilirubin <20 mmol/L within 6 months of the Kasai procedure) Cohort A 16/34 (47 %, 95% CI 30%-64%) Cohort B B 31/57 (54%, 95% CI 40-69%) < P 0.05	Overall mortality Cohort A 7/34(21%, 95% CI 10-37%) Cohort B 6/57 (11%, 95% CI 5-21%) P < 0.05
Tseng (2011)	440	1.48 per 10 000 live 440/3276803(=0.013%)	Not reported	Age Kasai (days) median Cohort A 51 Cohort B 48 (P =0.051) NB: range or ±SD not known Before 60 days Cohort A 106/144 (74%, 95% CI 66-80%) Cohort B 204/296 (69%, 95% CI 64-74%) P 0.31	Not reported	Not reported
Lee (2016)	513 Total cohort 3150271	0.16/1000	NLS (definition not known years) Cohort A 95/338 (32%, 95% CI 24-33%) Cohort B 88/175 (57%, 95% CI 43-58%) P<0.001).	Age Kasai (days) mean±SD Cohort A 59.9 (±76.4) Cohort B 48.2 (±24.5) Total (n=513) 55.88 (±63.9) days Kasai operation before 6 days, no. (%) Cohort A 239/334(72%, 95% CI 67-76%) Cohort B 134/175 (77%, 95% CI 70-82%) P 0.242	Not reported	Mortality Cohort A 33/175 (21%, 95% CI 14-25%) Cohort B 144/338 ( 48% , 95% CI 37-48%) P<0.001.
Hsiao (2008)	75	75/422273 (0,017%).	Not reported	Age Kasai (days) Mean±SD Cohort A: 55.1±15.8(range 24-84 days) Cohort B: 54.1±18.7 (range 11-90) Historic cohort not known	COJ (serum bilirubin < 2 mg/dl (34 μmol/l) with normal stool 3 months after Kasai). Cohort A+B: 44/74 (60%, 95% C 48-670%) Historic cohort:50/135 (37%, 95% CI 29-45%) RR 1.6 (1.2-2.1)P 0.00	Not reported
Gu (2017)	148	Not reported	NLS (Median months) Cohort A 197.2(95% CI: 136.0–258.4) Cohort B 81.0 months (95% CI: 20–142) NLS Probability 5, 10, 12.5 years Cohort A 88, 77, 49%, Cohort B 53, 44, 37%, Comparison of differences in survival times on log rank test p 0.017	Age Kasai (days) Mean±SD Cohort A 59.7 ± 19.4 Cohort B 68.1 ± 25.6 p 0.003	Not reported	Not reported
Serum bilirubin screening
Harpavat (2020)	Ba 7	0,006% (7/124385)	NLS (1 year ) Cohort A 17/24 (71%, 95% CI 51-85%) Cohort B 18/19 (95%, 95% CI 75-100%) Reciprocal RR 1.3 (95% CI 1-1.9) P 0.06	Age Kasai (days) Mean±SD Cohort A 56 ±19 Cohort B 36 ±22 Between group differences 19 days (95% CI 7-32 days) l P 0.004	COJ (90 days after Kasai) Cohort A 10/24 (42%, 95% CI: 25-61%) Cohort B 15/19 (79%, 95% CI 57-92%) P 0.03	Not reported
Centralization
Hukkinen (2018)	61 BA (2 2 with early mortality)	1 :18600	NLS (2 years) Cohort A 37.5% (±SE9.6%) Cohort B 77.6% (±SE7.5) NLS (5 years) Cohort A 37.5% (±SE9.9) Cohort B 70.2%(±SE8.4) P0.014 NLS (10 years) Cohort A 33.3%(±SE9.6) Cohort B 65.2%(±SE9.2)	Age Kasai (days) Cohort A 73(53-101) Cohort B 54(28-79) P 0.016	COJ (< 20umol/l at any time post Kasai) Overall Cohort A 10/24( 42%, 95% CI 25-61%) Cohort B 28/35 (80%, 95% 64-90%) P 0.005 Median rate to COJ Cohort A: 3.2[{IQR 1.8-6.3]months Cohort B: 2.3 [0.84-3.6 months] p 0.272	Overall survival (2-5-10 y) Cohort A 68% (9.3) Cohort B 93.7 (±4.3) P0.007
Davenport et al (2004)	BA 148 cases, 142 HPE	Not reported	NLS 5 years actuarial Cohort A 34/55 ( 61%, 95% CI 49-74%) Cohort B 5/36 (14%, 95% CI 6-29% reported: 0-35) After centralization Cohort C 4y actuarial 75/148 (51%, 95% CI 43-59%)	Age Kasai (Median days) Before centralization Group A 53 Group B: 54 After centralization 54 (range 7-175)	COJ (< 20umol/l at 6 months) Before centralization Cohort A 34/55 (62%, 95% CI 49-74%) Cohort B 16/36 (44%, 95% 30-60%) After centralization Cohort C 81/147 (57%, 96% CI 49-65%)	Not reported

Level of evidence of the literature

All included studies were observational studies with high risk of bias. Because of no randomized studies were included, level of evidence was low for all studies and outcomes. Because all studies included small numbers of included patients, regarding all outcomes the studies were downgraded because of imprecision. Regarding native liver survival the studies were also downgraded for inconsistency and publication bias.

Zoeken en selecteren

We performed a systematic review of the literature to answer the following question: What are the effects of early-detection-policy on long term outcome of children with biliary atresia?

P: neonate OR infant

I: intervention OR screening (example: stool color card, centralization, any)

C: historic controls

O: age at Kasai OR clearance of jaundice OR survival with native liver

Relevant outcome measures

The guideline development group considered survival with native liver as a critical outcome measure for decision making, whereas age at Kasai and clearance of jaundice were considered as important outcome measures for decision making. Earlier Kasai procedure is associated with improved native liver survival (NLS) at 5, 10, and 20 years of life (Hoshino, 2023). Jaundice clearance time seems to be a negative prognostic factor for NLS (Nakajima, 2018). Therefore, all three items could probably be used for decision making. Since age at Kasai and jaundice clearance are, in a sense, surrogate outcomes for NLS, we used NLS as critical outcome measure.

A priori, the guideline development group did not define the outcome measures listed above but used the definitions used in the studies.

Next to that, the guideline development group expected an insufficient amount of direct evidence from RCTs to inform recommendations. At an early stage in the process criteria were set for the selection of non-randomized studies (NRSs).

Search and select (Methods)

We searched for relevant studies published in Medline and Embase January 2000 until December 9th, 2020. A broad search strategy was used that covered the clinical question. Studies were selected based on the following criteria: comparisons between any intervention with effect on early detection of BA and historic data. No filters were used for type of study, except case series and reports. Studies were initially selected based on screening of title and abstract by two independent reviewers. If no consensus was made a third author made the final decision based on title, abstract or whole article if no consensus was made (see data extraction form). Quality assessment was based on GRADE system. Included studies were read by one reviewer who made the literature overview including evidence table.

Referenties

Davenport, M., De Goyet, J. D. V., Stringer, M. D., Mieli-Vergani, G., Kelly, D. A., McClean, P., & Spitz, L. (2004). Seamless management of biliary atresia in England and Wales (1999–2002). The Lancet, 363(9418), 1354-1357.
Gu, Y. H., & Matsui, A. (2017). Long‐term native liver survival in infants with biliary atresia and use of a stool color card: Case–control study. Pediatrics International, 59(11), 1189-1193.
Harpavat, S., Garcia-Prats, J. A., Anaya, C., Brandt, M. L., Lupo, P. J., Finegold, M. J., ... & Shneider, B. L. (2020). Diagnostic yield of newborn screening for biliary atresia using direct or conjugated bilirubin measurements. Jama, 323(12), 1141-1150.
Hoshino E, Muto Y, Sakai K, Shimohata N, Urayama KY, Suzuki M. Age at surgery and native liver survival in biliary atresia: a systematic review and meta-analysis. Eur J Pediatr. 2023 Jun;182(6):2693-2704. doi: 10.1007/s00431-023-04925-1. Epub 2023 Mar 31.
Hsiao, C. H., Chang, M. H., Chen, H. L., Lee, H. C., Wu, T. C., Lin, C. C., ... & Lai, M. W. (2008). Universal screening for biliary atresia using an infant stool color card in Taiwan. Hepatology, 47(4), 1233-1240.
Hukkinen, M., Kerola, A., Lohi, J., Heikkilä, P., Merras-Salmio, L., Jahnukainen, T., ... & Pakarinen, M. P. (2018). Treatment policy and liver histopathology predict biliary atresia outcomes: results after national centralization and protocol biopsies. Journal of the American College of Surgeons, 226(1), 46-57.
Kelly DA, Stanton A. Jaundice in babies: implications for community screening for biliary atresia. BMJ. 1995 May 6;310(6988):1172-3. doi: 10.1136/bmj.310.6988.1172. PMID: 7767152; PMCID: PMC2549543.
Lee, M., Chen, S. C. C., Yang, H. Y., Huang, J. H., Yeung, C. Y., & Lee, H. C. (2016). Infant stool color card screening helps reduce the hospitalization rate and mortality of biliary atresia: a 14-year nationwide cohort study in Taiwan. Medicine, 95(12).
Lien, T. H., Chang, M. H., Wu, J. F., Chen, H. L., Lee, H. C., Chen, A. C., ... & Taiwan Infant Stool Color Card Study Group. (2011). Effects of the infant stool color card screening program on 5‐year outcome of biliary atresia in Taiwan. Hepatology, 53(1), 202-208.
Masucci, L., Schreiber, R. A., Kaczorowski, J., Collet, J. P., & Bryan, S. (2019). Universal screening of newborns for biliary atresia: cost-effectiveness of alternative strategies. Journal of Medical Screening, 26(3), 113-119.
Mogul, D., Zhou, M., Intihar, P., Schwarz, K., & Frick, K. (2015). Cost-effective analysis of screening for biliary atresia with the stool color card. Journal of pediatric gastroenterology and nutrition, 60(1), 91-98.
Nakajima H, Koga H, Okawada M, Nakamura H, Lane GJ, Yamataka A. Does time taken to achieve jaundice-clearance influence survival of the native liver in post-Kasai biliary atresia? World J Pediatr. 2018 Apr;14(2):191-196. doi: 10.1007/s12519-018-0139-5. Epub 2018 Mar 26.
Nomden M, van Wessel DBE, Ioannou S, Verkade HJ, de Kleine RH, Alizadeh BZ, Bruggink JLM, Hulscher JBF. A Higher Incidence of Isolated Biliary Atresia in Rural Areas: Results From an Epidemiological Study in The Netherlands. J Pediatr Gastroenterol Nutr. 2021 Feb 1;72(2):202-209. doi: 10.1097/MPG.0000000000002916. PMID: 32833894.
Rabbani, T., Guthery, S. L., Himes, R., Shneider, B. L., & Harpavat, S. (2021). Newborn Screening for Biliary Atresia: a Review of Current Methods. Current gastroenterology reports, 23(12), 1-8.
Reyes-Cerecedo, A., Flores-Calderón, J., Villasís-Keever, M. Á., Chávez-Barrera, J. A., & Delgado-González, E. E. (2018). Stool color card use for early detection of biliary atresia. Bol Med Hosp Infant Mex, 75, 138-143.
Tseng, J. J., Lai, M. S., Lin, M. C., & Fu, Y. C. (2011). Stool color card screening for biliary atresia. Pediatrics, 128(5), e1209-e1215.
Vandriel SM, Li LT, She H, Wang JS, Gilbert MA, Jankowska I, Czubkowski P, Gliwicz-Miedzińska D, Gonzales EM, Jacquemin E, Bouligand J, Spinner NB, Loomes KM, Piccoli DA, D'Antiga L, Nicastro E, Sokal É, Demaret T, Ebel NH, Feinstein JA, Fawaz R, Nastasio S, Lacaille F, Debray D, Arnell H, Fischler B, Siew S, Stormon M, Karpen SJ, Romero R, Kim KM, Baek WY, Hardikar W, Shankar S, Roberts AJ, Evans HM, Jensen MK, Kavan M, Sundaram SS, Chaidez A, Karthikeyan P, Sanchez MC, Cavalieri ML, Verkade HJ, Lee WS, Squires JE, Hajinicolaou C, Lertudomphonwanit C, Fischer RT, Larson-Nath C, Mozer-Glassberg Y, Arikan C, Lin HC, Bernabeu JQ, Alam S, Kelly DA, Carvalho E, Ferreira CT, Indolfi G, Quiros-Tejeira RE, Bulut P, Calvo PL, Önal Z, Valentino PL, Desai DM, Eshun J, Rogalidou M, Dezsőfi A, Wiecek S, Nebbia G, Pinto RB, Wolters VM, Tamara ML, Zizzo AN, Garcia J, Schwarz K, Beretta M, Sandahl TD, Jimenez-Rivera C, Kerkar N, Brecelj J, Mujawar Q, Rock N, Busoms CM, Karnsakul W, Lurz E, Santos-Silva E, Blondet N, Bujanda L, Shah U, Thompson RJ, Hansen BE, Kamath BM; Global ALagille Alliance (GALA) Study Group. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study. Hepatology. 2023 Feb 1;77(2):512-529. doi: 10.1002/hep.32761. Epub 2022 Oct 13. PMID: 36036223; PMCID: PMC9869940.
Witt, M., Lindeboom, J., Wijnja, C., Kesler, A., Keyzer-Dekker, C. M., Verkade, H. J., & Hulscher, J. B. (2016). Early detection of neonatal cholestasis: inadequate assessment of stool color by parents and primary healthcare doctors. European Journal of Pediatric Surgery, 26(01), 067-073.
Zheng, J., Ye, Y., Wang, B., & Zhang, L. (2020). Biliary atresia screening in Shenzhen: implementation and achievements. Archives of Disease in Childhood, 105(8), 720-723.

Evidence tabellen

©	Study characteristics	Patient characteristics ²	Intervention (I)	Comparison / control (C) ³	Follow-up	Outcome measures and effect size ⁴	Comments
What are the effects of the early detection policy on long term outcomes of children with biliary atresia?
Gu et al (2015)	Type study Prospective cohort Setting Japan, Tochohi Prefecture	Inclusion - Children born in Tochigi prefecture 1994-2011 whose parents returned the SCC n=264.071 Exclusion - Children with BA and no open Kasai - SCC not returned by parents N total at baseline: I: 34 C1 (JBAR): not reported. C2: (Tochigi prefecture before screening): not reported. Important prognostic factors: Age ± SD: I: newborns C1 (JBAR): not reported. C2: (Tochigi prefecture before screening): not reported. Sex: I: 32 % M C1 (JBAR): not reported. C2: (Tochigi prefecture before screening) I: Demographic data not reported for children without BA. Groups comparable at baseline? Unclear	Distribution of the SCC among all pregnant women in Tochigi prefecture, Japan, from 1994 to 2011.	For age at Kasai hepatoportoenterostomy (KP): C1: Data from the Japanese Biliary Atresia Registry (JBAR) 1994-2011. C2: Data from Tochigi prefecture before introduction of SCC program (1987-1992)	Length of follow-up: not reported. Loss-to-follow-up: Intervention: N 49.159 (16 %) of parents did not return a filled-out SCC Reasons (describe) not reported. Control: N (%) Reasons (describe) Incomplete outcome data: Intervention: N (%) Reasons (describe) Control: N (%) Reasons (describe)	Age at Kasai hepatoportoenterostomy (KP), days I: 59.7 ± 19.4 C1 (JBAR): 67.7 C2: (Tochigi prefecture before screening): 70.3 p=.023 vs JBAR, p=.003 vs before screening Native liver survival (NLS) [Probabilities of NSL reported for 5, 10, and 15 years, but not the actual data]	No clearance of jaundice and pathological data BA cohort same as Gu 2017
Reyes-Cerecedo et al (2018)	Type of study Comparative study Setting Mexico, two reference hospitals of high specialty.	Inclusion Confirmed BA Exclusion Underwent Kasai at second level hospital. N total at baseline: Intervention: 32 Control: 27 Important prognostic factors: Age ± SD: I: newborns C: newborns Sex: I: 70 % M C: 56 % M Groups comparable at baseline? Yes	Distribution of SCC to parents of newborns, January 2013-June 2015	No distribution of SCC, January 2010- December 2012	Length of follow-up: not reported. Loss-to-follow-up: Intervention: N (%) Reasons (describe) Control: N (%) Reasons (describe) Incomplete outcome data: Intervention: N (%) Reasons (describe) Control: N (%) Reasons (describe)	Age at Kasai hepatoportoenterostomy (KP), days. Median (range) I: 90 (28-119) C: 84 (22-124) p=.1, (Mann–Whitney U-test, χ2 or Fisher’s exact test)	No long-term outcome Other population: 29 of the 59 case HPE, other referred > 3 months
Lien et al. (2011)	Type of study: Cohort study Setting Taiwan	Inclusion criteria Children with BA born in Taiwan between 1990 and 2005 Exclusion criteria Children with BA who did not undergo KP, or who were followed for <3 years after KP. N total at baseline: Intervention: 102 Control: 89 Important prognostic factors: Age ± SD: I: newborns C: newborns Sex: I: 55% M C: 43% M Groups comparable at baseline? More infants of male sex in the intervention group. No differences in sex, age	I1: Regional SCC screening, 2002- 2004 I2: Universal SCC screening, 2004-2005	C: No SCC screening, 1990-2002	Length of follow-up: at least 3 years after KP Loss-to-follow-up: Intervention: N (%) Reasons (describe) Control: N (%) Reasons (describe) Incomplete outcome data: Intervention: N (%) Reasons (describe) Control: N (%) Reasons (describe) C: 5 years follow up (except 1 pt, n=88) I1 5 years I2 3 years postoperative	Age <60 days at Kasai operation I1+I2: 67 of 102 (65.7%) C: 44 of 89 (49.4%) Chi-square, p=0.02 Jaundice-free survival 3 months after Kasai operation I1+I2: 62 of 102 (60.8%) C: 31 of 89 (34.8%) Chi-square, p<0.001 Jaundice free 3 months after Kasai I1+I2: 62 of 102 (60.8%) C: 31of 89(34.8%) Unadjusted OR 2.90 (1.61-5.23), p<0.001 3-year jaundice free survival with native liver I1+I2: 58 of 102 (56.9%) C: 28 of 89 (31.5%) Unadjusted OR 2.87 (1.58-5.21), p=0.001 5-year jaundice free survival with native liver I1: 18 of 28 (64.3%) C: 24 of 88 (27.3%) Unadjusted OR 4.80 (1.94-11.86), p=0.001 3-year survival with native liver I1+I2: 63 of 102 (61.8%) C: 46 of 89 (51.7%) Chi-square, p=0.16 5-year survival with native liver I1: 18 of 28 (64.3%) C: 33 of 89 (37.5%) Chi-square, p=0.01 Jaundice free 3 months after Kasai KP <60 days: 65 of 111 (58.6%) KP >60 days: 28 of 80 (35%) OR 2.62 (1.45-4.76), p=0.001
Zheng et al. (2020)	Type of study: Cohort study Setting and country: China Funding and conflicts of interest: No information about funding. No conflicts of interest reported.	Inclusion criteria: Children with BA (diagnosed by cholangiogram) born in Shenzhen who underwent Kasai. Exclusion criteria: N total at baseline: Total 118 Cohort A 34 (<2015) Cohort B57n(>2015) Important prognostic factors²: Age at diagnosis ±SD (days) A 81± 12 B 56±15 <0.05 Age at diagnosis A ≤60 days 12 (35.3%) B 37 (64.5%) <0.05 Sex ratio (boys to girls) A1.43 B 1.40 >0.05 Weight ±SD (kg) 5.0±0.5 4.7±0.8 >0.05	SCC	Without SCC	Length of follow-up: Phone calls and outpatient clinic visits 1-5 years. Loss-to-follow-up: None	The rate of jaundice clearance A 47.1 % B 54.4 < P 0.05 2-year native liver survival A 44.1 B 52,6 < 0.05	NB: not known in how many children are born in this period, prevalence not known. No recording system of SCC Substantial proportion guardians declined HPE A: 16/50 B 11/68 P < 0.05
Chen et al. (2006)	Type of study Pilot study Setting Taiwan	Inclusion All newborns 03-2002 till 12-2003, 2003 more regions. Total 96 hospitals 119973 children- response 78184 29 of 78 184; 95% confidence interval: 0.00024–0.00051 SCC in handbook newborns, take it back 1 month of age at health check. N=29 BA with screening Total BA n=30 1 patient died	SCC	Medical registry (one child not found with SCC).	Follow up clinical course each child with BA. 3 months follow up in acholic stool. mean duration of follow-up was 12.8 _ 6.5 months (mean SD; range: 4–25), and 9 (32.1%) of the 28 infants with BA who have received Kasai operation did not get jaundice-free postoperatively.	Age HPE 50.5 ±16.7 days(mean SD; range: 23–83) in infants with successful operation and 94.8 ± 54.6 days (mean SD; range: 31–186) in the failure group (P < .05). Total: 17 (58.6%) before 60 days Jaundice free survival Nineteen (67.9%) of the 28 infants (bilirubin <34 mol/L) < 60 days: 82.4% (14 of 17) > 60 days: 45.5% (5 of 11) Native liver survival 22/28 native liver survival end of follow up
Tseng et al. (2011)	Type of study Retrospective cohort study Setting Taiwan 1996-2008	Inclusion All children with BA N =472	Before SCC introduction N=312 Before screening 296 HPE	After SCC introduction N = 160 After screening 144 HPE	None: no native liver survival/ clearance of jaundice reported	Age HPE Before SCC era: 51 SCC era: 48 days. (P = .051	Could not analyze the proportion of infants with biliary atresia who were diagnosed by stool card screening
Lee et al. (2016)	Type study Cohort study Setting Taiwan Data set was generated from the claims data of the National Health Insurance system.	Inclusion BA cases (N= 513) The incidence of BA ranged between 0.12 and 0.19 per 1000 live births, Exclusion Other N	After introduction SCC N= 175	Before introduction SCC(2004) N= 338		Numbers HPE 457 Before n= 301 After n= 156 Age HPE Kasai operation age, average (SD) Before SCC 59.9 (76.4) After SCC 48.2 (24.5) P 0.064 Total (n=513) 55.88 (63.9) Kasai operation age >60 d, no. (%) Before SCC 95 ((31.6) After SCC 41 (26.3) P 0.242 Total 136 (29.8) Mortality Before SCC 47.8% After SCC 21.2% (P<0.001). Survival LT/death increased from 31.6% to 56.4% (P<0.001). = NLS 43,6 % vs 68,4 % (years???)	Overlap Lien 2011 No clearance of jaundice reported.
Hsaio et al (2008).	Type of study Cohort Setting Taiwan	All neonates born between January 2004 and December 2005	Introduction of SCC nationwide A pilot regional B national	Historic cohort	1 year	Age HPE: Clearance of jaundice 2004/2005: 59.5% Historic:37% RR 1.6 (1.2-2.1)P 0.002 Overall mean age first hospitalization and HPE2004/2005 44.1±1.8(24-84)	No NLS reported
Chiu et al. (2013)	Type of study Retrospective Cohort study Setting and country Taiwan	197 BA cases: 170 term 27 preterm No significance in gender More congenital defects in preterm infants	Children with BA in preterm infants	Children with BA in term infants	Study period 6 years NLS 18 months	Age HPE Term 52.9±18.7 Preterm 71.8±27.6 P < 0.0001 Clearance of jaundice Term 103/66 (62%) Preterm 10/27 (37%) Native liver survival 18 months(N BA =170) Term 109/150 (72.7%) Preterm 10/20 (50%) P 0.043
Harpavat et al. (2020)	Type of study Cross sectional screening study Setting USA	7 BA cases in screening group Prevalence 0.6/10000	After screening two phases Direct/conjugated bilirubin included hospitals + screening in nonstudy birth hospitals +clinical symptoms without screening N= 19	Before screening with direct/conjugated bilirubin N=24	Median follow up before implementation 3.3 years after 2.5 years	Age HPE Before implementation: 56, SD 19 After implementation: 36 (SD 22)95% CI 7-32 dagen verschil P 0.004 Clearance of jaundice Log rank P 0.03 1NLS Before: 70.8% After 94.7%Reciprocal RR 1.3 (95% CI 1-1.9) P 0.06
Gu 2017	Type study case–control study Setting Japan, Tochohi Prefecture	Inclusion Children with BA and open Kasai Exclusion Children with BA and no open Kasai, no use of SCC. Born outside August 1994–March 2012 No differences in gender, type BA	With SCC and BA N = 34	Without SCC and BA N = 114		Age at KPE Cases: 59.7 ± 19.4 Controls: 68.1 ± 25.6 p 0.003 NLS SCC group: Median 197.2 months (95% CI: 136.0–258.4) and probability of NLS at 5, 10, and 12.5 years, was 87.6%, 76.9%, and 48.5%, Non-SCC Median 81.0 months (95% CI: 20.1–141.9) and probability of NLS at 5, 10, and 12.5 years, was 53.1%, 43.9%, and 36.6%, Comparison of differences in survival times on log rank test p 0.017	No clearance of jaundice and pathological data BA cohort same as Gu 2015
Hukkinen 2018	Type of study Cohort study Setting Finland	Inclusion criteria All BA patients born between 1987 and 2016 with at least 4 months follow up Exclusion: Patients age HPE Before: 73(53-101) After: 54(28-79) P 0.016 No other significant differences	After centralization in one centre in Finland (Helsinki)	Before centralization	Till 2016 with at least follow-up 4 months	Clearance of jaundice Overall: Cohort A 10/24 Cohort B 28/35 P 0.005 3 months Cohort A 32% Cohort B 65% P 0.028 NLS2 Cohort A 37.5% (SE9.6% Cohort B 77.6% (±SE7.5) NLS5 Cohort A:37.5% (±SE9.9( Cohort B 70.2%(±SE8.4) P0.014 NLS10 Cohort A33.3%(±SE9.6) Cohort B 65.2%(±SE9.2) Overall survival (2-5-10 y) Cohort A 68% (9.3) Cohort B 93.7 (±4.3) P0.007
Davenport et al (2011)	Type of study Cohort study Setting Engeland en Wales	Inclusion criteria Children with BA (n=443,424 HPE) Exclusion criteria Congenital anomalies Cystic biliary atresia Primary liver transplantation	Centralization (3 center)	Published national studies		Age HPE 54 days (IQ 43-69) Clearance of jaundice 232/424 (55%) NLS5 (estimates) 46% (41-51) NLS10(estimate) 40% (34-46) Survival 5 years (estimates) 90% (88-93) Survival10y estimates 89% (86-93)	No comparison with historic cohort, do we have to include this study???
Davenport (2004)	Type of study Historic cohort Setting UK and Wales	Inclusion criteria Children with BA (n= 142) Exclusion criteria	Centralization	Before centralization (n=13) A: > 5/year B: < 5/year	At least 6 months	Median age HPE: 54 (range 7-175) Clearance of jaundice A 62% B:44% C:57% Native liver survival A (5y actuarial): 61 (49-74) B (5y actuarial)14 (0-35) C (4y actuarial)51 (42-59)
McKiernan et al (2000)	Type of study Cohort study Setting UK and Ireland	Inclusion Children with BA Exclusion	A: Centers with more than 5 children diagnosed per year	B: Centers with less than 5 diagnosed children per year	Median follow-up 3.5 (0.3-5.4) years	Age HPE:54 (14-294 Group A: 10 (2-55) B: 14 (1-94) P < 0.05 Primary success 50/91 (55%) A: 62% (95% CI 49-75) B: 44% (95% CI 28-60) NLS5 Total cohort: 30.1%(95% CI 4-56.2) Group A: 61.3% (95% CI 48.8-74) Group B: 13.7% (95% CI 0-35.2) Overall survival 85% (95% 77.7-92.3% A: 91.2% (95% CI 83.9-98.6) B: 75% (95% CI 60.8-89.2)

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

What are the effects of the early detection policy on long term outcomes of children with biliary atresia?

Gu et al (2015)

Type study

Prospective cohort

Setting

Japan, Tochohi Prefecture

Inclusion

- Children born in Tochigi prefecture 1994-2011 whose parents returned the SCC n=264.071

Exclusion

- Children with BA and no open Kasai

- SCC not returned by parents

N total at baseline:

I: 34

C1 (JBAR): not reported.

C2: (Tochigi prefecture before screening): not reported.

Important prognostic factors:

Age ± SD:

I: newborns

C1 (JBAR): not reported.

C2: (Tochigi prefecture before screening): not reported.

Sex:

I: 32 % M

C1 (JBAR): not reported.

C2: (Tochigi prefecture before screening)

I: Demographic data not reported for children without BA.

Groups comparable at baseline?

Unclear

Distribution of the SCC among all pregnant women in Tochigi prefecture, Japan, from 1994 to 2011.

For age at Kasai hepatoportoenterostomy (KP):

C1: Data from the Japanese Biliary Atresia Registry (JBAR) 1994-2011.

C2: Data from Tochigi prefecture before introduction of SCC program (1987-1992)

Length of follow-up: not reported.

Loss-to-follow-up:

Intervention:

N 49.159 (16 %) of parents did not return a filled-out SCC

Reasons (describe) not reported.

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Age at Kasai hepatoportoenterostomy (KP), days

I: 59.7 ± 19.4

C1 (JBAR): 67.7

C2: (Tochigi prefecture before screening): 70.3

p=.023 vs JBAR, p=.003 vs before screening

Native liver survival (NLS)

[Probabilities of NSL reported for 5, 10, and 15 years, but not the actual data]

No clearance of jaundice and pathological data

BA cohort same as Gu 2017

Reyes-Cerecedo et al (2018)

Type of study

Comparative study

Setting

Mexico, two reference hospitals of high

specialty.

Inclusion

Confirmed BA

Exclusion

Underwent Kasai at second level hospital.

N total at baseline:

Intervention: 32

Control: 27

Important prognostic factors:

Age ± SD:

I: newborns

C: newborns

Sex:

I: 70 % M

C: 56 % M

Groups comparable at baseline?

Yes

Distribution of SCC to parents of newborns, January 2013-June 2015

No distribution of SCC, January 2010- December 2012

Length of follow-up: not reported.

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Age at Kasai hepatoportoenterostomy (KP), days. Median (range)

I: 90 (28-119)

C: 84 (22-124)

p=.1, (Mann–Whitney U-test, χ2 or Fisher’s exact test)

No long-term outcome

Other population: 29 of the 59 case HPE, other referred > 3 months

Lien et al. (2011)

Type of study:

Cohort study

Setting

Taiwan

Inclusion criteria

Children with BA born in Taiwan between 1990 and 2005

Exclusion criteria

Children with BA who did not undergo KP, or who were followed for <3 years after KP.

N total at baseline:

Intervention: 102

Control: 89

Important prognostic factors:

Age ± SD:

I: newborns

C: newborns

Sex:

I: 55% M

C: 43% M

Groups comparable at baseline?

More infants of male sex in the intervention group.

No differences in sex, age

I1: Regional SCC screening, 2002- 2004

I2: Universal SCC screening, 2004-2005

C: No SCC screening, 1990-2002

Length of follow-up: at least 3 years after KP

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

C: 5 years follow up (except 1 pt, n=88)

I1 5 years

I2 3 years postoperative

Age <60 days at

Kasai operation

I1+I2: 67 of 102 (65.7%)

C: 44 of 89 (49.4%)

Chi-square, p=0.02

Jaundice-free survival

3 months after

Kasai operation

I1+I2: 62 of 102 (60.8%)

C: 31 of 89 (34.8%)

Chi-square, p<0.001

Jaundice free 3 months after Kasai

I1+I2: 62 of 102 (60.8%)

C: 31of 89(34.8%)

Unadjusted OR 2.90 (1.61-5.23), p<0.001

3-year jaundice free survival with native liver

I1+I2: 58 of 102 (56.9%)

C: 28 of 89 (31.5%)

Unadjusted OR 2.87 (1.58-5.21), p=0.001

5-year jaundice free survival with native liver

I1: 18 of 28 (64.3%)

C: 24 of 88 (27.3%)

Unadjusted OR 4.80 (1.94-11.86), p=0.001

3-year survival with native liver

I1+I2: 63 of 102 (61.8%)

C: 46 of 89 (51.7%)

Chi-square, p=0.16

5-year survival with native liver

I1: 18 of 28 (64.3%)

C: 33 of 89 (37.5%)

Chi-square, p=0.01

Jaundice free 3 months after Kasai

KP <60 days: 65 of 111 (58.6%)

KP >60 days: 28 of 80 (35%)

OR 2.62 (1.45-4.76), p=0.001

Zheng et al. (2020)

Type of study:

Cohort study

Setting and country: China

Funding and conflicts of interest:

No information about funding. No conflicts of interest reported.

Inclusion criteria:

Children with BA (diagnosed by cholangiogram) born in Shenzhen who underwent Kasai.

Exclusion criteria:

N total at baseline:

Total 118

Cohort A 34 (<2015)

Cohort B57n(>2015)

Important prognostic factors²:

Age at diagnosis ±SD (days)

A 81± 12

B 56±15 <0.05

Age at diagnosis

A ≤60 days 12 (35.3%)

B 37 (64.5%) <0.05

Sex ratio (boys to girls)

A1.43

B 1.40 >0.05

Weight ±SD (kg) 5.0±0.5

4.7±0.8 >0.05

SCC

Without SCC

Length of follow-up:

Phone calls and outpatient clinic visits 1-5 years.

Loss-to-follow-up:

None

The rate of jaundice clearance

A 47.1 %

B 54.4

< P 0.05

2-year native liver survival

A 44.1

B 52,6

< 0.05

NB: not known in how many children are born in this period, prevalence not known.

No recording system of SCC

Substantial proportion guardians declined HPE

A: 16/50

B 11/68

P < 0.05

Chen et al. (2006)

Type of study

Pilot study

Setting

Taiwan

Inclusion

All newborns 03-2002 till 12-2003, 2003 more regions.

Total 96 hospitals

119973 children- response 78184

29 of 78 184; 95%

confidence interval: 0.00024–0.00051

SCC in handbook newborns, take it back 1 month of age at health check.

N=29 BA with screening

Total BA n=30

1 patient died

SCC

Medical registry (one child not found with SCC).

Follow up clinical course each child with BA.

3 months follow up in acholic stool.

mean duration of follow-up was

12.8 _ 6.5 months (mean SD; range: 4–25), and 9

(32.1%) of the 28 infants with BA who have received

Kasai operation did not get jaundice-free postoperatively.

Age HPE

50.5 ±16.7 days(mean SD; range: 23–83) in infants with successful operation and 94.8 ± 54.6 days (mean SD; range: 31–186) in the failure group (P < .05).

Total: 17 (58.6%) before 60 days

Jaundice free survival

Nineteen (67.9%) of the 28 infants

(bilirubin <34 mol/L)

< 60 days:

82.4% (14 of

17)

> 60 days: 45.5% (5 of 11)

Native liver survival

22/28 native liver survival end of follow up

Tseng et al. (2011)

Type of study

Retrospective cohort study

Setting

Taiwan 1996-2008

Inclusion

All children with BA

N =472

Before SCC introduction

N=312

Before screening

296 HPE

After SCC introduction

N = 160

After screening

144 HPE

None: no native liver survival/ clearance of jaundice reported

Age HPE

Before SCC era: 51

SCC era: 48 days.

(P = .051

Could not analyze the proportion of infants

with biliary atresia who were diagnosed

by stool card screening

Lee et al. (2016)

Type study

Cohort study

Setting

Taiwan

Data set was generated from the claims data of the National

Health Insurance system.

Inclusion

BA cases

(N= 513)

The incidence of BA ranged between 0.12 and

0.19 per 1000 live births,

Exclusion

Other N

After introduction SCC

N= 175

Before introduction SCC(2004)

N= 338

Numbers HPE 457

Before n= 301

After n= 156

Age HPE

Kasai operation age, average (SD)

Before SCC

59.9 (76.4)

After SCC 48.2 (24.5) P 0.064

Total (n=513) 55.88 (63.9)

Kasai operation age >60 d, no. (%)

Before SCC 95 ((31.6)

After SCC 41 (26.3) P 0.242

Total 136 (29.8)

Mortality

Before SCC

47.8%

After SCC 21.2% (P<0.001).

Survival

LT/death increased

from 31.6% to 56.4% (P<0.001).

= NLS

43,6 % vs 68,4 %

(years???)

Overlap Lien 2011

No clearance of jaundice reported.

Hsaio et al (2008).

Type of study

Cohort

Setting

Taiwan

All neonates born between January

2004 and December 2005

Introduction of SCC nationwide

A pilot regional
B national

Historic cohort

1 year

Age HPE:

Clearance of jaundice

2004/2005: 59.5%

Historic:37% RR 1.6 (1.2-2.1)P 0.002

Overall mean age first hospitalization and HPE2004/2005 44.1±1.8(24-84)

No NLS reported

Chiu et al. (2013)

Type of study

Retrospective Cohort study

Setting and country

Taiwan

197 BA cases:

170 term
27 preterm

No significance in gender

More congenital defects in preterm infants

Children with BA in preterm infants

Children with BA in term infants

Study period 6 years

NLS 18 months

Age HPE Term 52.9±18.7 Preterm 71.8±27.6 P < 0.0001

Clearance of jaundice Term 103/66 (62%) Preterm 10/27 (37%)

Native liver survival 18 months(N BA =170) Term 109/150 (72.7%)

Preterm 10/20 (50%) P 0.043

Harpavat et al. (2020)

Type of study

Cross sectional screening study

Setting

USA

7 BA cases in screening group

Prevalence 0.6/10000

After screening two phases Direct/conjugated bilirubin included hospitals

+ screening in nonstudy birth hospitals

+clinical symptoms without screening

N= 19

Before screening with direct/conjugated bilirubin

N=24

Median follow up before implementation 3.3 years after 2.5 years

Age HPE Before implementation: 56, SD 19

After implementation: 36 (SD 22)95% CI 7-32 dagen verschil P 0.004

Clearance of jaundice Log rank P 0.03

1NLS Before: 70.8% After 94.7%Reciprocal RR 1.3 (95% CI 1-1.9) P 0.06

Gu 2017

Type study

case–control study

Setting

Japan, Tochohi Prefecture

Inclusion

Children with BA and open Kasai

Exclusion

Children with BA and no open Kasai, no use of SCC. Born outside August 1994–March 2012

No differences in gender, type BA

With SCC and BA

N = 34

Without SCC and BA

N = 114

Age at KPE

Cases: 59.7 ± 19.4

Controls: 68.1 ± 25.6

p 0.003

NLS

SCC group: Median 197.2 months (95% CI: 136.0–258.4) and probability of NLS

at 5, 10, and 12.5 years, was 87.6%, 76.9%, and 48.5%,

Non-SCC

Median 81.0 months (95% CI: 20.1–141.9) and probability of NLS at

5, 10, and 12.5 years, was 53.1%, 43.9%, and 36.6%,

Comparison of differences in survival times on log rank test p 0.017

No clearance of jaundice and pathological data

BA cohort same as Gu 2015

Hukkinen 2018

Type of study

Cohort study

Setting Finland

Inclusion criteria

All BA patients born between 1987 and 2016 with at least 4 months follow up

Exclusion:

Patients age HPE

Before: 73(53-101)

After: 54(28-79)

P 0.016

No other significant differences

After centralization in one centre in Finland (Helsinki)

Before centralization

Till 2016 with at least follow-up 4 months

Clearance of jaundice

Overall:

Cohort A

10/24

Cohort B

28/35

P 0.005

3 months

Cohort A

32%

Cohort B 65%

P 0.028

NLS2

Cohort A 37.5% (SE9.6%

Cohort B 77.6% (±SE7.5)

NLS5

Cohort A:37.5% (±SE9.9(

Cohort B 70.2%(±SE8.4)

P0.014

NLS10

Cohort A33.3%(±SE9.6)

Cohort B 65.2%(±SE9.2)

Overall survival

(2-5-10 y)

Cohort A 68% (9.3)

Cohort B 93.7 (±4.3)

P0.007

Davenport et al (2011)

Type of study

Cohort study

Setting

Engeland en Wales

Inclusion criteria

Children with BA (n=443,424 HPE)

Exclusion criteria

Congenital anomalies
Cystic biliary atresia
Primary liver transplantation

Centralization (3 center)

Published national studies

Age HPE

54 days (IQ 43-69)

Clearance of jaundice

232/424 (55%)

NLS5 (estimates) 46% (41-51)

NLS10(estimate)

40% (34-46)

Survival 5 years (estimates)

90% (88-93)

Survival10y estimates 89% (86-93)

No comparison with historic cohort, do we have to include this study???

Davenport (2004)

Type of study

Historic cohort

Setting

UK and Wales

Inclusion criteria

Children with BA (n= 142)

Exclusion criteria

Centralization

Before centralization (n=13)

A: > 5/year

B: < 5/year

At least 6 months

Median age HPE: 54 (range 7-175)

Clearance of jaundice

A 62%

B:44%

C:57%

Native liver survival

A (5y actuarial): 61 (49-74)

B (5y actuarial)14 (0-35)

C (4y actuarial)51 (42-59)

McKiernan et al (2000)

Type of study

Cohort study

Setting

UK and Ireland

Inclusion

Children with BA

Exclusion

A: Centers with more than 5 children diagnosed per year

B: Centers with less than 5 diagnosed children per year

Median follow-up 3.5 (0.3-5.4) years

Age HPE:54 (14-294

Group A: 10 (2-55)

B: 14 (1-94)

P < 0.05

Primary success

50/91 (55%)

A: 62% (95% CI 49-75)

B: 44% (95% CI 28-60)

NLS5

Total cohort: 30.1%(95% CI 4-56.2)

Group A: 61.3% (95% CI 48.8-74)

Group B: 13.7% (95% CI 0-35.2)

Overall survival 85% (95% 77.7-92.3%

A: 91.2% (95% CI 83.9-98.6)

B: 75% (95% CI 60.8-89.2)

Yachha 2020	Type of study Cohort Setting India	Children admitted at hospital	Photographs stool	SCC Taiwan	none
Harpavat 2018	Type study Retrospective Setting USA	Inclusion BA diagnosed in specific hospital Texas Exclusion BA diagnosed elsewhere N=65 BA cases	Before hospital period	After hospital referral		Factors Race/ethnicity was associated with age at referral, with non-Hispanic white subjects having significantly shorter P1 times than Hispanic and non-Hispanic black subjects (P<0.01) The mean P1 time was 72.9_39.9 days for the remaining 44 subjects P2: 16 subjects referred too late for the KP and 1 subject with congenital heart disease precluding, P2 time was 15.6_23.0 days for the remaining 48 subjects Shorter P2 times were strongly associated with older ages at referral. These associations were confirmed with Cox analyses, with subjects presenting after 30 DoL (HR 15.47, 95% CI 4.43–53.99, P<0.001), 45 DoL (HR 6.94, 95% CI 2.72–17.71, P<0.001), and 60 DoL (HR 3.12, 95% CI 1.55– 6.25, P¼0.001)	Not primary outcomes: age HPE, clearance of jaundice or NLS are described.
Madadi‑Sanjani (2019)	Type of study pilot project Setting Germany in Lower Saxony	Children with abnormal stool color card or BA	SCC: n=1 with BA N=1 with A1AT	Hannover referral center	1 patient with BA NLS, not fully described		No outcomes described. Lot of missing data
Lin (2015)	Type of study: Retrospective cohort study Setting and country: Taiwan Funding and conflicts of interest: No information about funding.	Inclusion criteria: Children with BA Exclusion criteria: N total at baseline: 540 BA cases				Age at Kasai operation (d), mean ± SD. 1) 58.2 ± 42.0 2)50.5 ± 30.8 3) 46.0 ± 23.8 P 0.0063 Kasai operation ≤ 60 d 1 1: 144 (76.6) 2: 154 (88.5) 3: 99 (81.1) 0.285 NLS 3 years: Liver transplant 1: 68 (32.7) 2: 82 (41.0) 3: 39 (29.6) p 0.7824 DUS: 140 (67%) 118 (59%) 93 (70,4%)	No comparison of screening implementation Three birth cohorts: (1) 1997 to 2001; (2) 2002 to 2006; and (3) 2007 to 2011 : @+# is with SCC, but they don’t describe this in the report. Conclusion authors: The decrease in ages at BA diagnosis and subsequent operation was not entirely due to the SCC screening program alone Kan wel iets extrapoleren maar omvat niet de onderzoeksvraag.
Masucci (2019)	Type of study Cost effectiveness study Setting Canada	Children with BA	Screening with SCC Conjugated bilirubin	Comparison No screening SCC	10 years	SCC: ICER = $24,065 per life year gained Conjugated bilirubin $473,840 per life year Gained	Pooled data from other studies, heterogenous studies.
Suzuki (2011)	Type of study Pilot screening study Setting Japan	Inclusion All children born between August 2006 and May 2007 Exclusion Premature < 36 weeks Birth weight < 2000 gram	Screening with urinary sulfated bile acid		4 months	47 (4.10%) exceed cutoff value 2/47 liver disease 1/47 BA (HPE day 49) sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 96%, 4%, and 100%, respectively	No long-term outcome
Wang 2015	Type of study Review Setting USA						Review, not systematic Wel duidelijk overzicht over bovengenoemde artikelen
Jancelewicz et al (2015)
Lam et al (2016)
Verkade et al (2016)	Type of study Review Setting The Netherlands						Review, not systematic
Davenport et al (2004)
Schreiber 2010	Inclusion Children with BA, born between 1 January 1992 and 31 December 2002 diagnosed and followed at 1 of 12 Canadian university-based pediatric tertiary care institutions. Exclusion	N 230 A: < 1cases/y B 1-3 cases/y C >3 cases/y	Total cohort	Centre caseload experience	overall patient survival defined as starting at birth and ending at death or last follow-up; liver transplant (LT) survival beginning at transplant and ending at death or last follow-up; and native liver survival starting at birth and ending at death, transplant, or last follow-up	Age HPE Total cohort 64 (6-173) A 66 B56 C 66 P 0.05 Overall NLS 60% NS between groups Overall survival Survival 4 y 83% (CI 78-88), NS between groups	No clearance of jaundice. No comparison of implementation
Lampela 2012					1987-2010	Clearance of jaundice Before 12/44 After 15/20 P 0.001 NLS1 B: 26/59 A:15/16 P0.012 NLS2 B: 12/27 A:9/12 P0.005 Overall survival1 B:33/75 A;16/17 P0.027 Overall survival2 B:28/64 A;11/12 P 0.082	Overlap data Hukkinen 2018 (FU 1987-2016)
Madidi-Sanjani et al (2021)
Benchimol 2009	Type of study: Clinical review Setting and country: Canada Funding and conflicts of interest: No information about funding. No conflicts of interest reported.	Inclusion criteria: cholestasis, jaundice and conjugated, mass screening, biliary atresia, galactosemia, tyrosinemia, congenital hypothyroidism, cystic fibrosis, Kasai, and hepatoportoenterostomy, with randomized controlled trial, controlled clinical trial, systematic review, cohort study, guideline, diagnosis, and early diagnosis. Exclusion criteria: Children older than 60 days N total at baseline: In methods not clearly how many studies/patients Important prognostic factors²:			Length of follow-up: Loss-to-follow-up:	SCC: sensitivity and specificity (see separate studies) utility of serum and urine bile acid measurements: no effect size described.	Page 7: description of several studies, but these are also separately included (see below). No systematic review or description of quality of included studies.
Fanna 2019	Type of study Cohort Setting France	Inclusion Children with BA in France born between January 1986 and December 2015 Exclusion: Patients with misdiagnosed BA who underwent a HPE. BA patient n= 1428			Loss to follow up was 7% in the last 3 years. Median 11.5 y(1m-31y)	Clearance of jaundice 516/1330 children. Ratio in different cohorts not different. NLS 5y: 41.2% 10y 35.4% 20y 26.3% 30y 22.4% Overall survival 1y 92.2% (SE 0.01) 5y 581.8% (SE 0.01) 10y 80.4% (SE 0.01) 20y 77.9% (SE 0.01), 30y 75.6% (SE 0.02) Five-year BA patient survival was 72.1% (SE 0.02), 88.1% (SE 0.02), 87.1% (SE 0.02), and 86.8% (SE 0.02) in cohorts 1 to 4 (P < 0.0001)	No comparison is made, no centralization. Only difference in time is less centres with <3HPE/year (24-18-17-8 in cohorts) and more collaboration. Meer background article
Serinet 2006							Same cohort as Fanna et al, earlier in time.
Serinet 2009							Same cohort as Fanna et al, earlier in time.
Bjornland et al 2018	Type of study Retrospective observational chart study Setting Norway	All patients with confirmed BA between January 2000 and February 2017 N= 45 cases Median age HPE: 65(14-104)	2009-2017(B)	2000-2008(A)	6 months	Clerance of jaundice Total 23/43 A 41% B 67% P 0.091 NLS3 47% NLS5 40%	Only one centre, no comparison of intervention only description of outcome
De Vries 2012	Type of study Retrospective cohort study Setting Netherlands	All children with BA N=231 Incidence: 1:18619	1987-1997	1998-2008	No loss of FU Median FU: 6.9y Survival 9.7 (0.5-21.9)		6 Centres, no comparison of intervention. Description of outcome
Gang Tu 2014	Type of study Retrospective cohort Setting South Australia	BA patients between 1989 and 2010			FU median 13.4y	Age HPE 46d (3-114)v Clearance of jaundice 42.9% NLS5 55.2% (CI 71.5-97.3) Overall survival 89.7% (95% CI 36-73%)	Single centre no comparison

Risk of bias table

Risk of bias assessment diagnostic accuracy studies (QUADAS II, 2011)

Research question: What are the effects of the early detection policy on long term outcomes of childeren?

Study reference	Patient selection	Index test	Reference standard	Flow and timing	Comments with respect to applicability
Woolfson et al (2018)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? Yes (First scc before biopsy/cholangiogram) If a threshold was used, was it pre-specified? Not applicable	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? No (only BA patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: Low	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Gu et al (2015)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Unclear	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Not applicable	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? No (only BA patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: Low	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Reyes-Cerecedo et al (2018)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? No; only two very specialistic hospitals were incuded.	Were the index test results interpreted without knowledge of the results of the reference standard? No If a threshold was used, was it pre-specified? Not used	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? Yes	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Lien et al (2011)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? No If a threshold was used, was it pre-specified? Not used	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? No (only HPE patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Zheng et al . (2020)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Unclear	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Not applicable	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? No (only BA patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: Low	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Chen et al. ( 2006)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Unclear	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Not applicable	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? No (only BA patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: Low	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Tseng et al (2011)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Unclear	Were the index test results interpreted without knowledge of the results of the reference standard? Unclear If a threshold was used, was it pre-specified? Unclear	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Unclear Did patients receive the same reference standard? Unclear Were all patients included in the analysis? No (only BA patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: Low	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Lee et al. (2016)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Unclear	Were the index test results interpreted without knowledge of the results of the reference standard? Unclear If a threshold was used, was it pre-specified? Unclear	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? Unclear	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Unclear Did patients receive the same reference standard? Unclear Were all patients included in the analysis? No (only BA patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Hsaio et al.(2008)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Unclear	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Not used	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? No (only BA patients)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Chiu et al. (2013)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? No	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Not used	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Two reference tests were used. Were all patients included in the analysis? Yes	Are there concerns that the included patients do not match the review question? Yes, more congenital defects. Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Harpavat et al (2020)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Yes (bili > 1 mg/dl)	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? Yes	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Gu et al. (2017)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? Yes If a threshold was used, was it pre-specified? Not used	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? Yes Did patients receive the same reference standard? Yes Were all patients included in the analysis? No (two who died early; 61/63 included)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Hukkinen 2018	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? nvt If a threshold was used, was it pre-specified? nvt	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? No	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? No, after 2005 yes. Did patients receive the same reference standard? After 2005 Were all patients included in the analysis? No (two who died early; 61/63 included)	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Davenport et al (2011)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? nvt If a threshold was used, was it pre-specified? nvt	Is the reference standard likely to correctly classify the target condition? nvt Were the reference standard results interpreted without knowledge of the results of the index test? Nvt No reference test??	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? nvt Did patients receive the same reference standard? nvt Were all patients included in the analysis? No	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
Davenport et al (2004)	Was a consecutive or random sample of patients enrolled? No Was a case-control design avoided? No Did the study avoid inappropriate exclusions? Yes	Were the index test results interpreted without knowledge of the results of the reference standard? nvt If a threshold was used, was it pre-specified? nvt Historic cohort	Is the reference standard likely to correctly classify the target condition? Yes Were the reference standard results interpreted without knowledge of the results of the index test? Nvt	Was there an appropriate interval between index test(s) and reference standard? Unclear Did all patients receive a reference standard? nvt Did patients receive the same reference standard? nvt Were all patients included in the analysis? No	Are there concerns that the included patients do not match the review question? No Are there concerns that the index test, its conduct, or interpretation differ from the review question? No Are there concerns that the target condition as defined by the reference standard does not match the review question? No
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High
	CONCLUSION: Could the selection of patients have introduced bias? RISK: High	CONCLUSION: Could the conduct or interpretation of the index test have introduced bias? RISK: High	CONCLUSION: Could the reference standard, its conduct, or its interpretation have introduced bias? RISK: High	CONCLUSION Could the patient flow have introduced bias? RISK: High

Study reference

Patient selection

Index test

Reference standard

Flow and timing

Comments with respect to applicability

Woolfson et al (2018)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes (First scc before biopsy/cholangiogram)

If a threshold was used, was it pre-specified?

Not applicable

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No (only BA patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: Low

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Gu et al (2015)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Not applicable

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No (only BA patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: Low

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Reyes-Cerecedo et al (2018)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

No; only two very specialistic hospitals were incuded.

Were the index test results interpreted without knowledge of the results of the reference standard?

If a threshold was used, was it pre-specified?

Not used

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Lien et al (2011)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

If a threshold was used, was it pre-specified?

Not used

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No (only HPE patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Zheng et al . (2020)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Not applicable

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No (only BA patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: Low

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Chen et al. ( 2006)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Not applicable

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No (only BA patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: Low

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Tseng et al (2011)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

Unclear

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Unclear

Did patients receive the same reference standard?

Unclear

Were all patients included in the analysis?

No (only BA patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: Low

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Lee et al. (2016)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

Unclear

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Unclear

Did patients receive the same reference standard?

Unclear

Were all patients included in the analysis?

No (only BA patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Hsaio et al.(2008)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Not used

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No (only BA patients)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Chiu et al. (2013)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Not used

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Two reference tests were used.

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Yes, more congenital defects.

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Harpavat et al (2020)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Yes (bili > 1 mg/dl)

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Gu et al. (2017)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Not used

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No (two who died early; 61/63 included)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Hukkinen 2018

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

nvt

If a threshold was used, was it pre-specified?

nvt

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

No, after 2005 yes.

Did patients receive the same reference standard?

After 2005

Were all patients included in the analysis?

No (two who died early; 61/63 included)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Davenport et al (2011)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

nvt

If a threshold was used, was it pre-specified?

nvt

Is the reference standard likely to correctly classify the target condition?

nvt

Were the reference standard results interpreted without knowledge of the results of the index test?

Nvt

No reference test??

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

nvt

Did patients receive the same reference standard?

nvt

Were all patients included in the analysis?

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Davenport et al (2004)

Was a consecutive or random sample of patients enrolled?

Was a case-control design avoided?

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

nvt

If a threshold was used, was it pre-specified?

nvt

Historic cohort

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Nvt

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

nvt

Did patients receive the same reference standard?

nvt

Were all patients included in the analysis?

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: High

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: High

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: High

CONCLUSION

Could the patient flow have introduced bias?

RISK: High

Verantwoording

Autorisatiedatum en geldigheid

Laatst beoordeeld : 22-05-2024

Laatst geautoriseerd : 22-05-2024

Geplande herbeoordeling : 22-05-2029

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Kindergeneeskunde

Algemene gegevens

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Kwaliteitsgelden Medisch Specialisten (SKMS).

De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijn is in 2020 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor patiënten bij wie diagnostiek naar galgangatresie plaatsvindt.

Samenstelling van de werkgroep

Prof. dr. H.J. (Henkjan) Verkade, kinderarts- MDL, werkzaam in het Universitair Medisch Centrum Groningen (Beatrix Kinderziekenhuis) te Groningen, NVK (voorzitter)
Dr. P.F. (Patrick) van Rheenen, kinderarts-MDL, werkzaam in het Universitair Medisch Centrum Groningen (Beatrix Kinderziekenhuis) te Groningen, NVK (vicevoorzitter)
Drs. J.M. (Jessica) Pruisen, fellowship MDL, werkzaam in het Universitair Medisch Centrum Groningen (Beatrix Kinderziekenhuis) te Groningen, NVK
Prof. dr. C.D.M. (Clara) van Karnebeek, kinderarts en geneticus metabole ziekten, werkzaam in het Amsterdam UMC, NVK
Dr. T.W. (Tjalling) de Vries, algemeen kinderarts (niet praktiserend). Indertijd werkzaam in het Medisch Centrum Leeuwarden, NVK
Prof. dr. J.B.F. (Jan) Hulscher, chirurg, werkzaam in het Universitair Medisch Centrum Groningen te Groningen, NVvH
Drs. C. (Carlijn) Frantzen, klinisch geneticus, werkzaam in het Universitair Medisch Centrum Groningen (Beatrix Kinderziekenhuis) te Groningen, VKGN
Drs. C.A. (Lineke) Dogger, arts Maatschappij en Gezondheid, jeugdarts werkzaam bij NSPOH als opleider/adviseur, AJN

Samenstelling klankbordgroep

J. (Janine) Pingen, St. Kind en Ziekenhuis
Drs. J.A. (José) Willemse, directeur Nederlandse Leverpatiënten Vereniging
Dr. V.M. (Victorien) Wolters, kinderarts-MDL, werkzaam in het Universitair Medisch Centrum Utrecht (Wilhelmina Kinderziekenhuis) te Utrecht, NVK

Met ondersteuning van:

Dr. T. (Tim) Christen, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. J. (Janneke) Hoogervorst – Schilp, senior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. M. (Mattias) Göthlin, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Drs. S. (Sjoukje) van der Werf, medisch informatiespecialist, UMCG

Belangenverklaringen

De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.

Werkgroeplid	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
*Werkgroep*
Prof. dr. H.J. (Henkjan) Verkade	Hoogleraar kindergeneeskunde/ Kinderarts Maag-, Darm- en Leverziekten	Consultancy voor Ausnutria, Albireo AB, Mirum, Friesland Campina, Vivet, lntercept, GMP-Orphan en Shire (elk op ad interim basis) Onbetaalde nevenwerkzaamheden: Associate Editor van Journal Pediatric Gastroenterology and Nutrition (JPGN). Lid Wetenschappelijke Adviesraad 'Najjar Stichting' (patiëntenorganisatie). Lid Medische Advies Raad van de Nederlandse Leverpatiënten Vereniging (NLV; patiëntenorganisatie).	n.v.t.	Geen actie, genoemde nevenwerkzaamheden betreffen een andere aandoening en oudere leeftijdsgroep
Dr. P.F. (Patrick) van Rheenen	Kinderarts-MDL	Geen	n.v.t.	Geen actie
Drs. J.M. (Jessica) Pruisen	Kinderarts-MDL	Geen	Geen	Geen actie
Prof. dr. C.D.M. (Clara) van Karnebeek	Hoofd afdeling kindermetabole ziekten	Programma directeur United for Metabolic Diseases (0,05fte betaald door St Metakids) Bestuurslid Jeroen Pit Huis (onbetaald) en Stichting van Karnebeek4Kids Editorial Board IEMbase (per nov 2020 betaald door Society for Inherited Metabolic Diseases; $10000/jr) Editorial board Frontiers in Neurology/Neurogenetics (onbetaald) Lid Raad van Advies Stichting TweegaMedica (onbetaald) Bestuurslid Van Wassenaer Stichting (onbetaald)	n.v.t.	Geen actie
Dr. T.W. (Tjalling) de Vries	Algemeen kinderarts	Redactielid Praktische Pediatrie, waarvoor vergoeding wordt ontvangen. Mede auteur boeken, waarvoor royalties worden ontvangen	Geen	Geen actie, genoemde nevenwerkzaamheden betreffen een ander onderwerp
Prof. dr. J.B.F. (Jan) Hulscher	Kinderchirurg UMCG, Hoogleraar Kinderchirurgie	Voorzitter Nederlandse Vereniging voor Kinderchirurgie Algemeen Bestuurslid Nederlandse Vereniging voor Heelkunde Coördinator Expertise Centra voor Zeldzame Aandoeningen UMCG Alle onbetaald	Ik ben nauw betrokken bij de ontwikkeling en het uitrollen van de ontlasting kleurenkaart voor het screenen van neonatale cholestase. Deze kaart is initieel mede gefinancieerd door het zeldzame ziektenfonds en recentelijk door Proctor & Gamble (Pampers). Tevens ben ik volgens sommigen het boegbeeld van de kinderchirurgie bij lever/galweg aandoeningen in Nederland (met zeer nauwe contacten met de patiëntenvereniging) waarbij mijn ziekenhuis het enige ziekenhuis in NL is waarin deze kinderen geopereerd worden.	Geen actie. Ontving geen betaling van Proctor & Gamble (Pampers) bij de ontwikkeling en het uitrollen van de ontlastingskleurenkaart
Drs. C. (Carlijn) Frantzen	Klinisch Geneticus	Geen	Geen	Geen actie
Drs. C.A. (Lineke) Dogger	Arts Maatschappij en Gezondheid	Geen	Geen	Geen actie
*Klankbordgroep*
J. (Janine) Pingen	Junior Projectmanager en Beleidsmedewerker (tot 1-12-2020)	Geen	Geen	Geen actie
Mevr. R. (Rowy) Uitzinger	Junior Projectmanager en Beleidsmedewerker (vanaf 1-12-2020)	Geen	Geen	Geen actie
Drs. J.A. (José) Willemse	Directeur Nederlandse Leverpatiënten Vereniging	Zitting diverse experts commissies NASH (onbezoldigd) bestuurslid ERN RARE LIVER (onbezoldigd) bestuurslid Liver Patients International (onbezoldigd) referent vanuit patiëntenperspectief Patiëntenfederatie NL (vrijwilligersvergoeding)	Deelname aan de richtlijn zal hooguit positieve publiciteit bij de achterban opleveren. Mogelijk kan het onderwerp dermate interessant zijn dat de aandacht voor dit onderwerp opgenomen kan worden op de website van de NLV, mits daar aanleiding voor is.	Geen actie
Dr. V.M. (Victorien) Wolters	Kinderarts-MDL, werkzaam in het Universitair Medisch Centrum Utrecht (Wilhelmina Kinderziekenhuis) te Utrecht, NVK	Geen	Geen	Geen actie

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door uitnodigen van patiëntvertegenwoordigers voor de invitational conference en het uitnodigen van afgevaardigden van patiëntenverenigingen in de klankbordgroep. Het verslag hiervan is besproken in de werkgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen. De conceptrichtlijn is tevens voor commentaar voorgelegd aan patiëntenverenigingen en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

Wkkgz & Kwalitatieve raming van mogelijke substantiële financiële gevolgen

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijn is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling zijn richtlijnmodules op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).

Uit de kwalitatieve raming blijkt dat er waarschijnlijk geen substantiële financiële gevolgen zijn, zie onderstaande tabel.

Module	Uitkomst raming	Toelichting
Module Kasai-operatie	Geen financiële gevolgen	Uit de toetsing volgt dat de aanbeveling(en) niet breed toepasbaar zijn (<5.000 patiënten) en zal daarom naar verwachting geen substantiële financiële gevolgen hebben voor de collectieve uitgaven.

Werkwijze

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).

Knelpuntenanalyse en uitgangsvragen

Tijdens de voorbereidende fase inventariseerde de werkgroep de knelpunten in de zorg voor patiënten met een verdenking op galgangatresie. Ook zijn er knelpunten aangedragen door:

Nederlandse Vereniging voor Kindergeneeskunde (NVK)
Nederlandse Vereniging voor Heelkunde (NVVH)
Vereniging Klinische Genetica Nederland (VKGN)
NHG (Nederlands Huisartsen Genootschap)
Jeugdartsen Nederland (AJN)
Stichting Kind en Ziekenhuis
Nederlandse Leverpatiënten Vereniging
IGJ (Inspectie Gezondheidszorg en Jeugd)
NFU (Nederlandse Federatie van Universitair Medische Centra)
NVZ (Nederlandse Vereniging van Ziekenhuizen)
Patiëntenfederatie Nederland
STZ (Samenwerkende Topklinische opleidingsZiekenhuizen)
V&VN (Verpleegkundigen & Verzorgenden Nederland)
NAPA (Nederlandse Associatie Physician Assistants)
ZiNL (Zorginstituut Nederland)
ZKN (Zelfstandige Klinieken Nederland)
ZN (Zorgverzekeraars Nederland) via een schriftelijke invitational conference. Een verslag hiervan is opgenomen onder aanverwante producten.

Op basis van de uitkomsten van de knelpuntenanalyse zijn door de werkgroep concept-uitgangsvragen opgesteld en definitief vastgesteld.

Uitkomstmaten

Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht. De gebruikte risk-of-bias instrumenten zijn gevalideerde instrumenten die worden aanbevolen door de Cochrane Collaboration: AMSTAR – voor systematische reviews; Cochrane – voor gerandomiseerd gecontroleerd onderzoek; ACROBAT-NRS – voor observationeel onderzoek; QUADAS II – voor diagnostisch onderzoek.

Beoordelen van de kracht van het wetenschappelijke bewijs

Voor interventievragen (vragen over therapie of screening)

De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).

GRADE	Definitie
Hoog	er is hoge zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; het is zeer onwaarschijnlijk dat de literatuurconclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Redelijk	er is redelijke zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; het is mogelijk dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Laag	er is lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; er is een reële kans dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Zeer laag	er is zeer lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt; de literatuurconclusie is zeer onzeker.

Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).

Voor vragen over diagnostische tests, schade of bijwerkingen, etiologie en prognose

De kracht van het wetenschappelijke bewijs werd eveneens bepaald volgens de GRADE-methode: GRADE-diagnostiek voor diagnostische vragen (Schünemann, 2008), en een generieke GRADE-methode voor vragen over schade of bijwerkingen, etiologie en prognose. In de gehanteerde generieke GRADE-methode werden de basisprincipes van de GRADE-methodiek toegepast: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van bewijskracht op basis van de vijf GRADE criteria (startpunt hoog; downgraden voor risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias).

Overwegingen (van bewijs naar aanbeveling)

Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.

Formuleren van aanbevelingen

De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.

In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers

	Sterke aanbeveling	Zwakke (conditionele) aanbeveling
Voor patiënten	De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet.	Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet.
Voor behandelaars	De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen.	Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren.
Voor beleidsmakers	De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid.	Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen.

Organisatie van zorg

In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.

Commentaar- en autorisatiefase

De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

Literatuur

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.

Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.

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Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

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