Internal validity

External validity

Study group

Selection bias (representative: yes/no):

• if it consisted of more than 90% of the original cohort of children with ALL treated with glucocorticoids; or

• if it was a random sample with respect to treatment.

Reporting bias (well defined: yes/no):

• if treatment protocol was mentioned; and

• if (cumulative) dose of glucocorticoid treatment was mentioned; and

• if type of glucocorticoid treatment was mentioned; and

• if duration of glucocorticoid treatment was mentioned; and

• if method of cessation of glucocorticoid treatment was mentioned.

Follow‐up

Attrition bias (adequate: yes/no):

• if outcome was assessed at end date of the study for 60% to 90% of study group; or

• if outcome was assessed for more than 90% of the study group but with an unknown end date.

Reporting bias (well defined: yes/no):

• if length of follow‐up was mentioned; and

• if frequency of measuring outcomes was mentioned.

Outcome

Detection bias (blinding: yes/no):

• if outcome assessor was blinded to glucocorticoid treatment.

Reporting bias (well defined: yes/no):

• if methods of detection were described; and

• if outcome definition was objective and precise.

Risk estimation

Confounding (adjustment for other factors: yes/no):

• if important prognostic factors (i.e. age, sex, cotreatment) or follow‐up was taken adequately into account.

Analysis (well defined: yes/no):

• if risk ratio, odds ratio, attributable risk, linear or logistic regression model, mean difference, or Chi² statistic was calculated.

Selection bias

Sequence generation (adequate: yes/no):

• if the rule for allocating interventions to participants was based on some chance (random) process.

Allocation concealment (adequate: yes/no):

• if the randomisation method did not allow investigator and child to know or influence allocation of treatment before eligible children entered the study.

Performance bias
Blinding of care providers (yes/no):

• if knowledge of the allocated intervention was adequately prevented during the study.

Blinding of participants (yes/no):

• if knowledge of the allocated intervention was adequately prevented during the study.

Detection bias
Blinding of outcome assessors (yes/no; assessed for each outcome separately):

• if knowledge of the allocated intervention was adequately prevented during the study.

Attrition bias
Incomplete outcome data (adequate: yes/no; assessed for each outcome separately):

• if incomplete outcome (attrition and exclusions) data have been adequately addressed.

Reporting bias
Selective outcome reporting (yes/no):

• if reports of the study were free of the suggestion of selective outcome reporting.

Other bias
Other bias (yes/no):

• if the study was free of other problems (i.e. potential source of bias related to specific study design, premature termination of the study due to some data‐dependent process, extreme baseline imbalance) that could put it at high risk of bias.

Study

Representative study group

Complete follow‐up assessment

Blinded outcome assessor

Adjustment for important confounders

Well‐defined study group

Well‐defined follow‐up

Well‐defined outcome

Well‐defined risk estimation

Cunha 2004

No, based on additional information provided by trial authors, the study group described did not consist of more than 90% of the original cohort and was not a random sample.

Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.

Unclear whether outcome assessor was blinded to glucocorticoid treatment

Yes, treatment protocol and (cumulative) dose, type, duration, and form of cessation of glucocorticoid treatment were mentioned.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

Felner 2000

Yes, based on additional information provided by trial authors, the study group described consisted of more than 90% of the original cohort.

Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.

Unclear whether outcome assessor was blinded to glucocorticoid treatment

No, treatment protocol was not mentioned.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

Kuperman 2001

Yes, based on additional information provided by trial authors, the study group described consisted of more than 90% of the original cohort.

Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.

Unclear whether outcome assessor was blinded to glucocorticoid treatment

No, treatment protocol was not mentioned.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

Mahachoklertwattana 2004

Unclear whether the study group consisted of more than 90% of the original cohort, or if it was a random sample

Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.

Unclear whether outcome assessor was blinded to glucocorticoid treatment

Yes, treatment protocol and (cumulative) dose, type, duration, and form of cessation of glucocorticoid treatment were mentioned.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

Perdomo‐Ramírez 2016

Unclear whether the study group consisted of more than 90% of the original cohort, or if it was a random sample

Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.

No, outcome assessor was not blinded to glucocorticoid treatment. This information was based on additional information provided by trial authors.

Yes, treatment protocol and (cumulative) dose, type, and duration of glucocorticoid therapy were mentioned.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

Yes, mean difference was calculated.

Petersen 2003

Yes, the study group described consisted of more than 90% of the original cohort.

Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.

Unclear whether outcome assessor was blinded to glucocorticoid treatment.

Yes, important prognostic factors or follow‐up was taken into account.

Yes, treatment protocol and (cumulative) dose, type, and duration of glucocorticoid treatment were mentioned. Information on the method of cessation of glucocorticoid treatment was based on additional information provided by trial authors.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

No, risk ratio, odds ratio, attributable risk, linear or logistic regression model, mean difference, or Chi² statistic was not calculated.

Rix 2005

Yes, the study group described consisted of more than 90% of the original cohort.

Yes, outcome was assessed for 60% to 90% of the study group at the end date of the study.

No, outcome assessor was not blinded to glucocorticoid treatment.

Yes, treatment protocol and (cumulative) dose, type, and duration of glucocorticoid treatment were mentioned. Information on the method of cessation of glucocorticoid treatment was based on additional information provided by trial authors.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

Salem 2015

Unclear whether the study group consisted of more than 90% of the original cohort, or if it was a random sample

Unclear whether outcome was assessed for 60% to 90% at the end date of the study.

Unclear whether outcome assessor was blinded to glucocorticoid treatment

Yes, important prognostic factors or follow‐up was taken into account.

No, duration of tapering of glucocorticoid treatment was not mentioned.

Yes, length of follow‐up and frequency of measuring were mentioned.

Yes, methods of detection were described, and outcome definition was objective and precise.

Yes, mean difference was calculated.

Study

Adequate sequence generation?

Adequate allocation concealment?

Blinding?

Incomplete outcome data addressed?

Free of selective reporting?

Free of other bias?

Einaudi 2008

Yes, according to additional information provided by trial authors, the rule for allocating interventions to children was based on some chance (random) process.

Yes, according to additional information provided by trial authors, the randomisation method did not allow investigator and child to know or influence allocation of treatment before eligible children entered the study.

Based on additional information provided by trial authors, care providers, children, and outcome assessors were not blinded.

Yes, no outcome data were missing.

No, "adrenal function completely recovered in the 12 children evaluated with subsequent low‐dose ACTH test (in 4, 3, and 5 patients after 4, 8, and 10 weeks, respectively)". However, it was not reported which of these children received prednisone and which received dexamethasone. Therefore, not all of the study's prespecified primary outcomes were reported.

Yes

Kuperman 2012

Yes, the rule for allocating interventions to children was based on some chance (random) process.

Yes, according to additional information provided by trial authors, the randomisation method did not allow investigator and child to know or influence allocation of treatment before eligible children entered the study.

Yes, based on additional information provided by trial authors, care providers, children, and outcome assessors were all blinded.

Outcomes were assessed for 83% to 93% of the study population.

Yes

Yes

Felner et al

Therapy: dexamethasone (cumulative dose 168 mg/m²)

Time after cessation

Before

1 day

4 weeks

8 weeks

n insufficient/n total

0/10

10/10

3/10

0/10

Petersen et al (1)

Therapy: prednisolone (cumulative dose 2257.5 mg/m²)^a

Time after cessation

1 week

3 weeks

7 weeks

End of follow‐up: 10, 11, 11, and 19 weeks, respectively

n insufficient/n total

7/10

6/10

4/10

4/10

Petersen et al (2)

Therapy: dexamethasone (cumulative dose 236.25 mg/m²)^b

Time after cessation

1 week

3 weeks

7 weeks

End of follow‐up: 16, 33, and 34 weeks, respectively

n insufficient/n total

5/7

4/7

3/7

3/7

Mahachoklertwattana et al

Therapy: prednisolone (cumulative dose 1120 mg/m²)^a

Time after cessation

2 weeks

4 weeks

8 weeks

12 weeks

20 weeks

n insufficient/n total^b

11/24

9/24

7/24

3/24

3/24

Rix et al (1)

Therapy: prednisolone (cumulative dose 2257.5 mg/m²)

Time after cessation

Before

1 day

3 days

5 days

‐

n insufficient/n total^b

0/13

16/17

8/15

8/17

‐

Rix et al (2)

Therapy: prednisolone (cumulative dose 420 mg/m²)^c

Time after cessation

Before

2 days

‐

‐

‐

n insufficient/n total^b

2/13

13/13

‐

‐

‐

Rix et al (3)

Therapy: dexamethasone (cumulative dose 236.25 mg/m²)^c

Time after cessation

Before

1 day

3 days

7 days

‐

n insufficient/n total^b

0/5

2/2

3/5

1/5

‐

Einaudi et al (1)

Therapy: prednisone (cumulative dose 1477.5 mg/m²)^d

Time after cessation

1 day

7 to 14 days

28 days

42 days

10 weeks

n insufficient/n total^b

32/40

8/32

5/8

5/5

0/5

Einaudi et al (2)

Therapy: dexamethasone (cumulative dose 246.25 mg/m²)^d

Time after cessation

1 day

7 to 14 days

28 days

42 days

10 weeks

n insufficient/n total^b

20/24

4/20

3/4

3/3

0/3

Kuperman et al 2012 (1)

Therapy: prednisone (cumulative dose 1120 mg/m²)

Time after cessation

Before (4 weeks after start of glucocorticoid treatment)

1 week

2 weeks

3 weeks

4 weeks

n insufficient/n total^b

5/14

3/13

4/14

5/14

4/15

Kuperman et al 2012 (2)

Therapy: dexamethasone (cumulative dose 168 mg/m²)

Time after cessation

Before (4 weeks after start of glucocorticoid treatment)

1 week

2 weeks

3 weeks

4 weeks

n insufficient/n total^b

1/12

3/13

5/11

3/10

3/12

Perdomo‐Ramírez et al 2015

Therapy: prednisone (cumulative dose 1837.5 mg/m²)

Time after cessation

Before

3 days

1 week

2 weeks

4 weeks

n insufficient/n total^b

0/40

29/40

11/28

3/11

0/3

Salem et al 2015 (1)

(both induction and reinduction phases)

Therapy: dexamethasone (cumulative dose unknown)

Time after cessation

Before (at diagnosis)

1 day to 18 weeks

20 weeks

n insufficient/n total^b

5/20

No data on patient level were available.

All children recovered.^e

Salem et al 2015 (2)

(both induction and reinduction phases)

Therapy: prednisone (cumulative dose unknown)

Time after cessation

Before (at diagnosis)

1 day to 18 weeks

20 weeks

n insufficient/n total^b

6/20

No data on patient level were available.

All children recovered.^e

Cunha et al

No data on patient levels were available.

Time after cessation

n insufficient/n total

Kuperman et al 2001

Therapy: dexamethasone (cumulative dose 252 mg/m²)^a

Time after cessation

Before

1 week

2 weeks

n insufficient/n total

0/15

4/15

4/14