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抗血管内皮生长因子药物(VEGF)治疗早产儿视网膜病变

Appendices

Appendix 1. Cochrane Neonatal standard search strategy

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomised controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial [ptyp] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh]))

EMBASE: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomised controlled trial or controlled clinical trial or randomised or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomised controlled trial OR controlled clinical trial OR randomised OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

The Cochrane Library: (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW)

Appendix 2. 'Risk of bias' tool

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we categorised the method used to generate the allocation sequence as:

  • low risk (any truly random process, e.g. random number table; computer random number generator);

  • high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

  • unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorised the method used to conceal the allocation sequence as:

  • low risk (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes);

  • high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

  • unclear risk.

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the methods as:

  • low risk, high risk, or unclear risk for participants; and

  • low risk, high risk, or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we categorised the methods used to blind outcome assessment. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the methods as:

  • low risk for outcome assessors;

  • high risk for outcome assessors; or

  • unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re‐included missing data in the analyses. We categorised the methods as:

  • low risk (< 20% missing data);

  • high risk (≥ 20% missing data); or

  • unclear risk.

6. Selective reporting bias. Are reports of the study free of the suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. For studies for which study protocols were published in advance, we compared prespecified outcomes versus outcomes reported in the published results. If the study protocol was not published in advance, we contacted study authors to gain access to the study protocol. We assessed the methods as:

  • low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; the study failed to include results of a key outcome that would have been expected to have been reported); or

  • unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias?

For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

  • low risk;

  • high risk; or

  • unclear risk.

If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.

Study flow diagram: review update.
Figuras y tablas -
Figure 1

Study flow diagram: review update.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 1 Structural outcome ‐ partial or complete retinal detachment.
Figuras y tablas -
Analysis 1.1

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 1 Structural outcome ‐ partial or complete retinal detachment.

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 2 Structural outcome ‐ complete retinal detachment (unit of analysis: eyes).
Figuras y tablas -
Analysis 1.2

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 2 Structural outcome ‐ complete retinal detachment (unit of analysis: eyes).

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 3 Refractive error ‐ very high myopia ‐ at or after 12 months of age (unit of analysis: eyes).
Figuras y tablas -
Analysis 1.3

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 3 Refractive error ‐ very high myopia ‐ at or after 12 months of age (unit of analysis: eyes).

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes).
Figuras y tablas -
Analysis 1.4

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes).

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 5 Mortality before discharge from primary hospital.
Figuras y tablas -
Analysis 1.5

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 5 Mortality before discharge from primary hospital.

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 6 Mortality at 30 months of age.
Figuras y tablas -
Analysis 1.6

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 6 Mortality at 30 months of age.

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 7 Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes).
Figuras y tablas -
Analysis 1.7

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 7 Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes).

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 8 Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes).
Figuras y tablas -
Analysis 1.8

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 8 Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes).

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 9 Local adverse effects ‐ endophthalmitis.
Figuras y tablas -
Analysis 1.9

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 9 Local adverse effects ‐ endophthalmitis.

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 10 Local adverse effects ‐ vitreous haemorrhage.
Figuras y tablas -
Analysis 1.10

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 10 Local adverse effects ‐ vitreous haemorrhage.

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 11 Recurrence of ROP.
Figuras y tablas -
Analysis 1.11

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 11 Recurrence of ROP.

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 12 Recurrence of ROP (unit of analysis: eyes).
Figuras y tablas -
Analysis 1.12

Comparison 1 Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy, Outcome 12 Recurrence of ROP (unit of analysis: eyes).

Comparison 2 Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy, Outcome 1 Structural outcome ‐ retinal detachment (unit of analysis: eyes).
Figuras y tablas -
Analysis 2.1

Comparison 2 Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy, Outcome 1 Structural outcome ‐ retinal detachment (unit of analysis: eyes).

Comparison 2 Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy, Outcome 2 Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes).
Figuras y tablas -
Analysis 2.2

Comparison 2 Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy, Outcome 2 Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes).

Comparison 2 Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy, Outcome 3 Recurrence of ROP by 55 weeks' postmenstrual age.
Figuras y tablas -
Analysis 2.3

Comparison 2 Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy, Outcome 3 Recurrence of ROP by 55 weeks' postmenstrual age.

Summary of findings for the main comparison. Anti‐vascular endothelial growth factor therapy compared to conventional laser/cryotherapy in preterm infants with type 1 retinopathy of prematurity

Anti‐vascular endothelial growth factor (anti‐VEGF) therapy compared to conventional laser/cryotherapy in preterm infants with type 1 retinopathy of prematurity (ROP)

Patient or population: preterm infants with type 1 ROP
Setting: neonatal units
Intervention: anti‐VEGF therapy
Comparison: conventional laser/cryotherapy

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with conventional laser/cryotherapy

Risk with anti‐VEGF therapy

Structural outcome ‐ retinal detachment

Study population

RR 1.04
(0.21 to 5.13)

272
(3 RCTs)

⊕⊝⊝⊝
VERY LOW 1 2 3

15 per 1000

16 per 1000
(3 to 77)

Structural outcome ‐ complete retinal detachment

(unit of analysis: eyes)

Study population

RR 0.33
(0.01 to 7.50)

26
(1 RCT)

⊕⊝⊝⊝
VERY LOW 2 3 4 5

77 per 1000

25 per 1000
(1 to 577)

Refractive error ‐ very high myopia ‐ at 30 months of age

(unit of analysis: eyes)

Study population

RR 0.06
(0.02 to 0.20)

211
(1 RCT)

⊕⊕⊝⊝
LOW 1 4

416 per 1000

25 per 1000
(8 to 83)

Mortality before discharge from primary hospital

Study population

RR 1.50
(0.26 to 8.75)

229
(2 RCTs)

⊕⊕⊝⊝
LOW 2 3 5

18 per 1000

27 per 1000
(5 to 158)

Mortality at 30 months of age

Study population

RR 0.86
(0.30 to 2.45)

150
(1 RCT)

⊕⊕⊝⊝
LOW 2 3 5

93 per 1000

80 per 1000
(28 to 229)

Local adverse effects ‐ corneal opacity requiring corneal transplant

(unit of analysis: eyes)

Study population

RR 0.34
(0.01 to 8.26)

286
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1 2 3 4

7 per 1000

2 per 1000
(0 to 57)

Local adverse effects ‐ lens opacity requiring cataract removal

(unit of analysis: eyes)

Study population

RR 0.15
(0.01 to 2.79)

544
(3 RCTs)

⊕⊝⊝⊝
VERY LOW 1 2 3 4

11 per 1000

2 per 1000
(0 to 31)

Recurrence of ROP (up to 6 months of age)

Study population

RR 0.88
(0.47 to 1.63)

193
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1 2 6

204 per 1000

180 per 1000
(96 to 333)

Recurrence of ROP

(unit of analysis: eyes)

Study population

RR 5.36
(1.22 to 23.50)

188
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 1 3 7

23 per 1000

123 per 1000
(28 to 540)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Outcome assessment not masked.
295% CI around the pooled estimate includes both 1) no effect and 2) appreciable benefit or appreciable harm.
3Number of events too small.
4Serious risk of bias in analysis (unit of analysis error) in one or more of the included studies.
5Outcome assessment not masked, but outcome is objective.
6Evidence of large heterogeneity (I2 = 86%).
7Unclear risk of selection bias (details of allocation concealment not provided in the individual studies).

Figuras y tablas -
Summary of findings for the main comparison. Anti‐vascular endothelial growth factor therapy compared to conventional laser/cryotherapy in preterm infants with type 1 retinopathy of prematurity
Summary of findings 2. Anti‐vascular endothelial growth factor therapy combined with laser/cryotherapy compared to laser/cryotherapy in preterm infants with type 1 retinopathy of prematurity

Anti‐vascular endothelial growth factor (anti‐VEGF) therapy combined with laser/cryotherapy compared to laser/cryotherapy in preterm infants with type 1 retinopathy of prematurity (ROP)

Patient or population: preterm infants with type 1 ROP
Settings: neonatal units
Intervention: anti‐VEGF combined with laser/cryotherapy
Comparison: laser/cryotherapy

Outcomes*

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with conventional laser/cryotherapy

Risk with anti‐VEGF therapy

Structural outcome ‐ retinal detachment

(unit of analysis: eyes)

Study population

RR 0.26
(0.12 to 0.55)

152
(1 RCT)

⊕⊕⊝⊝
LOW 1,2,3

393 per 1000

102 per 1000
(47 to 216)

Local adverse effects ‐ perioperative retinal haemorrhages

(unit of analysis: eyes)

Study population

RR 0.62
(0.24 to 1.56)

152
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2,3,4

143 per 1000

89 per 1000
(34 to 223)

Recurrence of ROP by 55 weeks' postmenstrual age

Study population

RR 0.29
(0.12 to 0.7)

76
(1 RCT)

⊕⊕⊝⊝
LOW 1,3

500 per 1000

145 per 1000
(60 to 350)

*Only the outcomes for which data are available are reported here.

#The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RCT: randomised controlled trial; RR: risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

1Outcome assessment not masked.
2Serious risk of bias in analysis (unit of analysis error).
3Unclear risk of selection bias
495% CI around the pooled estimate includes both 1) no effect and 2) appreciable benefit or appreciable harm.

Figuras y tablas -
Summary of findings 2. Anti‐vascular endothelial growth factor therapy combined with laser/cryotherapy compared to laser/cryotherapy in preterm infants with type 1 retinopathy of prematurity
Comparison 1. Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Structural outcome ‐ partial or complete retinal detachment Show forest plot

3

272

Risk Ratio (M‐H, Fixed, 95% CI)

1.04 [0.21, 5.13]

1.1 Zone I

1

64

Risk Ratio (M‐H, Fixed, 95% CI)

0.21 [0.01, 4.26]

1.2 Zone II

3

208

Risk Ratio (M‐H, Fixed, 95% CI)

5.13 [0.25, 103.45]

2 Structural outcome ‐ complete retinal detachment (unit of analysis: eyes) Show forest plot

1

26

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.50]

3 Refractive error ‐ very high myopia ‐ at or after 12 months of age (unit of analysis: eyes) Show forest plot

1

211

Risk Ratio (M‐H, Fixed, 95% CI)

0.06 [0.02, 0.20]

3.1 Zone I

1

87

Risk Ratio (M‐H, Fixed, 95% CI)

0.07 [0.02, 0.30]

3.2 Zone II posterior

1

124

Risk Ratio (M‐H, Fixed, 95% CI)

0.05 [0.01, 0.34]

4 Refractive error ‐ spherical equivalent refractions ‐ at 30 months of age (unit of analysis: eyes) Show forest plot

1

211

Mean Difference (IV, Fixed, 95% CI)

5.68 [4.33, 7.02]

4.1 Zone I

1

87

Mean Difference (IV, Fixed, 95% CI)

6.93 [4.26, 9.60]

4.2 Zone II posterior

1

124

Mean Difference (IV, Fixed, 95% CI)

5.25 [3.69, 6.81]

5 Mortality before discharge from primary hospital Show forest plot

2

229

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [0.26, 8.75]

5.1 Zone I

1

67

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.07, 15.80]

5.2 Zone II

2

162

Risk Ratio (M‐H, Fixed, 95% CI)

1.95 [0.18, 20.71]

6 Mortality at 30 months of age Show forest plot

1

150

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.30, 2.45]

6.1 Zone I

1

67

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.16, 2.38]

6.2 Zone II posterior

1

83

Risk Ratio (M‐H, Fixed, 95% CI)

1.46 [0.26, 8.31]

7 Local adverse effects ‐ corneal opacity requiring corneal transplant (unit of analysis: eyes) Show forest plot

1

286

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.26]

7.1 Zone I

1

128

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

7.2 Zone II posterior

1

158

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.26]

8 Local adverse effects ‐ lens opacity requiring cataract removal (unit of analysis: eyes) Show forest plot

3

544

Risk Ratio (M‐H, Fixed, 95% CI)

0.15 [0.01, 2.79]

8.1 Zone I

1

128

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

8.2 Zone II

3

416

Risk Ratio (M‐H, Fixed, 95% CI)

0.15 [0.01, 2.79]

9 Local adverse effects ‐ endophthalmitis Show forest plot

2

129

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

10 Local adverse effects ‐ vitreous haemorrhage Show forest plot

2

129

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

11 Recurrence of ROP Show forest plot

2

193

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.47, 1.63]

11.1 Zone I

1

64

Risk Ratio (M‐H, Fixed, 95% CI)

0.15 [0.04, 0.62]

11.2 Zone II

2

129

Risk Ratio (M‐H, Fixed, 95% CI)

2.53 [1.01, 6.32]

12 Recurrence of ROP (unit of analysis: eyes) Show forest plot

2

188

Risk Ratio (M‐H, Fixed, 95% CI)

5.36 [1.22, 23.50]

12.1 Zone I or zone II

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.35, 25.68]

12.2 Zone II

1

158

Risk Ratio (M‐H, Fixed, 95% CI)

7.53 [0.98, 58.07]

Figuras y tablas -
Comparison 1. Anti‐vascular endothelial growth factor therapy versus cryo/laser therapy
Comparison 2. Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Structural outcome ‐ retinal detachment (unit of analysis: eyes) Show forest plot

1

152

Risk Ratio (M‐H, Fixed, 95% CI)

0.26 [0.12, 0.55]

2 Local adverse effects ‐ perioperative retinal haemorrhages (unit of analysis: eyes) Show forest plot

1

152

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.24, 1.56]

3 Recurrence of ROP by 55 weeks' postmenstrual age Show forest plot

1

76

Risk Ratio (M‐H, Fixed, 95% CI)

0.29 [0.12, 0.70]

Figuras y tablas -
Comparison 2. Anti‐vascular endothelial growth factor therapy plus cryo/laser therapy versus cryo/laser therapy