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补充维生素A用于降低1‐6月龄幼儿的发病率和死亡率。

Appendices

Appendix 1. Standard search methodology

Search Strategy 2010:

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 (randomized 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 (randomized controlled trial or controlled clinical trial or randomized 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 (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

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

Updated Search Date: March 5, 2016

Search Terms: (vitamin A OR retinol OR retinoid OR retinoic OR vitamin A[MeSH])

Plus the following database‐specific terms:

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 (randomized 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 (randomized controlled trial or controlled clinical trial or randomized 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 (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

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

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 Young infant vitamin A supplementation versus placebo, Outcome 1 All‐cause mortality: longest follow‐up.
Figuras y tablas -
Analysis 1.1

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 1 All‐cause mortality: longest follow‐up.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 2 Diarrhoea‐specific mortality at longest follow‐up.
Figuras y tablas -
Analysis 1.2

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 2 Diarrhoea‐specific mortality at longest follow‐up.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 3 Acute respiratory infection‐specific mortality at longest follow‐up.
Figuras y tablas -
Analysis 1.3

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 3 Acute respiratory infection‐specific mortality at longest follow‐up.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 4 Meningitis‐specific mortality.
Figuras y tablas -
Analysis 1.4

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 4 Meningitis‐specific mortality.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 5 Morbidity: diarrhoea: point prevalence.
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Analysis 1.5

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 5 Morbidity: diarrhoea: point prevalence.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 6 Morbidity: lower respiratory tract infection: period prevalence.
Figuras y tablas -
Analysis 1.6

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 6 Morbidity: lower respiratory tract infection: period prevalence.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 7 Morbidity: fever: period prevalence.
Figuras y tablas -
Analysis 1.7

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 7 Morbidity: fever: period prevalence.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 8 Adverse effects: bulging fontanelle.
Figuras y tablas -
Analysis 1.8

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 8 Adverse effects: bulging fontanelle.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 9 Adverse effects: vomiting.
Figuras y tablas -
Analysis 1.9

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 9 Adverse effects: vomiting.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 10 Adverse effects: irritability.
Figuras y tablas -
Analysis 1.10

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 10 Adverse effects: irritability.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 11 Adverse effects: diarrhoea.
Figuras y tablas -
Analysis 1.11

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 11 Adverse effects: diarrhoea.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 12 Adverse effects: fever.
Figuras y tablas -
Analysis 1.12

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 12 Adverse effects: fever.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 13 Adverse effects: convulsions.
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Analysis 1.13

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 13 Adverse effects: convulsions.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 14 Vitamin A deficiency: retinol < 0.7 μmol/L.
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Analysis 1.14

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 14 Vitamin A deficiency: retinol < 0.7 μmol/L.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 15 Subgroup analysis: all‐cause mortality: co‐supplementation with vaccination.
Figuras y tablas -
Analysis 1.15

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 15 Subgroup analysis: all‐cause mortality: co‐supplementation with vaccination.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 16 Subgroup analysis: all‐cause mortality: maternal vitamin A supplementation.
Figuras y tablas -
Analysis 1.16

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 16 Subgroup analysis: all‐cause mortality: maternal vitamin A supplementation.

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 17 Subgroup analysis: adverse effects: bulging fontanelle: supplementation at the time of vaccination.
Figuras y tablas -
Analysis 1.17

Comparison 1 Young infant vitamin A supplementation versus placebo, Outcome 17 Subgroup analysis: adverse effects: bulging fontanelle: supplementation at the time of vaccination.

Summary of findings for the main comparison. Vitamin A supplementation for the prevention of morbidity and mortality in infants one to six months of age

Vitamin A supplementation for the prevention of morbidity and mortality in infants one to six months of age

Patient or population: infants 1 to 6 months of age
Setting: rural, urban/peri‐urban; low‐ to middle‐income countries
Intervention: synthetic vitamin A supplementation
Comparison: placebo or no intervention

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with young infant vitamin A supplementation

All‐cause mortality: longest follow‐up, i.e. until 1 year of age

Study population

RR 1.05
(0.89 to 1.25)

21,339

(9 RCTs)

⊕⊕⊕⊝
Moderate 1

2 studies contributed about 76% to the overall estimate (West 1995; WHO 1998). There was no substantial heterogeneity in the pooled data. Two studies were 2 x 2 factorial design trials and data were added as two data sets for each study.

25 per 1000

26 per 1000
(22 to 31)

Morbidity: diarrhoea: point prevalence

Study population

RR 0.99
(0.93 to 1.05)

9891

(2 RCTs)

⊕⊕⊕⊝
Moderate 1

Even though the final quality assignment was moderate, the effect was from only 2 studies. In addition, prevalence was not as good an indicator as incidence to establish a causal association

0 per 1000

0 per 1000
(0 to 0)

Adverse effects: bulging fontanelle

within 48 to 72 hours

Study population

RR 3.10
(1.89 to 5.09)

13,493
(9 RCTs)

⊕⊕⊕⊕
High

Consistent effect across the studies

3 per 1000

8 per 1000
(6 to 15)

Adverse effects: vomiting

48 to 72 hours

Study population

RR 0.95
(0.67 to 1.35)

2187
(2 RCTs)

⊕⊕⊝⊝
Low 2,3

49 per 1000

47 per 1000
(33 to 66)

Adverse effects: diarrhoea

48 to 72 hours

Study population

RR 1.07
(0.82 to 1.40)

2176
(3 RCTs)

⊕⊕⊝⊝
Low 1,2

89 per 1000

95 per 1000
(73 to 124)

Adverse effects: fever

48 to 72 hours

Study population

RR 0.94
(0.83 to 1.07)

3187
(3 RCTs)

⊕⊕⊝⊝
Low 1,2

194 per 1000

183 per 1000
(161 to 208)

Vitamin A deficiency: retinol < 0.7 μmol/L

Study population

RR 0.86

(0.70 to 1.06)

1204
(4 RCTs)

⊕⊕⊕⊝
Moderate 1

221 per 1000

190 per 1000
(155 to 234)

*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

1 Downgraded one level due to serious imprecision (confidence interval for summary estimate included unity).

2 Downgraded one level due to serious risk of bias.

3 Downgraded one level due to serious inconsistency (statistical heterogeneity was 94%).

Figuras y tablas -
Summary of findings for the main comparison. Vitamin A supplementation for the prevention of morbidity and mortality in infants one to six months of age
Table 1. Effect of vitamin A supplementation on response to vaccination in first six months of life

Study ID

Intervention

Type of vaccination

Response to vaccine

Kutukculer 2000

Vitamin A dose and frequency: vitamin A 30,000 IU for 3 days just after each 3 doses of DPT

Control: no vitamin A supplementation

DPT

Vitamin A administered orally for 3 consecutive days after each 3 doses of DPT for primary immunisation did not affect the specific antibody response against tetanus toxoid

Newton 2005

Vitamin A dose and frequency: vitamin A 25,000 IU RE at 6, 10 and 14 weeks

Control: placebo

DPT/OPV

Vitamin A supplementation does not affect infants' antibody responses to tetanus toxoid or OPV delivered at EPI contacts

Newton 2010

Vitamin A dose and frequency: vitamin A 50,000 IU at 6, 10 and 14 weeks

Control: no vitamin A supplementation

Hib + Hep

No significant difference (P = 0.93) in the geometric mean concentration of Haemophilus influenzae type b antibodies in the intervention (2.45) and in the control group (2.51); ratio of geometric mean concentration 0.98 (95% CI 0.59 to 1.62). Similarly, no significant difference (P = 0.29) in the geometric mean concentration of hepatitis B antibodies in the intervention (1.28) and in the control group (1.71); ratio of geometric mean concentration 0.74 (95% CI 0.43 to 1.28)

Semba 2001

Vitamin A dose and frequency: vitamin A 25,000 RE; vitamin A 50,000 IU at 6, 10 and 14 week of age; vitamin A 100 000 IU at 9 months of age

Placebo

DPT/OPV and measles

There was no differential effect of vitamin A supplementation in favour or against measles vaccination

WHO 1998

Vitamin A dose and frequency: vitamin A 25,000 IU with the first, second and third doses of DPT/OPV at 6, 10 and 14 weeks in India and Ghana and at 2, 3 and 4 months in Peru; vitamin A 25,000 IU at 9 months

Placebo: soybean oil. Received vitamin A 100,000 IU at 9 months

DPT/OPV and measles

"Vitamin A given to the mothers in the postpartum period and their infants with OPV did not interfere with the antibody response to any of the three polioviruses and enhanced the response to poliovirus type 1"

(Data from Indian site only)

DPT: diphtheria, pertussis (whooping cough) and tetanus; EPI: extended programme of immunisation; Hep: hepatitis; Hib: Haemophilus influenzae type b; IU: international unit; OPV: oral polio vaccine; RE: retinol equivalent.

Figuras y tablas -
Table 1. Effect of vitamin A supplementation on response to vaccination in first six months of life
Comparison 1. Young infant vitamin A supplementation versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality: longest follow‐up Show forest plot

9

21339

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.89, 1.25]

2 Diarrhoea‐specific mortality at longest follow‐up Show forest plot

1

200

Risk Ratio (M‐H, Fixed, 95% CI)

0.59 [0.20, 1.70]

3 Acute respiratory infection‐specific mortality at longest follow‐up Show forest plot

1

200

Risk Ratio (M‐H, Fixed, 95% CI)

2.12 [0.40, 11.33]

4 Meningitis‐specific mortality Show forest plot

1

200

Risk Ratio (M‐H, Fixed, 95% CI)

0.35 [0.01, 8.58]

5 Morbidity: diarrhoea: point prevalence Show forest plot

2

Risk Ratio (Fixed, 95% CI)

0.99 [0.93, 1.05]

6 Morbidity: lower respiratory tract infection: period prevalence Show forest plot

1

Risk Ratio (Fixed, 95% CI)

0.98 [0.81, 1.19]

7 Morbidity: fever: period prevalence Show forest plot

1

Risk Ratio (Fixed, 95% CI)

0.69 [0.56, 0.85]

8 Adverse effects: bulging fontanelle Show forest plot

9

13493

Risk Ratio (M‐H, Fixed, 95% CI)

3.10 [1.89, 5.09]

9 Adverse effects: vomiting Show forest plot

2

2187

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.67, 1.35]

10 Adverse effects: irritability Show forest plot

4

3416

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.65, 1.20]

11 Adverse effects: diarrhoea Show forest plot

3

2176

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.82, 1.40]

12 Adverse effects: fever Show forest plot

3

3187

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.83, 1.07]

13 Adverse effects: convulsions Show forest plot

1

1077

Risk Ratio (M‐H, Fixed, 95% CI)

0.19 [0.01, 3.85]

14 Vitamin A deficiency: retinol < 0.7 μmol/L Show forest plot

4

1204

Risk Ratio (M‐H, Fixed, 95% CI)

0.86 [0.70, 1.06]

15 Subgroup analysis: all‐cause mortality: co‐supplementation with vaccination Show forest plot

9

21339

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.89, 1.25]

15.1 Supplementation at the time of vaccination

7

12350

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.82, 1.28]

15.2 Supplementation independent of vaccination

2

8989

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.86, 1.40]

16 Subgroup analysis: all‐cause mortality: maternal vitamin A supplementation Show forest plot

9

21339

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.89, 1.25]

16.1 Maternal vitamin A supplementation

3

10249

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.79, 1.32]

16.2 No maternal vitamin A supplementation

6

11090

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.87, 1.34]

17 Subgroup analysis: adverse effects: bulging fontanelle: supplementation at the time of vaccination Show forest plot

9

13493

Risk Ratio (M‐H, Fixed, 95% CI)

3.10 [1.89, 5.09]

17.1 Supplementation at the time of vaccination

8

11352

Risk Ratio (M‐H, Fixed, 95% CI)

3.09 [1.81, 5.30]

17.2 Supplementation independent of vaccination

1

2141

Risk Ratio (M‐H, Fixed, 95% CI)

3.13 [0.86, 11.32]

Figuras y tablas -
Comparison 1. Young infant vitamin A supplementation versus placebo