Vitamin A supplementation for the prevention of morbidity and mortality in infants one to six months of age.
BACKGROUND
Vitamin A deficiency is a significant public health problem in low- and middle-income countries. Vitamin A supplementation provided to infants less than six months of age is one of the strategies to improve the nutrition of infants at high risk of vitamin A deficiency and thus potentially reduce their mortality and morbidity.


OBJECTIVE
To evaluate the effect of synthetic vitamin A supplementation in infants one to six months of age in low- and middle-income countries, irrespective of maternal antenatal or postnatal vitamin A supplementation status, on mortality, morbidity and adverse effects.


METHODS
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2), MEDLINE via PubMed (1966 to 5 March 2016), Embase (1980 to 5 March 2016) and CINAHL (1982 to 5 March 2016). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.


METHODS
Randomised or quasi-randomised, individually or cluster randomised trials involving synthetic vitamin A supplementation compared to placebo or no intervention provided to infants one to six months of age were eligible.


METHODS
Two review authors assessed the studies for eligibility and assessed their risk of bias and collected data on outcomes.


RESULTS
The review included 12 studies (reported in 22 publications). The included studies assigned 24,846 participants aged one to six months to vitamin A supplementation or control group. There was no effect of vitamin A supplementation for the primary outcome of all-cause mortality based on seven studies that included 21,339 (85%) participants (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.25; I2= 0%; test for heterogeneity: P = 0.79; quality of evidence: moderate). Also, there was no effect of vitamin A supplementation on mortality or morbidity due to diarrhoea and respiratory tract infection. There was an increased risk of bulging fontanelle within 24 to 72 hours of supplementation in the vitamin A group compared to control (RR 3.10, 95% CI 1.89 to 5.09; I2= 9%, test for heterogeneity: P = 0.36; quality of evidence: high). There was no reported subsequent increased risk of death, convulsions or irritability in infants who developed bulging fontanelle after vitamin A supplementation, and it resolved in most cases within 72 hours. There was no increased risk of other adverse effects such as vomiting, irritability, diarrhoea, fever and convulsions in the vitamin A supplementation group compared to control. Vitamin A supplementation did not have any statistically significant effect on vitamin A deficiency (RR 0.86, 95% CI 0.70 to 1.06; I2= 27%; test for heterogeneity: P = 0.25; quality of evidence: moderate).


CONCLUSIONS
There is no convincing evidence that vitamin A supplementation for infants one to six months of age results in a reduction in infant mortality or morbidity in low- and middle-income countries. There is an increased risk of bulging fontanelle with vitamin A supplementation in this age group; however, there were no reported subsequent complications because of this adverse effect.
Department of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, TN, USA, 37212.
Aamer
A
Imdad
Zunirah
Z
Ahmed
Zulfiqar A
ZA
Bhutta
Indian Pediatr. 1998 Mar;35(3):217-22
9707874
Clin Infect Dis. 2002 Sep 1;35(5):618-24
12173139
Indian Pediatr. 2000 Nov;37(11):1188-93
11086300
Cochrane Database Syst Rev. 2011 Jan 19;(1):CD003648
21249656
Asia Pac J Clin Nutr. 2007;16(2):301-9
17468087
Contemp Clin Trials. 2014 Nov;39(2):269-79
25269669
J Clin Epidemiol. 2011 Apr;64(4):401-6
21208779
J Infect Dis. 2010 Sep 1;202 Suppl:S243-51
20684711
Am J Clin Nutr. 1995 Jul;62(1):143-8
7598058
Vaccine. 2008 Dec 2;26(51):6608-13
18835314
J Nutr. 2002 Sep;132(9 Suppl):2857S-2866S
12221262
Cochrane Database Syst Rev. 2015 Oct 27;(10):CD008666
26503498
Eur J Clin Nutr. 1997 May;51(5):302-7
9152680
Cochrane Database Syst Rev. 2016 Mar 25;3:CD005944
27012320
Postgrad Med J. 2003 Jul;79(933):397-402
12897218
Crit Rev Food Sci Nutr. 2017 Nov 22;57(17):3703-3714
27128154
J Nutr. 2001 May;131(5):1510-2
11340108
J Nutr. 2005 Nov;135(11):2669-73
16251628
Am J Clin Nutr. 2000 Jun;71(6):1570-6
10837300
Science. 2016 Feb 19;351(6275):
26912898
Acta Paediatr. 1995 Aug;84(8):863-6
7488807
J Nutr. 2002 Sep;132(9 Suppl):2867S-2880S
12221263
AIDS. 2002 Sep 27;16(14):1935-44
12351954
Indian Pediatr. 1996 Apr;33(4):279-86
8772901
PLoS One. 2011;6(7):e21862
21760916
Lancet. 1998 Oct 17;352(9136):1257-63
9788455
AIDS. 1999 Aug 20;13(12):1517-24
10465076
PLoS One. 2011;6(8):e23265
21853099
J Nutr. 1993 Apr;123(4):666-75
8463867
Pediatrics. 2012 Apr;129(4):e960-6
22412025
Annu Rev Nutr. 2001;21:167-92
11375434
J Nutr. 1999 Dec;129(12):2192-5
10573548
BMJ. 1992 Jan 25;304(6821):207-10
1739794
J Nutr. 2014 Sep;144(9):1474-9
24991044
Nat Rev Genet. 2012 Mar 13;13(4):260-70
22411464
Br J Nutr. 2007 Aug;98(2):422-30
17391562
BMJ. 2010 Mar 09;340:c1101
20215360
Ann Trop Paediatr. 2000 Dec;20(4):259-64
11219162
Vaccine. 2000 Jul 1;18(26):2979-84
10825599
Indian J Pediatr. 1991 Nov-Dec;58(6):837-47
1818881
Lancet Glob Health. 2015 Sep;3(9):e528-36
26275329
J Nutr. 2001 Feb;131(2):255-61
11160543
J Nutr. 2007 May;137(5):1272-7
17449592
J Pediatr. 1996 Apr;128(4):489-96
8618182
Am Fam Physician. 2003 Jun 15;67(12):2547-52
12825844
Am J Clin Nutr. 2005 Feb;81(2):454-60
15699235
Lancet. 1993 Aug 28;342(8870):526-7
8102669
Am J Clin Nutr. 2006 Jul;84(1):212-22
16825698
J Infect Dis. 2006 Mar 15;193(6):860-71
16479521
Cochrane Database Syst Rev. 2011 Oct 05;(10):CD000501
21975731
Vaccine. 2010 Jul 5;28(30):4738-41
20488261
J Nutr. 2007 Nov;137(11):2470-4
17951487
Pediatrics. 2008 Jul;122(1):e242-50
18595969
J Pediatr Gastroenterol Nutr. 2000 Nov;31(5):562-5
11144444
Eur J Clin Nutr. 2008 Jul;62(7):842-8
17538544
Eur J Clin Nutr. 1995 Jan;49(1):73-4
7713054
J Perinatol. 2011 Jun;31(6):397-403
21164424
Rev Panam Salud Publica. 2007 Jul;22(1):51-4
17931488
Eur J Clin Nutr. 2002 Apr;56(4):338-46
11965510
J Acquir Immune Defic Syndr. 2000 May 1;24(1):37-44
10877493
BMC Pediatr. 2014 Aug 28;14:214
25163399
Lancet. 2010 May 8;375(9726):1640-9
20435345
Acta Paediatr. 2001 Oct;90(10):1107-11
11697418
Allergy. 2013 Sep;68(9):1168-76
23991838
J Nutr. 2011 Oct;141(10):1907-11
21832026
BMC Pediatr. 2013 May 23;13:87
23702185
Cochrane Database Syst Rev. 2011 Oct 05;(10):CD007480
21975770
Bull World Health Organ. 1992;70(2):225-32
1600583
Cochrane Database Syst Rev. 2010 Dec 08;(12):CD008524
21154399
Eur J Clin Nutr. 1995 Jun;49(6):439-45
7656887
Cochrane Database Syst Rev. 2011 Oct 05;(10):CD006980
21975758
J Nutr. 1999 Feb;129(2):356-65
10024613
Lancet. 1998 May 16;351(9114):1477-82
9605804
Bull World Health Organ. 1992;70(6):733-9
1486669
Am J Clin Nutr. 1997 Jan;65(1):144-8
8988926
Bull World Health Organ. 1994;72(6):859-68
7867131
BMC Pediatr. 2014 Apr 04;14:92
24708735
J Nutr. 1996 Mar;126(3):628-33
8598547
Public Health. 1997 Jul;111(4):245-7
9242038
J Nutr. 2002 Nov;132(11):3243-8
12421835
BMC Public Health. 2011 Apr 13;11 Suppl 3:S20
21501438
BMJ. 2003 Aug 2;327(7409):254
12896935
Lancet. 2007 Jun 23;369(9579):2088-96
17586304
BMJ. 2008 Jun 21;336(7658):1416-20
18558641
Eur J Clin Nutr. 2002 Apr;56(4):321-5
11965508
Indian J Pediatr. 1997 Jul-Aug;64(4):503-9
10771879