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Supplémentation en vitamines pour prévenir les fausses couches

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Referencias

Bhutta 2009 {published data only}

Bhutta ZA, Rizvi A, Raza F, Hotwani S, Zaidi S, Moazzam Hossain S, et al. A comparative evaluation of multiple micronutrient and iron‐folic acid supplementation during pregnancy in Pakistan: impact on pregnancy outcomes. Food & Nutrition Bulletin 2009;30(4):S496‐505.

Briscoe 1959 {published data only}

Briscoe CC. The role of vitamin C‐hesperidin in the prevention of abortion. Obstetrics & Gynecology 1959;14(3):288‐90.

Chappell 1999 {published data only}

Chappell LC, Seed PT, Briely AL, Kelly FJ, Lee R, Hunt BJ, et al. Effect of antioxidants on the occurrence of pre‐eclampsia in women at increased risk: a randomised trial. Lancet 1999;354:810‐6.

Czeizel 1994 {published data only}

Czeizel A, Rode K. Trial to prevent first occurrence of neural tube defects by periconceptional multivitamin supplementation [letter]. Lancet 1984;2:40.
Czeizel AE. Controlled studies of multivitamin supplementation on pregnancy outcomes. Annals of the New York Academy of Science 1993;678:266‐75.
Czeizel AE. Limb reduction defects and folic acid supplementation [letter]. Lancet 1995;345:932.
Czeizel AE. Nutritional supplementation and prevention of congenital abnormalities. Current Opinion in Obstetrics and Gynecology 1995;7:88‐94.
Czeizel AE. Prevention of congenital abnormalities by periconceptional multivitamin supplementation. BMJ 1993;306:1645‐8.
Czeizel AE, Dudás I. Prevention of the first occurrence of anencephaly and spina bifida with periconceptional multivitamin supplementation (conclusion). Orvosi Hetilap 1994;135:2313‐7.
Czeizel AE, Dudás I. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. New England Journal of Medicine 1992;327:1832‐5.
Czeizel AE, Dudás I, Frotz G, Técsöi A, Hanck A, Kunovits G. The effect of periconceptional multivitamin‐mineral supplementation on vertigo, nausea and vomiting in the first trimester of pregnancy. Archives of Gynecology and Obstetrics 1992;251:181‐5.
Czeizel AE, Dudás I, Metneki J. Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report. Archives of Gynecology and Obstetrics 1994;255:131‐9.
Czeizel AE, Fritz G. Randomized trial of periconceptional vitamins [letter]. JAMA 1989;262:1634.
Czeizel AE, Métneki J, Dudás I. Higher rate of multiple births after periconceptional vitamin supplementation [letter]. New England Journal of Medicine 1994;330:1687‐8.
Czeizel AE, Métneki J, Dudás I. The higher rate of multiple births after periconceptional multivitamin supplementation: an analysis of causes. Acta Geneticae Medicae et Gemellologiae (Roma) 1994;43:175‐84.
Czeizel AE, Rockenbauer M, Susánsky E. No change in sexual activity during preconceptional multivitamin supplementation. British Journal of Obstetrics & Gynaecology 1996;103:569‐73.
Dudás I, Rockenbauer M, Czeizel AE. The effect of preconceptional multivitamin supplementation on the menstrual cycle. Archives of Gynecology and Obstetrics 1995;256:115‐23.
Eros E, Geher P, Gomor B, Czeizel AE. Epileptogenic activity of folic acid after drug induces SLE (folic acid and epilepsy). European Journal of Obstetrics & Gynecology and Reproductive Biology 1998;80:75‐8.
Métneki J, Dudás I, Czeizel AE. Periconceptional multivitamin administration may result in higher frequency of twin pregnancies. Orvosi Hetilap 1996;137:2401‐5.

Fawzi 1998 {published data only}

Baylin A, Villamor E, Rifai N, Msamanga G, Fawzi WW. Effect of vitamin supplementation to HIV‐infected pregnant women on the micronutrient status of their infants. European Journal of Clinical Nutrition 2005;59(8):960‐8.
Fawzi W, Msamanga G, Renjifo B, Spiegelman D, Urassa E, Hashemi L, et al. Predictors of intrauterine and intrapartum transmission of HIV‐1 among Tanzanian women. AIDS 2001;15(9):1157‐65.
Fawzi WW, Msamanga G, Hunter D, Urassa E, Renjifo B, Mwakagile D, et al. Randomized trial of vitamin supplements in relation to vertical transmission of HIV‐1 in Tanzania. Journal of Acquired Immune Deficiency Syndromes 2000;23(3):246‐54.
Fawzi WW, Msamanga GI, Kupka R, Spiegelman D, Villamor E, Mugusi F, et al. Multivitamin supplementation improves hematologic status in HIV‐infected women and their children in Tanzania. American Journal of Clinical Nutrition 2007;85(5):1335‐43.
Fawzi WW, Msamanga GI, Spielgelman D, Urassa EJN, McGrath N, Mwakagile D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV‐1 infected women in Tanzania. Lancet 1998;351:1477‐82.
Villamor E, Msamanga G, Saathoff E, Manji K, Fawzi WW. Effect of vitamin supplements on the incidence of malaria among children born to HIV‐infected Women. FASEB Journal 2006;20(4 Pt 1):A125.

Fawzi 2007 {published data only}

Fawzi WW, Msamanga GI, Urassa W, Hertzmark E, Petraro P, Willett WC, et al. Vitamins and perinatal outcomes among HIV‐negative women in Tanzania. New England Journal of Medicine 2007;356(14):1423‐31.

Fleming 1968 {published data only}

Fleming AF, Hendrickse JP, Allan NC. The prevention of megaloblastic anaemia in pregnancy in Nigeria. Journal of Obstetrics and Gynaecology of the British Commonwealth 1968;75:425‐32.

Fleming 1986 {published data only}

Fleming AF, Ghatoura GBS, Harrison KA, Briggs ND, Dunn DT. The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Annals of Tropical Medicine and Parasitology 1986;80(2):211‐33.
Harrison KA, Fleming AF, Briggs ND, Rossiter CE. Growth during pregnancy in Nigerian teenage primigravidae. British Journal of Obstetrics and Gynaecology 1985;Suppl 5:32‐9.

Hans 2010 {published data only}

Hans U, Edward B. Regular vitamin C supplementation during pregnancy reduces hospitalization: outcomes of a Ugandan rural cohort study. Pan African Medical Journal 2010;5:15.

Hemmi 2003 {published data only}

Hemmi H, Endo T, Kitajima Y, Manase K, Hata H, Kudo R. Effects of ascorbic acid supplementation on serum progesterone levels in patients with a luteal phase defects. Fertility & Sterility 2003;80(2):456‐61.

ICMR 2000 {published data only}

ICMR Collaborating Centres and Central Technical Co‐ordinating Unit. Multicentric study of efficacy of periconceptional folic acid containing vitamin supplementation in prevention of open neural tube defects from India. Indian Journal of Medical Research 2000;112:206‐11.

Jauniaux 2004 {published data only}

Jauniaux E. The effect of vitamin C and E supplementation in women with a history of two early pregnancy failures ‐ a randomised controlled trial. ISRCTN Registry (http://www.isrctn.com/) [accessed 28 October 2015]2004.

Katz 2000 {published data only}

Christian P, Khatry SK, Yamini S, Stallings R, LeClerq SC, Shrestha SR, et al. Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women. American Journal of Clinical Nutrition 2001;73(6):1045‐51.
Christian P, West KP, Khatry SK, Katz J, LeClerq SC, Kimbrough‐Pradhan E, et al. Vitamin A or beta‐carotene supplementation reduces symptoms of illness in pregnant and lactating Nepali women. Journal of Nutrition 2000;130(11):2675‐82.
Christian P, West KP, Khatry SK, Katz J, Shrestha SR, Pradhan EK, et al. Night blindness of pregnancy in rural Nepal‐‐nutritional and health risk. International Journal of Epidemiology 1998;27(2):231‐7.
Christian P, West KP, Khatry SK, Kimbrough‐Pradhan E, LeClerq SC, Shrestha SR, et al. Night blindness during pregnancy and subsequent mortality among women in Nepal: effects of vitamin A and beta‐carotene supplementation. American Journal of Epidemiology 2000;152(6):542‐7.
Katz J, West KP, Khatry S, Pradhan EK, LeClerq SC, Christian P, et al. Maternal low‐dose vitamin A or beta‐carotene supplementation has no effect on fetal loss and early infant mortality: a randomized cluster trial in Nepal. American Journal of Clinical Nutrition 2000;71:1570‐6.
Katz J, West KP, Khatry SK, LeClerq SC, Christian P, Pradhan EK, et al. Twinning rates and survival of twins in rural Nepal. International Journal of Epidemiology 2001;30(4):802‐7.
Palmer AC, Schulze KJ, Khatry SK, De Luca LM, West KP. Maternal vitamin A supplementation increases natural antibody concentrations of preadolescent offspring in rural Nepal. Nutrition (Burbank, Los Angeles County, Calif.) 2015;31(6):813‐9.
Stewart CP, Christian P, Katz J, Schulze KJ, Wu LSF, LeClerq SC, et al. Maternal supplementation with vitamin A or B‐carotene and cardiovascular risk factors among pre‐adolescent children in rural Nepal. Journal of Developmental Origins of Health and Disease 2010;1(4):262‐70.
West KP, Katz J, Khatry SK, LeClerq SC, Pradhan EK, Shrestha SR, et al. Double blind, cluster randomised trial of low dose supplementation with vitamin A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS‐2 Study Group. BMJ 1999;318:570‐5.

Kirke 1992 {published data only}

Kirke PN, Daly LE, Elwood JH for the Irish Vitamin Study Group. A randomised trial of low dose folic acid to prevent neural tube defects. Archives of Disease in Childhood 1992;67:1442‐6.

Kumwenda 2002 {published data only}

Kumwenda N, Miotti PG, Taha TE, Broadhead R, Biggar RJ, Brookes Jackson JB, et al. Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus‐infected women in Malawi. Clinical Infectious Diseases 2002;35(5):618‐74.

McCance 2010 {published data only}

McCance DR, Holmes VA, Maresh MJ, Patterson CC, Walker JD, Pearson DW, et al. Diabetes and Pre‐eclampsia Intervention Trial (DAPIT) Study Group. Vitamins C and E for prevention of pre‐eclampsia in women with type 1 diabetes(DAPIT): a randomised placebo‐controlled trial. Lancet 2010;376(9737):259‐66.
Weissgerber T, Gandley R. Risk of types of pregnancy associated hypertension according to haptoglobin phenotype. Reproductive Sciences 2011;18(3 Suppl 1):69A.
Weissgerber TL, Gandley RE, McGee PL, Spong CY, Myatt L, Leveno KJ, et al. Haptoglobin phenotype, preeclampsia risk and the efficacy of vitamin C and E supplementation to prevent preeclampsia in a racially diverse population. PLoS ONE [Electronic Resource] 2013;8(4):e60479.
Weissgerber TL, Gandley RE, Roberts JM, Patterson CC, Holmes VA, Young IS, et al. Haptoglobin phenotype, pre‐eclampsia, and response to supplementation with vitamins C and E in pregnant women with type‐1 diabetes. BJOG : an International Journal of Obstetrics and Gynaecology 2013;120(10):1192‐9.
Weissgerber TL, Gandley RE, Roberts JM, Patterson CC, Holmes VA, Young IS, et al. Haptoglobin phenotype, preeclampsia risk and response to vitamin C and E supplementation in pregnant women with type 1 diabetes. Reproductive Sciences (Thousand Oaks, Calif.) 2013;20(3 Suppl):268A.

MRC 1991 {published data only}

MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 1991;338:131‐7.
Mathews F, Murphy M, Wald NJ, Hackshaw A. Twinning and folic acid use. Lancet 1999;353:291‐2.

Osrin 2005 {published data only}

Devakumar D, Chaube SS, Wells JC, Saville NM, Ayres JG, Manandhar DS, et al. Effect of antenatal multiple micronutrient supplementation on anthropometry and blood pressure in mid‐childhood in Nepal: follow‐up of a double‐blind randomised controlled trial. The Lancet. Global Health 2014;2(11):e654‐63.
Devakumar D, Stocks J, Ayres JG, Kirkby J, Yadav SK, Saville NM, et al. Effects of antenatal multiple micronutrient supplementation on lung function in mid‐childhood: follow‐up of a double‐blind randomised controlled trial in Nepal. European Respiratory Journal 2015;45(6):1566‐75.
Devakumar D, Wells JCK, Chaube SS, Saville NM, Manandhar DS, Costello A, et al. The phenotypic effects of antenatal multiple micronutrient supplementation in Nepalese children. Archives of Disease in Childhood 2014;99(Suppl 1):A2, Abstract no: P04.
Hindle LJ, Gitau R, Filteau SM, Newens KJ, Osrin D, Costello AM, et al. Effect of multiple micronutrient supplementation during pregnancy on inflammatory markers in Nepalese women. American Journal of Clinical Nutrition 2006;84(5):1086‐92.
MIRA (Mother Infant Research Unit). MIRA Janakpur. Multiple micronutrient supplementation study. The effects of multiple micronutrient supplementation on birthweight, gestation and infection: a double blind, randomised controlled trial conducted in Nepal. Personal communication2003:1‐18.
Osrin D, Vaidya A, Shrestha Y, Baniya RB, Manandhar DS, Adhikari RK, et al. Effects of antenatal multiple micronutrient supplementation on birthweight and gestational duration in Nepal: double‐blind, randomised controlled trial. Lancet 2005;365:955‐62.
Vaidya A, Saville N, Shrestha BP, Costello AM, Manandhar DS, Osrin D. Effects of antenatal multiple micronutrient supplementation on children's weight and size at 2 years of age in Nepal: follow‐up of a double‐blind randomised controlled trial. Lancet 2008;371(9611):492‐9.

People's League 1942 {published data only}

People's League of Health. Nutrition of expectant and nursing mothers: interim report. Lancet 1942;2:10‐2.
People's League of Health. The nutrition of expectant and nursing mothers in relation to maternal and infant mortality and morbidity. Journal of Obstetrics and Gynaecology of the British Empire 1946;53:498‐509.

Poston 2006 {published data only}

Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH, for the Vitamins in Pre‐eclampsia (VIP) Trial Consortium. Vitamin C and vitamin E in pregnant women at risk forpre‐eclampsia (VIP trial): randomised placebo‐controlled trial. Lancet 2006;367:1145–54.

Prawirohartono 2011 {published data only}

Prawirohartono EP, Nystrom L, Ivarsson A, Stenlund H, Lind T. The impact of prenatal vitamin A and zinc supplementation on growth of children up to 2 years of age in rural Java, Indonesia. Public Health Nutrition 2011;14(12):2197‐206.
Prawirohartono EP, Nystrom L, Nurdiati DS, Hakimi M, Lind T. The impact of prenatal vitamin A and zinc supplementation on birth size and neonatal survival ‐ a double‐blind, randomized controlled trial in a rural area of Indonesia. International Journal for Vitamin and Nutrition Research 2013;83(1):14‐25.

Roberfroid 2008 {published data only}

Roberfroid D, Huybregts L, Habicht JP, Lanou H, Henry MC, Meda N, et al. Randomized controlled trial of 2 prenatal iron supplements: is there a dose‐response relation with maternal hemoglobin?. American Journal of Clinical Nutrition 2011;93(5):1012‐8.
Roberfroid D, Huybregts L, Lanou H, Habicht JP, Henry MC, Meda N, et al. Prenatal micronutrient supplements cumulatively increase fetal growth. Journal of Nutrition 2012;142(3):548‐54.
Roberfroid D, Huybregts L, Lanou H, Henry MC, Meda N, Kolsteren FP, et al. Effect of maternal multiple micronutrient supplements on cord blood hormones: a randomized controlled trial. American Journal of Clinical Nutrition 2010;91(6):1649‐58.
Roberfroid D, Huybregts L, Lanou H, Henry MC, Meda N, Menten J, et al. Effects of maternal multiple micronutrient supplementation on fetal growth: a double‐blind randomized controlled trial in rural Burkina Faso. American Journal of Clinical Nutrition 2008;88(5):1330‐40.
Roberfroid D, Huybregts L, Lanou H, Ouedraogo L, Henry MC, Meda N, et al. Impact of prenatal multiple micronutrients on survival and growth during infancy: a randomized controlled trial. American Journal of Clinical Nutrition 2012;95(4):916‐24.

Roberts 2010 {published data only}

Gandley R, Abramovici A. Prenatal vitamin C and e supplementation is associated with a reduction in placental abruption and preterm birth in smokers. Pregnancy Hypertension 2012;2(3):331‐2.
Hauth J, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal‐Fetal Medicine Units Network. Vitamin C and E supplementation to prevent preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology 2009;201(6 Suppl 1):S175‐S176.
Hauth JC. Maternal insulin resistance and preeclampsia. American Journal of Obstetrics & Gynecology 2011;204(1 Suppl):S12.
Hauth JC, Clifton RG, Roberts JM, Myatt L, Spong CY, Leveno KJ, et al. Maternal insulin resistance and preeclampsia. American Journal of Obstetrics and Gynecology 2011;204(4):327.e1‐6.
Hauth JC, Clifton RG, Roberts JM, Spong CY, Myatt L, Leveno KJ, et al. Vitamin C and E supplementation to prevent spontaneous preterm birth: a randomized controlled trial. Obstetrics & Gynecology 2010;116(3):653‐8.
NICHD MFMUMFMUN. Combined antioxidants and preeclampsia prediction studies. Biostatistics Center ‐ George Washington University (http://www.bsc.gwu.edu.mfmu/projects/capps.cgi) (accessed September 1 2004)2004.
National Institute of Child Health and Human Development (NICHD). Antioxidant therapy to prevent preeclampsia. ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 14 June 2005)2005.
Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, et al. Vitamins C and E to prevent complications of pregnancy‐associated hypertension. New England Journal of Medicine 2010;362(14):1282‐91.
Roberts JM, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). A randomized controlled trial of antioxidant vitamins to prevent serious complications associated with pregnancy related hypertension in low risk, nulliparous women. American Journal of Obstetrics and Gynecology 2008;199(6 Suppl 1):S4.

Rumbold 2006 {published data only}

Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS. Australian collaborative trial of supplements (ACTS) with vitamin C and E for the prevention of pre‐eclampsia ‐ a randomised controlled trial. Perinatal Society of Australia and New Zealand 10th Annual Congress; 2006 April 3‐6; Perth, Australia. 2006:180.
Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS, for the ACTS Study Group. Vitamins C and E and the risks of preeclampsia and perinatal complications. New England Journal of Medicine 2006;354(17):1796‐806.

Rumiris 2006 {published data only}

Rumiris D, Purwosunu Y, Wibowo N, Farina A, Sekizawa A. Lower rate of preeclampsia after antioxidant supplementation in pregnant women with low antioxidant status. Hypertension in Pregnancy 2006;25(3):241‐53.

Rush 1980 {published data only}

Rush D, Kristal A, Navarro C, Chaunhan P, Blanc W, Naeye R, et al. The effects of dietary supplementation during pregnancy on placental morphology, pathology and histomorphometry. American Journal of Clinical Nutrition 1984;39:863‐71.
Rush D, Stein Z, Susser M. A randomized trial of prenatal nutritional supplementation in New York City. Pediatrics 1980;65(4):683‐97.

Schmidt 2001 {published data only}

Muslimatun S, Schmidt MK, Schultink W, West CE, Hautvast JA, Gross R, et al. Weekly supplementation with iron and vitamin A during pregnancy increases hemoglobin concentration but decreases serum ferritin concentration in Indonesian pregnant women. Journal of Nutrition 2001;131(1):85‐90.
Muslimatun S, Schmidt MK, West CE, Schultink W, Gross R, Hautvast JG. Determinants of weight and length of Indonesian neonates. European Journal of Clinical Nutrition 2002;56(10):947‐51.
Muslimatun S, Schmidt MK, West CE, Schultink W, Hautvast JG, Karyadi D. Weekly vitamin A and iron supplementation during pregnancy increases vitamin A concentration of breast milk but not iron status in Indonesian lactating women. Journal of Nutrition 2001;131(10):2664‐9.
Schmidt MK, Muslimatun S, West CE, Schultink W, Hautvast JG. Randomised double‐blind trial of the effect of vitamin A supplementation of Indonesian pregnant women on morbidity and growth of their infants during the first year of life. European Journal of Clinical Nutrition 2002;56:338‐46.
Schmidt MK, Muslimatun S, West CE, Schultink W, Hautvast JG. Vitamin A and iron supplementation of Indonesian pregnant women benefits vitamin A status of their infants. British Journal of Nutrition 2001;86:607‐15.

Spinnato 2007 {published data only}

Spinnato II JA, Freire S, Silva JL, Cunha Rudge MV, Martins‐Costa S, Koch MA, et al. Antioxidant therapy to prevent preeclampsia: a randomized controlled trial. Obstetrics & Gynecology 2007;110(6):1311‐8.

Steyn 2003 {published data only}

Schoeman J, Steyn PS, Odendaal HJ, Grove D. Bacterial vaginosis diagnosed at the first antenatal visit better predicts preterm labour than diagnosis later in pregnancy. Journal of Obstetrics and Gynaecology 2005;25(8):751‐3.
Steyn PS, Odendaal HJ, Schoeman J, Grove D. Vitamin c, pre‐eclampsia and preterm labour: a randomized, placebo‐controlled, double blind trial [abstract]. Hypertension in Pregnancy 2002;21(Suppl 1):43.
Steyn PS, Odendaal HJ, Schoeman J, Stander C, Fanie N, Grove D. A randomised, double blind placebo‐controlled trial of ascorbic acid supplementation for the prevention of preterm labour. Journal of Obstetrics and Gynaecology 2003;23(2):150‐5.

Summit 2008 {published data only}

Prado E, Sebayang S, Apriatni M, Hidayati N, Adawiyah S, Islamiyah A, et al. Maternal multiple micronutrient supplementation and children's cognition at age 9‐12 years in Indonesia. FASEB Journal 2015;29(1 Suppl):[28.7].
Prado EL, Alcock KJ, Muadz H, Ullman MT, Shankar AH, for the SUMMIT Study Group. Maternal multiple micronutrient supplements and child cognition: a randomized trial in Indonesia. Pediatrics 2012;130(3):e536‐e546.
Prado EL, Ullman MT, Muadz H, Alcock KJ, Shankar AH. The effect of maternal multiple micronutrient supplementation on cognition and mood during pregnancy and postpartum in indonesia: A randomized trial. PLoS ONE 2012;7(3):e32519.
Sebayang SK, Dibley MJ, Kelly P, Shankar AV, Shankar AH. Modifying effect of maternal nutritional status on the impact of maternal multiple micronutrient supplementation on birthweight in Indonesia. European Journal of Clinical Nutrition 2011;65(10):1110‐7.
Shankar AV, Asrilla Z, Kadha JK, Sebayang S, Apriatni M, Sulastri A, et al. Programmatic effects of a large‐scale multiple‐micronutrient supplementation trial in Indonesia: using community facilitators as intermediaries for behavior change. Food and Nutrition Bulletin 2009;30(2 Suppl):S207‐14.
The Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group, Shankar AH, Jahari AB, Sebayang SK, Aditiawarman, Apriatni M, et al. Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia: a double‐blind cluster‐randomised trial. Lancet 2008;371(9608):215‐27.

Sunawang 2009 {published data only}

Sunawang, Utomo B, Hidayat A, Kusharisupeni, Subarkah. Preventing low birthweight through maternal multiple micronutrient supplementation: a cluster‐randomized, controlled trial in Indramayu, West Java. Food & Nutrition Bulletin 2009;30(4):S488‐95.

Tofail 2008 {published data only}

Ekstrom EC, Eneroth H, Arifeen SE, Persson L. Efficacy of micronutrient supplement intake in increasing hemoglobin in pregnancy: Dose‐effect comparisons with multiple micronutrient in the MINIMat trial in rural Bangladesh. FASEB Journal 2013;27 Suppl:Abstract no: 845.25.
Eneroth H, El Arifeen S, Persson LA, Lonnerdal B, Hossain MB, Stephensen CB, et al. Maternal multiple micronutrient supplementation has limited impact on micronutrient status of Bangladeshi infants compared with standard iron and folic acid supplementation. Journal of Nutrition 2010;140(3):618‐24.
Eneroth H, Persson LA, El Arifeen S, Ekstrom EC. Infant anaemia is associated with infection, low birthweight and iron deficiency in rural Bangladesh. Acta Paediatrica 2011;100(2):220‐5.
Hawkesworth S, Wagatsuma Y, Kahn AI, Hawlader MD, Fulford AJ, Arifeen SE, et al. Combined food and micronutrient supplements during pregnancy have limited impact on child blood pressure and kidney function in rural Bangladesh. Journal of Nutrition 2013;143(5):728‐34.
Khan A, Kabir I, Ekstrom EC, Asling‐Monemi K, Alam D, Frongillo EA, et al. Effects of prenatal food and micronutrient supplementation on child growth from birth to 54 months of age: A randomized trial in Bangladesh. Nutrition Journal 2011;10(1):134.
Khan AI. Effects of pre‐ and postnatal nutrition interventions on child growth and body composition: the MINIMat trial in rural Bangladesh. Global Health Action 2013;6:22476.
Khan AI, Hawkesworth S, Ekstrom EC, Arifeen S, Moore SE, Frongillo EA, et al. Effects of exclusive breastfeeding intervention on child growth and body composition: The MINIMat trial, Bangladesh. Acta Paediatrica 2013;102(8):815‐23.
Lindström E, Hossain MB, Lönnerdal B, Raqib R, El Arifeen S, Ekström EC. Prevalence of anemia and micronutrient deficiencies in early pregnancy in rural Bangladesh, the MINIMat trial. Acta Obstetricia et Gynecologica Scandinavica 2011;90(1):47‐56.
Moore SE, Fulford AJ, Wagatsuma Y, Persson LA, Arifeen SE, Prentice AM. Thymus development and infant and child mortality in rural Bangladesh. International Journal of Epidemiology 2014;43:216‐23.
Persson LA, Arifeen S, Ekstrom EC, Rasmussen KM, Frongillo EA, Yunus M. Effects of prenatal micronutrient and early food supplementation on maternal hemoglobin, birth weight, and infant mortality among children in Bangladesh: The MINIMat randomized trial. JAMA 2012;307(19):2050‐9.
Shaheen R, Persson LA, Ahmed S, Lindholm L. Early invitation to prenatal food combined with multiple micronutrients is cost‐effective compared to iron‐folic acid supplementations: Results from MINIMat trial. Tropical Medicine and International Health 2013;18(Suppl 1):88.
Shaheen R, Persson LA, Ahmed S, Streatfield PK, Lindholm L. Cost‐effectiveness of invitation to food supplementation early in pregnancy combined with multiple micronutrients on infant survival: analysis of data from MINIMat randomized trial, Bangladesh. BMC Pregnancy and Childbirth 2015;15(1):125.
Shaheen R, Streatfield PK, Naved RT, Lindholm L, Persson LA. Equity in adherence to and effect of prenatal food and micronutrient supplementation on child mortality: results from the MINIMat randomized trial, Bangladesh. BMC Public Health 2014;14:5.
Tofail F, Persson LA, El Arifeen S, Hamadani JD, Mehrin F, Ridout D, et al. Effects of prenatal food and micronutrient supplementation on infant development: a randomized trial from the maternal and infant nutrition interventions, Matlab (MIMIMat) study. American Journal of Clinical Nutrition 2008;87(3):704‐11.

Van den Broek 2006 {published data only}

Van den Broek N. Vitamin A supplementation for anaemia in pregnancy. Personal communication 1998.
Van den Broek NR, White SA, Flowers C, Cook JD, Letsky EA, Tanumihardjo SA, et al. Randomised trial of vitamin A supplementation in pregnant women in rural Malawi found to be anaemic on screening by HemoCue. BJOG: an International Journal of Obstetrics and Gynaecology 2006;113(5):569‐76.

Villar 2009 {published data only}

Villar J, Purwar M, Merialdi M, Zavaleta N, Ngoc N, Anthony J, et al. Effect of vitamin C & E supplementation of pregnant women at risk of preeclampsia plus low nutritional status: the WHO trial. Hypertension in Pregnancy 2008;27(4):501.
Villar J, Purwar M, Merialdi M, Zavaleta N, Thi Nhu Ngoc N, Anthony J, et al. World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre‐eclampsia in populations of low nutritional status from developing countries. BJOG: an international journal of obstetrics and gynaecology 2009;116(6):780‐8.
Villar J, Purwar M, Merialdi M, Zavaleta N, Tien NN, Anthony J. WHO randomized trial of vitamin C and E supplementation among women at high risk for preeclampsia and nutritional deficiency. American Journal of Obstetrics and Gynecology 2007;197(6 Suppl 1):S4, Abstract no: 8.

West 2011 {published data only}

Christian P, Klemm R, Shamim AA, Ali H, Rashid M, Shaikh S, et al. Effects of vitamin A and beta‐carotene supplementation on birth size and length of gestation in rural Bangladesh: a cluster‐randomized trial. American Journal of Clinical Nutrition 2013;97(1):188‐94.
Christian P, Labrique AB, Ali H, Richman MJ, Wu L, Rashid M, et al. Maternal vitamin A and beta‐carotene supplementation and risk of bacterial vaginosis: a randomized controlled trial in rural Bangladesh. American Journal of Clinical Nutrition 2011;94(6):1643‐9.
Labrique AB, Christian P, Klemm RDW, Rashid M, Shamim AA, Massie A, et al. A cluster‐randomized, placebo‐controlled, maternal vitamin A or beta‐carotene supplementation trial in Bangladesh: design and methods. Trials 2011;12:102.
West KPJ, Christian P, Labrique AB, Rashid M, Shamim AA, Klemm RD, et al. Effects of vitamin A or beta carotene supplementation on pregnancy‐related mortality and infant mortality in rural Bangladesh: a cluster randomized trial. JAMA 2011;305(19):1986‐95.

West 2014 {published data only}

Gernand AD, Schulze KJ, Nanayakkara‐Bind A, Arguello M, Shamim AA, Ali H, et al. Effects of prenatal multiple micronutrient supplementation on fetal growth factors: a cluster‐randomized, controlled trial in rural Bangladesh. Plos One 2015;10(10):e0137269.
West KP. Antenatal micronutrient supplementation and infant survival (JiVitA‐3). ClinicalTrials.gov (http://clinicaltrials.gov) (accessed 8 July 2011). NCT00860470 2011.
West KP, Shamim AA, Labrique AB, Ali H, Shaikh S, Mehra S, et al. Efficacy of antenatal multiple micronutrient (MM) vs iron‐folic acid (IFA) supplementation in improving gestational and postnatal viability in rural Bangladesh: The JiVitA‐3 trial. FASEB Journal 2013;27 Suppl:Abstract no: 358.6.
West KPJ, Shamim AA, Mehra S, Labrique AB, Ali H, Shaikh S, et al. Effect of maternal multiple micronutrient vs iron‐folic acid supplementation on infant mortality and adverse birth outcomes in rural Bangladesh: the JiVitA‐3 randomized trial. JAMA 2014;312(24):2649‐58.

Wibowo 2012 {published data only}

Sezikawa A. Antioxidant supplementation in pregnant women with low antioxidant status. ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 21 June 2007)2007.
Wibowo N, Purwosunu Y, Sekizawa A, Farina A, Idriansyah L, Fitriana I. Antioxidant supplementation in pregnant women with low antioxidant status. Journal of Obstetrics & Gynaecology Research 2012;38(9):1152‐61.

Xu 2010 {published data only}

Xu H, Perez‐Cuevas R, Xiong X, Reyes H, Roy C, Julien P, et al. An international trial of antioxidants in the prevention of preeclampsia (INTAPP). American Journal of Obstetrics and Gynecology 2010;202(3):239.e1‐10.

Zagre 2007 {published data only}

Zagre NM, Desplats G, Adou P, Mamadoultaibou A, Aguayo VM. Prenatal multiple micronutrient supplementation has greater impact on birthweight than supplementation with iron and folic acid: a cluster‐randomized, double‐blind, controlled programmatic study in rural Niger. Food and Nutrition Bulletin 2007;28(3):317‐27.

Zeng 2008 {published data only}

Cao Y, Wang T, Zeng L. Risk of childhood malnutrition at 24 months related to small for gestational age and low birth weight in rural Western China. Annals of Nutrition & Metabolism 2013;63(Suppl 1):556, Abstract no: PO619.
Chang S, Zeng L, Brouwer ID, Kok FJ, Yan H. Effect of iron deficiency anemia in pregnancy on child mental development in rural China. Pediatrics 2013;131(3):e755‐63.
Li Q, Yan H, Zeng L, Cheng Y, Liang W, Dang S, et al. Effects of maternal multimicronutrient supplementation on the mental development of infants in rural western China: follow‐up evaluation of a double‐blind, randomized, controlled trial. Pediatrics 2009;123(4):e685‐92.
Wang W, Yan H, Zeng L, Cheng Y, Wang D, Li Q. No effect of maternal micronutrient supplementation on early childhood growth in rural western China: 30 month follow‐up evaluation of a double blind, cluster randomized controlled trial. European Journal of Clinical Nutrition 2012;66(2):261‐8.
Yan H. Impact of iron/folate versus multi‐micronutrient supplementation during pregnancy on birth weight: a randomised controlled trial in rural Western China. ISRCTN Registry (http://www.isrctn.com/) [accessed 15 February 2007]2007.
Zeng L, Dibley MJ, Cheng Y, Dang S, Chang S, Kong L, et al. Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: double blind cluster randomised controlled trial. BMJ 2008;337:a2001.
Zeng L, Yan H, Cheng Y, Dang S, Dibley MJ. Adherence and costs of micronutrient supplementation in pregnancy in a double‐blind, randomized, controlled trial in rural western China. Food and Nutrition Bulletin 2009;30(4):S480‐7.
Zeng L, Yan H, Cheng Y, Dibley M. Modifying effects of maternal nutrition status on the response to multiple micronutrients supplementation on preterm and neonatal mortatility in China. Annals of Nutrition & Metabolism 2013;63(Suppl 1):859‐60, Abstract no: PO1241.
Zeng L, Yan H, Cheng Y, Dibley MJ. Modifying effects of wealth on the response to nutrient supplementation in pregnancy on birth weight, duration of gestation and perinatal mortality in rural western China: double‐blind cluster randomized controlled trial. International Journal of Epidemiology 2011;40(2):350‐62.

Baumslag 1970 {published data only}

Baumslag N, Edelstein T, Metz J. Reduction of incidence of prematurity by folic acid supplementation in pregnancy. British Medical Journal 1970;1:16‐7.

Biswas 1984 {published data only}

Biswas MK, Pernoll MJ, Mabie WC. A placebo‐controlled comparative trial of various prenatal vitamin formulations in pregnant women. Clinical Therapeutics 1984;6(6):763‐7.

Blot 1981 {published data only}

Blot I, Papiernik E, Kaltwasser JP, Werner E, Tchernia G. Influence of routine administration of folic acid and iron during pregnancy. Gynecologic and Obstetric Investigation 1981;12:294‐304.

Chanarin 1968 {published data only}

Chanarin I, Rothman D, Perry J, Stratfull D. Normal dietary folate, iron and protein intake, with particular reference to pregnancy. British Medical Journal 1968;2:394‐7.
Chanarin I, Rothman D, Ward A, Perry J. Folate status and requirement in pregnancy. British Medical Journal 1968;2:390‐4.

Chelchowska 2004 {published data only}

Chelchowska M, Laskowska‐Klita T, Kubik P, Leibschang J. The effect of vitamin‐mineral supplementation on the level of MDA and activity of glutathione peroxidase and superoxide dismutase in blood of matched maternal‐cord pairs [Wplyw suplementacji witaminowo‐mineralnej na poziom MDA oraz aktywnosc peroksydazy glutationowej i dysmutazy ponadtlenkowej w krwi kobiet ciezarnych i krwi pepowinowej ich dzieci]. Przeglad Lekarski 2004;61(7):760‐3.
Kubik P, Kowalska B, Laskowska‐Klita T, Chelchowska M, Leibschang J. Effect of vitamin‐mineral supplementation on the status of some microelements in pregnant women [Wplyw suplementacji preparatem witaminowo‐mineralnym na status wybranych mikroelementow u kobiet ciezarnych]. Przeglad Lekarski 2004;61(7):764‐8.

Christian 2003 {published data only}

Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq SC, Shrestha SR, et al. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial. BMJ 2003;326(7389):571.
Christian P, Murray‐Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM, et al. Prenatal micronutrient supplementation and intellectual and motor function in early school‐aged children in Nepal. JAMA 2010;304(24):2716‐23.
Christian P, Shrestha J, LeClerq S, Khatry SK, Jiang T, Wagner T, et al. Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal. Journal of Nutrition 2003;133:3492‐8.
Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, West KP, et al. Antenatal and postnatal iron supplementation and childhood mortality in rural Nepal: a prospective follow‐up in a randomized, controlled community trial. American Journal of Epidemiology 2009;170(9):1127‐36.
Christian P, West KP, Khatry SK, Leclerq SC, Pradhan EK, Katz J, et al. Effects of maternal micronutrient supplementation on fetal loss and infant mortality. American Journal of Clinical Nutrition 2003;78(6):1194‐202.
Kulkarni B, Christian P, LeClerq SC, Khatry SK. Determinants of compliance to antenatal micronutrient supplementation and women's perceptions of supplement use in rural Nepal. Public Health Nutrition 2010;13(1):82‐90.
Stewart CP, Christian P, LeClerq SC, West KP, Khatry SK. Antenatal supplementation with folic acid + iron + zinc improves linear growth and reduces peripheral adiposity in school‐age children in rural Nepal. American Journal of Clinical Nutrition 2009;90(1):132‐40.
Stewart CP, Christian P, Schulze KJ, Arguello M, Leclerq SC, Khatry SK, et al. Low maternal vitamin B‐12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal. Journal of Nutrition 2011;141(10):1912‐7.

Colman 1974 {published data only}

Colman N, Barker M, Green R, Metz J. Prevention of folate deficiency in pregnancy by food fortification. American Journal of Clinical Nutrition 1974;27:339‐44.
Colman N, Larsen JV, Barker M, Barker A, Green R, Metz J. Prevention of folate deficiency by food fortification. III. Effect in pregnant subjects of varying amounts of added folic acid. American Journal of Clinical Nutrition 1975;28:465‐70.

Correia 1982 {published data only}

Correia JM, Silva Cruz A, Silva Meirinho M. The importance of the contribution of folic acid in gestation [Importancia del aporte de acido folico en las gestacion]. Progresos de Obstetricia y Ginecologia 1982;25(6):381‐6.

Coutsoudis 1999 {published data only}

Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother‐to‐child HIV‐1 transmission in Durban, South Africa. South African vitamin A study group. AIDS 1999;13(12):1517‐24.

Dawson 1962 {published data only}

Dawson DW, More JR, Aird DC. Prevention of megalo‐blastic anaemia in pregnancy by folic acid. Lancet 1962;2(7264):1015‐8.

Edelstein 1968 {published data only}

Edelstein T, Stevens K, Baumslag N, Metz J. Folic acid and vitamin B12 supplementation during pregnancy in a population subsisting on a suboptimal diet. Journal of Obstetrics and Gynaecology of the British Commonwealth 1968;75(2):133‐7.

Ferguson 1955 {published data only}

Ferguson JH. Methionine‐vitamin B therapy. Obstetrics & Gynecology 1955;6(2):221‐7.

Feyi‐Waboso 2005 {published data only}

Feyi‐Waboso PA, Chris A, Nwaogu GC, Archibong EI, Ejikem EC. The role of parenteral multivitamin preparation (Eldervit‐12) in the prevention of anaemia in pregnancy. Tropical Journal of Obstetrics and Gynaecology 2005;22(2):159‐63.

Fletcher 1971 {published data only}

Fletcher J, Gurr A, Fellingham FR, Prankerd TAJ, Brant HA, Menzies DN. The value of folic acid supplements in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1971;78:781‐5.

Giles 1971 {published data only}

Giles PFH, Harcourt AG, Whiteside MG. The effect of prescribing folic acid during pregnancy on birth weight and duration of pregnancy, a double blind trial. Medical Journal of Australia 1971;5:17‐21.

Hampel 1974 {published data only}

Hampel KP, Roetz R. Influence of a long term substitution with a folate‐iron preparation on serum folate, serum iron and haematological data during pregnancy: result of a prospective study. Geburtshilfe und Frauenheilkd 1974;34:409‐17.

Hankin 1966 {published data only}

Hankin ME, Cellier KM. Studies of nutrition in pregnancy V: ascorbic acid levels of blood and milk in pregnancy and lactation. Australian and New Zealand Journal of Obstetrics and Gynaecology 1966;6:153‐60.

Hekmatdoost 2011 {published data only}

Hekmatdoost A. Comparison of the effect of folic acid and 5‐methyltetrahydrofolate (5MTHF) on serum folate and homocysteine levels, and abortion rates in women suffering from recurrent abortion. IRCT Iranian Registry of Clinical Trials (www.irct.ir) (accessed 8 July 2011)2011.
Hekmatdoost A, Vahid F, Yari Z, Sadeghi M, Eini‐Zinab H, Lakpour Niknam, et al. Methyltetrahydrofolate vs folic acid supplementation in idiopathic recurrent miscarriage with respect to methylenetetrahydrofolate reductase C677T and A1298C polymorphisms: a randomized controlled trial. PLoS ONE 2015;10(12):e0143569.

Hibbard 1969 {published data only}

Hibbard BM, Hibbard ED. The prophylaxis of folate deficiency in pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1969;48:339‐48.
Hibbard BM, Hibbard ED. The treatment of folate deficiency in pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1969;48:349‐56.

Hunt 1984 {published data only}

Hunt IF, Murphy NJ, Cleaver AE, Faraji B, Swendseid ME, Coulson AH, et al. Zinc supplementation during pregnancy: effects on selected blood constituents and on progress and outcome of pregnancy in low‐income women of Mexican descent. American Journal of Clinical Nutrition 1984;40:508‐21.

Huybregts 2009 {published data only}

Huybregts L, Roberfroid D, Lanou H, Kolsteren P, Camp J. Prenatal lipid‐based nutrient supplements increase cord leptin concentration in pregnant women from rural Burkina Faso. Annals of Nutrition & Metabolism 2013;63(Suppl 1):799, Abstract no: PO1134.
Huybregts L, Roberfroid D, Lanou H, Meda N, Taes Y, Valea I, et al. Prenatal lipid‐based nutrient supplements increase cord leptin concentration in pregnant women from rural Burkina Faso. Journal of Nutrition 2013;143(5):576‐83.
Huybregts L, Roberfroid D, Lanou H, Menten J, Meda N, Van Camp J, et al. Prenatal food supplementation fortified with multiple micronutrients increases birth length: a randomized controlled trial in rural Burkina Faso. American Journal of Clinical Nutrition 2009;90(6):1593‐600.
Lanou H, Huybregts L, Roberfroid D, Kolsteren P. Effect of prenatal lipid‐based nutrient supplementation on gestational weight gain. Annals of Nutrition & Metabolism 2013;63(Suppl 1):783, Abstract no: PO1099.
Lanou H, Huybregts L, Roberfroid D, Nikiema L, Kouanda S, Van Camp J, et al. Prenatal nutrient supplementation and postnatal growth in a developing nation: an RCT. Pediatrics 2014;133(4):e1001‐8.

Kaestel 2005 {published data only}

Andersen GS, Friis H, Michaelsen KF, Rodrigues A, Benn CS, Aaby P, et al. Effects of maternal micronutrient supplementation on fetal loss and under‐2‐years child mortality: long‐term follow‐up of a randomised controlled trial from Guinea‐Bissau. African Journal of Reproductive Health 2010;14(2):17‐26.
Kaestel P, Michaelsen KF, Aaby P, Friis H. Effects of prenatal multimicronutrient supplements on birth weight and perinatal mortality: a randomised, controlled trial in Guinea‐Bissau. European Journal of Clinical Nutrition 2005;59(9):1081‐9.

Laurence 1981 {published data only}

Laurence KM. Prevention of neural tube defects by improvement in maternal diet and preconceptional folic acid supplementation. Progress in Clincial and Biological Research 1985;163:383‐8.
Laurence KM, James N, Miller MH, Tennant GB, Campbell H. Double‐blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural‐tube defects. British Medical Journal (Clinical Research Edition) 1981;282:1509‐11.

Lin 2010 {published data only}

Lin JH, Yang YK, Liu H, Lin QD, Zhang WY. Effect of antioxidants on amelioration of high‐risk factors inducing hypertensive disorders in pregnancy. Chinese Medical Journal 2010;123(18):2548‐54.

Lira 1989 {published data only}

Lira P, Barrena N, Foradori A, Gormaz G, Grebe G. Folate deficiency in pregnancy: effect of supplemental folate [Deficiencia de folatos en el embarazo: Efecto de una suplementacion con acido folico]. Sangre 1989;34(1):24‐7.

Lumeng 1976 {published data only}

Lumeng L, Cleary RE, Wagner R, Pao‐Lo Y, Ting‐Kai L. Adequacy of vitamin B6 supplementation during pregnancy: a prospective study. American Journal of Clinical Nutrition 1976;29:1379‐83.

Marya 1981 {published data only}

Marya RK, Rathee S, Lata V, Mudgil S. Effects of vitamin D supplementation in pregnancy. Gynecologic and Obstetric Investigation 1981;12:155‐61.

Meirinho 1987 {published data only}

Meirinho M, Correia JM, Silva Cruz A. Administration of folic acid during pregnancy and trophoblastic disease [Administracion de acido folico en la gestacion y actividad trofoblastica]. Progresos de Obstetricia y Ginecologia 1987;30(2):87‐91.

Metz 1965 {published data only}

Metz J, Festenstein H, Welch P. Effect of folic acid and vitamin B12 supplementation on tests of folate and vitamin B12 nutrition in pregnancy. American Journal of Clinical Nutrition 1965;16:472‐9.

Mock 2002 {published data only}

Mock DM, Quirk JG, Mock NI. Marginal biotin deficiency during normal pregnancy. American Journal of Clinical Nutrition 2002;75:295‐9.

Moldenhauer 2002 {published data only}

Moldenhauer J, Guo S, Liang R, Prada J. Dietary intake levels of the antioxidants vitamin C and vitamin E are adequately achieved with standard prenatal vitamin supplementation in high risk pregnancy groups [abstract]. American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S99.

Owen 1966 {published data only}

Owen GM, Nelsen CE, Baker GL, Connor WE, Jacobs JP. Use of vitamin K1 in pregnancy: effect of serum bilirubin and plasma prothrombin in the newborn. American Journal of Obstetrics and Gynecology 1967;99(3):368‐73.
Owen GM, Nelsen CE, Baker GL, Connor WE, Jacobs JP. Use of vitamin K1 in pregnancy: effect on bilirubin metabolism and coagulation mechanism in the newborn. Pediatrics 1966;68(5):850.

Potdar 2014 {published data only}

Fall C. Mumbai maternal nutrition project. Current Controlled Trials (www.controlled‐trials.com) (accessed 15 February 2007).
Potdar RD, Sahariah SA, Gandhi M, Kehoe SH, Brown N, Sane H, et al. Improving women's diet quality preconceptionally and during gestation: effects on birth weight and prevalence of low birth weight—a randomized controlled efficacy trial in India (Mumbai Maternal Nutrition Project). American Journal of Clinical Nutrition 2014;100(5):1257‐68.
Potdar RD, Sahariah SA, Gandhi M, Sane H, Brown NB, Fall C, et al. Preconceptual nutrition and weight gain in a) women during pregnancy and b) in babies at birth in Mumbai Maternal Nutrition Project (a RCT). The Power of Programming 2014: International Conference on Developmental Origins of Adiposity and Long‐Term Health. Munich, Germany, March 2014; Vol. 61:13‐15.

Ross 1985 {published data only}

Ross SM, Nel E, Naeye RL. Differing effects of low and high bulk maternal dietary supplements during pregnancy. Early Human Development 1985;10:298‐302.

Schuster 1984 {published data only}

Schuster K, Bailey LB, Mahan CS. Effect of maternal pyridoxine‐HCl supplementation on the vitamin B‐6 status of mother and infant and on pregnancy outcomes. Journal of Nutrition 1984;114:977‐88.

Semba 2001 {published data only}

Semba RD, Kumwenda N, Taha TE, Mtimavalye L, Broadhead R, Garrett E, et al. Impact of vitamin A supplementation on anaemia and plasma erthryopoietin concentrations in pregnant women: a controlled clinical trial. European Journal of Haematology 2001;66:389‐95.

Shu 2002 {published data only}

Shu J, Miao P, Wang RJ. Clinical observation on effect of Chinese herbal medicine plus human chorionic gonadotropin and progesterone in treating anticardiolipin antibody‐positive early recurrent spontaneous abortion. [Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi/Chinese Journal of Integrated Traditional & Western Medicine/Zhongguo Zhong Xi Yi Jie He Xue Hui, Zhongguo Zhong Yi Yan Jiu Yuan Zhu Ban 2002;22(6):414‐6.

Smithells 1981 {published data only}

Smithells RW, Sheppard S, Schorah CJ, Sellar MJ, Nevin NC, Harris R, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Archives of Disease in Childhood 1981;56:911‐8.

Suharno 1993 {published data only}

Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet 1993;342:1325‐8.

Tanumihardjo 2002 {published data only}

Tanumihardjo SA. Vitamin A and iron status are improved by vitamin A and iron supplementation in pregnant Indonesian women. Journal of Nutrition 2002;132:1909‐12.

Taylor 1982 {published data only}

Taylor DJ, Mallen C, McDougall N, Lind T. Effect of iron supplementation on serum ferritin levels during and after pregnancy. British Journal of Obstetrics and Gynaecology 1982;89:1011‐7.

Thauvin 1992 {published data only}

Thauvin E, Fusselier M, Arnaud J, Faure H, Favier H, Coudray C, et al. Effects of a multivitamin mineral supplement on zinc and copper status during pregnancy. Biological Trace Elements Research 1992;32:405‐14.

Trigg 1976 {published data only}

Trigg KH, Rendall EJC, Johnson A, Fellingham FR, Prankerd TAJ. Folate supplements during pregnancy. Journal of the Royal College of General Practitioners 1976;26:228‐30.

Ulrich 1999 {published data only}

Rolschau J, Kristoffersen K, Ulrich M, Grinsted P, Schaumburg E, Foged N. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part I. European Journal of Obstetrics & Gynecology and Reproductive Biology 1999;87(2):105‐10.
Ulrich M, Kristoffersen K, Rolschau J, Grinsted P, Schaumburg E, Foged N. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part II. Congenital anomalies. A randomised study. European Journal of Obstetrics & Gynecology and Reproductive Biology 1999;87(2):111‐3.
Ulrich M, Kristoffersen K, Rolschau J, Grinsted P, Schaumburg E, Foged N. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. Part III. Congenital anomalies. An observational study. European Journal of Obstetrics & Gynecology and Reproductive Biology 1999;87(2):115‐8.

Villamor 2002 {published data only}

Villamor E, Msamanga G, Spielgelman D, Antelman G, Peterson KE, Hunter DJ, et al. Effect of multivitamin and vitamin A supplements on weight gain during pregnancy among HIV‐1‐infected women. American Journal of Clinical Nutrition 2002;76:1082‐90.

Vutyavanich 1995 {published data only}

Vutyavanich T, Wongtra‐ngan S, Ruangsri R. Pyroxidone for nausea and vomiting of pregnancy: a randomized, double‐blind, placebo controlled trial. American Journal of Obstetrics and Gynecology 1995;173(3):881‐4.

Wehby 2012 {published data only}

Javois L. Birth defects treatment and prevention program: oral cleft prevention program (ongoing trial). ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 21 March 2006)2006.
Vila‐Nova C, Wehby GL, Queiros FC, Chakraborty H, Felix TM, Goco N, et al. Periconceptional use of folic acid and risk of miscarriage ‐ findings of the Oral Cleft Prevention Program in Brazil. Journal of Perinatal Medicine 2013;41(4):461‐6.
Wehby GL, Felix TM, Goco N, Richieri‐Costa A, Chakraborty H, Souza J, et al. High dosage folic acid supplementation, oral cleft recurrence and fetal growth. International Journal of Environmental Research and Public Health 2013;10(2):590‐605.
Wehby GL, Goco N, Moretti‐Ferreira D, Felix T, Richieri‐Costa A, Padovani C, et al. Oral cleft prevention program (OCPP). BMC Pediatrics 2012;12(184):1‐33.

Young 2015 {published data only}

Ramakrishnan U, DiGirolamo A, Nguyen P, Gonzalez‐Casanova I, Nguyen H, Pham H, et al. Effects of preconceptual micronutrient supplementation on maternal depression in Vietnamese women. FASEB Journal 2015;29(1 Suppl):28.1.
Young MF, Nguyen PH, Addo OY, Hao W, Nguyen H, Pham H, et al. The relative influence of maternal nutritional status before and during pregnancy on birth outcomes in Vietnam. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2015;194:223‐7.

Adu‐Afarwuah 2015 {published data only}

Adu‐Afarwuah S, Lartey A, Okronipa H, Peerson J, Ashorn P, Dewey K. Effects of small‐quantity lipid‐based nutrient supplement on hemoglobin and iron status of pregnant Ghanaian women. FASEB Journal 2015;29(1 Suppl):[39.5].

Agarwal 2012a {published data only}

Agarwal N, Dora S, Kriplani A, Garg P, Vivekanandhan S, Kulshrestha V. Response of therapy with vitamin B6, B12 and folic acid on homocysteine level and pregnancy outcome in hyperhomocysteinemia with unexplained recurrent abortions. International Journal of Gynecology and Obstetrics 2012;119(Suppl 3):S759.

Frenzel 1956 {published data only}

Frenzel KH, Geissler R. The importance of prophylaxis with multivitamin preparations during pregnancy, childbirth and nursing period [Die Bedeutung der Prophylaxe mit Multivitaminpraparaten wahrend Schwangerschaft, Wochenbett und Stillperiode]. Die Medizinsche Welt 1956;7(20):767‐9.

Prado 2015 {published data only}

Prado E, Abbeddou S, Adu‐Afarwuah S, Arimond M, Ashorn P, Ashorn U, et al. Associations between linear growth and language development in Ghana, Malawi, and Burkina Faso. FASEB Journal2015; Vol. 29, issue 1 Suppl.

Johns 2004 {published data only}

Johns J. The effect of antioxidant supplementation on women with threatened miscarriage. ISRCTN Registry (http://www.isrctn.com/) [accessed 28 October 2015]2004.

Agarwal 2012b

Agarwal A, Aponte‐Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: a review. Reproductive Biology and Endocrinology 2012;10(1):49.

Al‐Gubory 2010

Al‐Gubory KH, Fowler PA, Garrel C. The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. International Journal of Biochemistry & Cell Biology 2010;42(10):1634‐50.

Alderson 2004

Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers’ Handbook 4.2.2 [updated December 2003]. In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

Beazley 2005

Beazley D, Ahokas R, Livingston J, Griggs M, Sibai BM. Vitamin C and E supplementation in women at high risk for preeclampsia: a double‐blind, placebo‐controlled trial. American Journal of Obstetrics and Gynecology 2005;192(2):520‐1. [PUBMED: 15695996]

Chaudhuri 1969

Chaudhuri SK. Effect of nutrient supplementation on the incidence of toxaemia of pregnancy. Journal of Obstetrics and Gynecology of India 1969;19:156‐61.

De‐Regil 2015

De‐Regil LM, Peña‐Rosas JP, Fernández‐Gaxiola AC, Rayco‐Solon P. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database of Systematic Reviews 2015, Issue 12. [DOI: 10.1002/14651858.CD007950.pub3]

Devaseelan 2010

Devaseelan P, Fogarty PP, Regan L. Human chorionic gonadotrophin for threatened miscarriage. Cochrane Database of Systematic Reviews 2010, Issue 5. [DOI: 10.1002/14651858.CD007422.pub2]

Di Cintio 2001

Di Cintio E, Parazzini F, Chatenoud L, Surace M, Benzi G, Zanconato G, et al. Dietary factors and risk of spontaneous abortion. European Journal of Obstetrics & Gynecology and Reproductive Biology 2001;95:132‐6.

Garcıa‐Enguıdanos 2002

Garcıa‐Enguıdanos A, Calle M, Valero J, Luna S, Domınguez‐Rojas V. Risk factors in miscarriage: a review. European Journal of Obstetrics & Gynecology and Reproductive Biology 2002;102(2):111‐119.

Garrido‐Gimenez 2015

Garrido‐Gimenez C, Alijotas‐Reig J. Recurrent miscarriage: causes, evaluation and management. Postgraduate Medical Journal 2015;91(1073):151‐62.

George 2002

George L, Mills JL, Johansson AL, Nordmark A, Olander B, Granath F, Cnattingius S. Plasma folate levels and risk of spontaneous abortion. JAMA 2002;288(15):1867‐73.

Guerra‐Shinohara 2010

Guerra‐Shinohara EM, Pereira PM, Kubota AM, Silva TA, Reis JL, Miyashita GS, et al. Increased MMA concentration and body mass index are associated with spontaneous abortion in Brazilian women: a pilot study. Clinica Chimica Acta 2010;411(5):423‐7.

Gupta 2007

Gupta S, Agarwal A, BanerjeeJ, Alvarez JG. The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstetrical & Gynecological Survey 2007;62(5):335‐47.

Haas 2009

Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD003511.pub2]

Haas 2013

Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database of Systematic Reviews 2013, Issue 10. [DOI: 10.1002/14651858.CD003511.pub3]

Hague 2003

Hague WM. Homocysteine and pregnancy. Best Practice & Research Clinical Obstetrics & Gynaecology 2003;17(3):459‐69.

Haider 2015

Haider BA, Bhutta ZA. Multiple‐micronutrient supplementation for women during pregnancy. Cochrane Database of Systematic Reviews 2015, Issue 11. [DOI: 10.1002/14651858.CD004905.pub4]

Hasan 2009

Hasan R, Olshan AF, Herring AH, Savitz DA, Siega‐Riz AM, Hartmann KE. Self‐reported vitamin supplementation in early pregnancy and risk of miscarriage. American Journal of Epidemiology 2009;169(11):1312‐8.

Higgins 2011

Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Hovdenak 2012

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bhutta 2009

Methods

Randomisation and allocation concealment: random allocation of the entire population of the urban and rural areas (population, 110,000; 20,400 households) into 28 discrete clusters (16 rural and 12 urban) on the basis of household characteristics, socioeconomic criteria, and geographic location. Each cluster was allocated to a community health worker who distributed the supplements on a cluster‐based allocation strategy of supplements ("either iron–folic acid or multiple micronutrients"). Distribution of the sealed, coded supplement bottles were independently controlled by the pharmacy at Aga Khan University.

Blinding of outcome assessment: medical officers, community health workers, social scientists, and data collection team remained blinded to the supplementation allocation.

Documentation of exclusion: 373 women (16.5%) were excluded.

Use of placebo control: no placebo given, women in the control group were given IFA.

Participants

2378 women from community settings in urban and rural Sindh (Pakistan) less than 16 weeks of gestation. Eligible women were women with a confirmed pregnancy at less than 16 weeks of gestation. Women who did not have a confirmed pregnancy on ultrasound scanning or women who were clearly advanced beyond 24 weeks of gestation were excluded.

Interventions

Multiple micronutrients comprised 30 mg of iron (ferrous fumarate) and 400 mcg of folic acid along with 800 mcg of retinol (retinyl acetate), 200 IU of vitamin D (ergocalciferol), 10 mg of vitamin E (α‐tocopherol acetate), 70 mg of ascorbic acid, 1.4 mg of vitamin B1 (thiamine mononitrate), 18 mg of niacin (niacinamide) 1.4 mg of vitamin B2, 1.9 mg of vitamin B6 (pyridoxine), 2.6 mcg of vitamin B12 (cyanocobalamin), 15 mg of zinc (zinc gluconate), 2 mg of copper, 65 mcg of selenium, and 150 mcg of iodine. Intervention was timed to start at less than 16 weeks' gestation. Comparison was iron (60 mg) and folic acid (400 mcg).

Outcomes

Maternal outcomes:

  1. Blood Hb level as well as serum ferritin, zinc, and vitamin A.

  2. Physical and clinical examination, including a morbidity assessment and measurement of fundal height.

  3. Height, weight, and mid‐upper‐arm circumference.

Infant outcomes:

  1. Birthweight.

  2. Gestational age.

  3. Neonatal death and cause of death.

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear.

Womens' BMI, Hb, ferritin, zinc, and serum retinol at admission are reported.

Sample‐size calculation reported by 2 methods: 1. based on a potential 5% gain in birthweight, 2. based to estimate a difference in birthweight of 150 g between the 2 groups.

No intention‐to‐treat analyses performed.

Compliance: community health worker performed a tablet count every fourth nightly visit. Proportion of tablets consumed 75.65 in the intervention group and 76.7% in the control group.

Location: urban population (Bilal Colony, Karachi) and rural villages (Kot Diji district, rural Sindh), Pakistan.

Timeframe: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"We randomly allocated the entire population of the urban and rural area." Pg S497.

Allocation concealment (selection bias)

Low risk

"cluster‐based allocation strategy of supplements (either iron–folic acid or multiple micronutrients) by the community health workers was implemented. The allocation of either iron–folic acid or multiple micronutrient supplements and the distribution of the sealed, coded supplement bottles were independently controlled by the pharmacy at Aga Khan University, which maintained the allocation codes by individual community health workers." Pg S498.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All pregnant women were allocated a unique code and a uniquely labelled and numerically coded specific supplement supply for the duration of pregnancy. Blinding is unlikely to have been broken. Pg S498.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The field staff (medical officers, community health workers, social scientists, and data collection team) remained completely blinded as to the supplement allocation." Pg S498.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Approximately 16.5% of attrition with balanced number and similar reason for each group. S500 Figure1.

Selective reporting (reporting bias)

Unclear risk

No information about trial registration.

Other bias

High risk

The distribution of study participants across the urban and rural areas is unclear from the text and no adjustments were made for cluster design.

Briscoe 1959

Methods

Randomisation and allocation concealment: unclear, no methodological details given, dubious as the number of women allocated to the treatment group was more than double that allocated to the placebo group. "Unselected patients were each given 200 capsules... these were given a code, unknown to us and contained either an inert powder or 100 mg each of ascorbic acid and hesperidin."

Blinding of outcome assessment: women and study investigators did not know the treatment codes.

Documentation of exclusion: none reported.

Use of placebo control: placebo given; however, all women received an additional multivitamin supplement.

Participants

406 women were recruited in the study. Eligible women were "unselected patients" in private obstetrics care, who were less than or equal to 10 weeks' pregnant, and were eligible regardless of whether they were currently bleeding or the number of previous pregnancies. Women greater than 10 weeks' gestation were excluded. 406 women were randomised to either vitamin C (n = 303) or placebo (n = 103), no losses to follow‐up were reported. 77 women in the study had more than 2 previous miscarriages and/or bleeding in the pregnancy, and 329 had 2 or fewer miscarriages and no bleeding in the pregnancy.

Interventions

All women were given 200 tablets, containing either 100 mg each of ascorbic acid and hesperidin or placebo (an inert powder).
The study lasted for 7 weeks. For the first 2 weeks, women were asked to take 8 tablets daily (i.e. daily 800 mg each of vitamin C and hesperidin or placebo). For the following 5 weeks, women took 4 tablets daily (i.e. daily 400 mg each of vitamin C and hesperidin or placebo). All women received a multiple vitamin supplement containing 50 mg vitamin C.

Outcomes

  1. Spontaneous miscarriage.

  2. Spontaneous miscarriage in women with 2 or fewer previous miscarriages and no bleeding in the current pregnancy.

  3. Spontaneous miscarriage in women with more than 2 previous miscarriages and/or bleeding in the current pregnancy.

  4. Spontaneous miscarriage in women who experienced recurrent miscarriage.

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear, as there is no information about concurrent medical conditions or other risk factors for miscarriage. 9 of the 406 women were classified as experiencing recurrent miscarriage.
No information is available about women's nutritional status.
No sample‐size calculation reported.
Intention‐to‐treat analyses performed (no losses to follow‐up reported).
Compliance: no compliance information reported.
Location: Philadelphia, USA.
Timeframe: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No methodological details given.

Allocation concealment (selection bias)

Unclear risk

No methodological details given.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women and study investigators did not know the treatment allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Double‐blind study, but it is unclear who was blinded and if the code was broken before or after outcome assessment pg289.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up reported.

Selective reporting (reporting bias)

Unclear risk

Limited information about selection bias, stated that 'unselected patients' were included.

Other bias

Unclear risk

Limited methodological details provided including patient compliance.

Chappell 1999

Methods

Randomisation and allocation concealment: a computer‐generated randomisation list using blocks of 10 was given to the hospital pharmacy departments. Researchers allocated the next available number to participants and women collected the trial tablets from the pharmacy department.

Blinding of outcome assessment: women, caregivers and researchers were blinded to the treatment allocation until recruitment, data collection and laboratory analyses were complete.

Documentation of exclusion: 123 (43.5%) women were excluded, of which 70 women were withdrawn because their second Doppler scan was normal. Pregnancy outcome data were reported for all women randomised.

Use of placebo control: placebo control.

Participants

283 women were recruited into the study. Inclusion criteria: abnormal Doppler waveform in either uterine artery at 18‐22 weeks' gestation or a history in the preceding pregnancy of pre‐eclampsia necessitating delivery before 37 weeks' gestation, eclampsia or the syndrome of HELLP.
Exclusion criteria: heparin or warfarin treatment, abnormal fetal‐anomaly scan or multiple pregnancy.
Women were randomised at 18‐22 weeks' gestation; however, women with a previous history who were identified at an earlier stage were randomised at 16 weeks' gestation. Women with abnormal Doppler waveform analysis returned for a second scan at 24 weeks' gestation, those with a normal waveform at this time stopped treatment and were withdrawn from the study. The remaining women who had persistently abnormal waveforms, and those with a previous history or pre‐eclampsia remained in the study and were seen every 4 weeks through the rest of pregnancy. 1512 women underwent Doppler screening, 273 women had abnormal waveforms and of these, 242 women consented to the study. An additional 41 women who had a history of pre‐eclampsia consented. 283 women were randomised to either the vitamin C and E group (n = 141) or the placebo group (n = 142), 72 women had normal Doppler scans at 24 weeks' gestation and 24 women did not return for a second scan and were withdrawn. A further 27 women withdrew from the trial after 24 weeks' gestation for various reasons. In total, 160 women completed the trial protocol until delivery, 79 in the vitamin C and E group and 81 in the placebo group. Pregnancy outcome data were presented for all women randomised (n = 283) as well as only for those women completing the trial protocol (n = 160).

Interventions

Women randomised to the vitamin C and E group received tablets containing 1000 mg vitamin C daily and capsules containing 400 IU vitamin E daily.
Women randomised to the placebo group received tablets containing microcrystalline cellulose and soyabean oil, that were identical in appearance to the vitamin C tablets and vitamin E capsules. After 24 weeks' gestation women were seen every 4 weeks, and blood samples were taken at each visit.

Outcomes

  1. Ratio of PAI‐1 to PAI‐2.

  2. Incidence of pre‐eclampsia.

  3. Placental abruption.

  4. Spontaneous preterm delivery (< 37 weeks).

  5. Intrauterine death.

  6. Small‐for‐gestational‐age infants (on or below the 10th centile).

  7. Mean systolic and diastolic blood pressure before delivery.

  8. Gestational age at delivery (median, IQR).

  9. Birthweight (median, IQR).

  10. Birthweight centile (median, IQR).

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear, women were at high risk of pre‐eclampsia.
No information is available about women's nutritional status.
Sample‐size calculation reported, based on a 30% reduction in PAI‐1.
Intention‐to‐treat analyses performed.
Compliance: "within the treated group, plasma ascorbic acid concentration increased by 32% from baseline values and plasma alpha‐tocopherol increased by 54%".
Location: London, UK.
Timeframe: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number list.

Allocation concealment (selection bias)

Low risk

Random number list used blocks of 10 and was held by the pharmacy department.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women, caregivers and researchers were blinded until the analyses were completed.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The code was revealed to the researchers once recruitment, data collection, and laboratory analyses were complete" pg811.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

123 (43.5%) women were excluded, of which, 70 women were withdrawn because their second Doppler scan was normal. Data were reported for all women randomised.

Selective reporting (reporting bias)

Low risk

Data reported for all outcomes in methods.

Other bias

Low risk

The study appears to be free of other sources of bias.

Czeizel 1994

Methods

Randomisation and allocation concealment: unclear, "women agreed to their allocation on the basis of a random table".

Blinding of outcome assessment: unclear, women were aware of the "blind use of one of two kinds of tablets", but no other details given.

Documentation of exclusion: 49 women (1%) were lost to follow‐up and excluded.

Use of placebo control: "trace element control" given.

Participants

7765 women were recruited into the study. Women participating in the HOFPP who volunteered to take part, were not currently pregnant, and who conceived within 12 months of ceasing contraception. In the first 2 years of the HOFPP, women were also required to be aged < 35 years, and not to have had a previous pregnancy except a prior induced abortion. 7905 women were approached, of which 140 refused participation, 7765 were randomised and 5502 women had a confirmed pregnancy and were allocated to either multivitamins (n = 2819) or control (n = 2683). 49 women of the 5502 confirmed pregnancies were lost to follow‐up.

Interventions

Women were provided with multivitamin or trace element 'control' from at least 28 days before conception continuing until at least the second missed menstrual period.
The multivitamin with folic acid contained 6000 IU vitamin A, 1.6 mg vitamin B1, 1.8 mg vitamin B2, 2.6 mg vitamin B6, 4.0 mcg vitamin B12, 100 mg vitamin C, 500 IU vitamin D, 15 mg vitamin E, 19 mg nicotinamide, 10 mg calcium pantothenate, 0.2 mg biotin, 0.8 mg folic acid, 125 mg calcium, 125 mg phosphorus, 100 mg magnesium, 60 mg iron, 1 mg copper, 1 mg manganese, 7.5 mg zinc.
The trace element control contained 7.5 mg vitamin C, 1 mg copper, 1 mg manganese and 7.5 mg zinc.

Outcomes

  1. NTDs and other birth defects.

  2. Miscarriage.

  3. Ectopic pregnancy.

  4. Termination of pregnancy.

  5. Live births.

  6. Stillbirths.

  7. Multiple gestation.

  8. Subgroup data are available on menstrual cycle, first trimester symptoms and sexual activity.

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear.
Information on their dietary status is unknown.
No sample‐size calculation reported.
Partial intention‐to‐treat analyses performed.
Compliance: compliance was assessed by questioning, checking the tick‐off on the basal temperature chart and counting of unused tablets. 70% of women in the multivitamin group and 71% in the control group took the full course of the supplements, with an additional 20% and 21% in the multivitamin and control groups respectively receiving a partial course of supplementation.
Location: Hungary.
Time frame: 1 February 1984 to 30 April 1992.
The denominators used for this trial are the number of women randomised and with a confirmed pregnancy (i.e. 2819 for the multivitamin group and 2683 for the control group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Methodological details unclear.

Allocation concealment (selection bias)

Unclear risk

Methodological details unclear, 'women agreed to their allocation on the basis of a random table'.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Women were aware of the 'blind use of one of two kinds of tablets', but no other details given.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details are given if outcome assessment was blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

49 women (1%) excluded, partial intention‐to‐treat analyses performed.

Selective reporting (reporting bias)

Unclear risk

Denominators vary with serial publications.

Other bias

Unclear risk

Limited methodological details provided.

Fawzi 1998

Methods

Randomisation and allocation concealment: block randomisation using blocks of 20, eligible women were "assigned the next numbered bottle of regimen". The study used a 2 by 2 factorial design and women were randomised to 1 of 4 groups. Tablets were indistinguishable and packaged in identically coded bottles.

Blinding of outcome assessment: women and study investigators were unaware of the treatment allocation, no information given about blinding of outcome assessors.

Documentation of exclusion: 64 women (6%) were lost to follow‐up and excluded.

Use of placebo control: placebo given.

Participants

1085 women were recruited into the study. Pregnant women between 12 and 27 weeks' gestation who were HIV‐1 infected, living in Dar es Salaam and intended to stay there for at least 1 year were eligible for the study. Women not HIV‐1 positive or moving out of Dar es Salaam were excluded. 13,879 pregnant women consented to be HIV‐1 tested, of which 1806 were positive, and 1085 were randomised. Of these, 3 women were not pregnant and 7 women died before delivery and were excluded from the trial. Of the remaining 1075 women, 54 women (5%) were lost to follow‐up by the time of delivery, leaving birth outcomes reported for 1021 women. Women were randomised to 1 of 4 groups: vitamin A (n = 269), multivitamins excluding vitamin A (n = 269); multivitamins including vitamin A (n = 270) or placebo (n = 267).

Interventions

Women were randomised to 1 of 4 groups:

  1. vitamin A (30 mg beta‐carotene plus 5000 IU preformed vitamin A);

  2. multivitamins excluding vitamin A (20 mg vitamin B1, 20 mg vitamin B2, 25 mg vitamin B6, 100 mg niacin, 50 mcg vitamin B12, 500 mg vitamin C, 30 mg vitamin E, 0.8 mg folic acid);

  3. multivitamins including vitamin A, all formulated in 2 tablets; or

  4. placebo.

All women received 400 mg ferrous sulphate and 5 mg folic acid daily, as well as 500 mg chloroquine phosphate weekly. At delivery, all women taking vitamin A were to receive an additional oral dose of 200,000 IU vitamin A and the others an extra dose of a placebo. Pill counts were conducted at each visit and new tablets were given out at each visit.

Outcomes

  1. Miscarriage, defined as delivery before 28 weeks' gestation.

  2. Stillbirth, defined as delivery of a dead baby at or after 28 weeks' gestation.

  3. Fetal death, defined as either miscarriage or stillbirth.

  4. Low birthweight, defined as birthweight less than 2500 g.

  5. Very low birthweight, defined as birthweight less than 2000 g.

  6. Preterm delivery, defined as delivery before 37 weeks.

  7. Severe preterm birth, defined as delivery before 34 weeks.

  8. Small‐for‐gestational age, defined as birthweight less than the 10th percentile for gestational age.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear, although may be increased due to their HIV‐1 positive status.
Women's nutritional status is also unclear.
Figures change with serial publications, particularly for secondary outcomes, and results are not reported separately for the individual 4 groups. Results are reported as: any multivitamins, multivitamin, any vitamin A or no vitamin A.
Sample‐size calculation performed allowing for 20% loss to follow‐up.
Intention‐to‐treat analyses performed.
Compliance: compliance assessed by the percentage of prescribed tablets absent from the returned bottles, and in plasma vitamin A concentrations in a subset of 100 women. Median compliance assessed using pill counts was 90% by the time of delivery.
Location: Tanzania.
Timeframe: April 1995 to July 1997.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Block randomisation using blocks of 20.

Allocation concealment (selection bias)

Unclear risk

Women assigned the 'next numbered bottle of regimen'.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women and investigators were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Double‐blinded study, but unclear if ocutome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

64 women (6%) were lost to follow‐up and excluded, intention‐to‐treat analyses performed.

Selective reporting (reporting bias)

Unclear risk

Figures change with serial publications, particularly for secondary outcomes, and results are not reported separately for the individual 4 groups.

Other bias

Unclear risk

Limited methodological details provided.

Fawzi 2007

Methods

Randomisation: unclear about sequence generation.

Allocation concealment: states a list was prepared according to the randomisation sequence in blocks of 20, tablets were bottled in identical coded bottles, eligible women were given the next numbered bottle.

Blinding of outcome assessment: women and research assistants who assessed the study outcomes were unaware of the intervention groups.

Documentation of exclusion: 49 women lost to follow‐up (multivitamin group: 23, placebo group: 26), no post‐randomisation exclusions.

Use of placebo control: placebo given.

Participants

8428 women were randomised in the study. Pregnant women between 12 and 27 weeks who had a negative test for HIV infection and planned to stay in the city until delivery and for 1 year thereafter recruited through antenatal clinics in Dar es Salaam. 8468 women were enrolled, however 40 women were then found to be ineligible. 8428 women were randomly assigned to receive either a multivitamin (n = 4214) or placebo (n = 4214) from the time of enrolment until 6 weeks after delivery. 6 women died before delivery and 43 were lost to follow‐up by the time of delivery.

Interventions

The supplements included 20 mg of vitamin B1, 20 mg of vitamin B2, 25 mg of vitamin B6, 100 mg of niacin, 50 mcg of vitamin B12, 500 mg of vitamin C, 30 mg of vitamin E, and 0.8 mg of folic acid.

The active tablets and placebo were similar in shape, size, and colour.

All women, irrespective of the assigned study regimen, were given daily doses of iron (60 mg of elemental iron) and folic acid (0.25 mg). They were also given malaria prophylaxis in the form of sulfadoxine‐pyrimethamine tablets at 20 weeks and 30 weeks of gestation.

Outcomes

  1. Low birthweight (< 2500 g).

  2. Preterm delivery (before 37 weeks' gestation).

  3. Fetal death.

  4. Birthweight below 2000 g.

  5. Extremely preterm delivery (before 34 weeks).

  6. Small‐for‐gestational age (birthweight below the 10th percentile for gestational age).

  7. Fetal death and death in the first 6 weeks of life.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear.

Intention‐to‐treat analyses performed.

Compliance: average compliance was 88%, no difference in compliances between the 2 groups.

Location: Tanzania.

Timeframe: August 2001 and July 2004.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Generation of sequence not reported, except that there were blocks of 20 in the sequence.

Allocation concealment (selection bias)

Low risk

Identical coded bottles prepared according to the randomisation list, eligible women were assigned the next numbered bottle.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women and outcome assessors were blinded to allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Research assistants who assessed the study outcomes were unaware of the intervention groups." pg1424.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

49 (1%) women lost to follow‐up, balanced across groups, analyses by intention‐to‐treat.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes appear to be reported.

Other bias

Low risk

The study appears to be free of other sources of bias.

Fleming 1968

Methods

Randomisation and allocation concealment: quasi‐randomised, alternate women were allocated to receive folic acid or placebo according to the order in which they attended antenatal clinic. No other methodological details were given.

Blinding of outcome assessment: women and investigators were blinded to the treatment allocation, until after the completion of the trial.

Documentation of exclusion: 21 women (28%) excluded from the analysis.

Use of placebo control: control tablet containing iron given.

Participants

75 women were recruited into the trial. Women were eligible if they were primigravida, less than 26 weeks' pregnant (range of gestation 10 to 26 weeks'), with haematocrit value (PCV) 27% or more, and who had not received treatment so far as was known. Women with Hb SC, Hb SS, Hb CC were excluded. Alternate patients were allocated to group A (placebo) or B (folic acid). 75 women were included (40 in group A and 35 in group B) initially; however, only 26 in group A and 28 in group B completed the trial. 16 women (10 in group A and 8 in group B) defaulted from the trial, 3 (2 in group A and 1 in group B) were anaemic on the second visit warranting folic acid treatment, 1 in group A self‐medicated with folic acid and 1 in group A 'aborted'.

Interventions

All women received antimalarials and iron supplements as per the standard antenatal care at the hospital.
Women in group B received 5 mg folic acid tablets on each attendance, which was fortnightly initially and weekly in the last trimester.
Group A received "one tablet of lactose base and colouring matter in the same manner".

Outcomes

  1. PCV and reticulocyte index.

  2. Serum folic acid concentration and 'megaloblastic score'.

  3. Malarial infection.

  4. Maternal morbidity (pyelonephritis, pre‐eclamptic toxaemia, septicaemia, puerperal psychosis).

  5. Prematurity.

  6. Birthweight (mean birthweight but no standard deviation).

  7. Fetal mortality.

Notes

Results not reported as intention‐to‐treat; however, where possible, the review authors included data in the review as intention‐to‐treat.
Unclear of women's risk of spontaneous and recurrent miscarriage.
16 women in the trial showed evidence of folic acid deficiency at trial entry.
Sample‐size calculation: none reported.
No intention‐to‐treat analyses performed.
Compliance: no compliance information reported specifically; however, women were "seen to swallow" the tablets at their fortnightly and weekly visits.
Location: Nigeria.
Time frame: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quasi‐randomised, alternate allocation.

Allocation concealment (selection bias)

High risk

Quasi‐randomised, alternate allocation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women and investigators blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The identity of the tablets was not known to investigators until after the completion of the trial." pg426.

Incomplete outcome data (attrition bias)
All outcomes

High risk

21 women (28%) excluded from the analysis.

Selective reporting (reporting bias)

Unclear risk

Results not reported as intention to treat; however, where possible, the review authors included data in the review as intention to treat.

Other bias

Unclear risk

Limited methodological details provided.

Fleming 1986

Methods

Randomisation and allocation concealment: women were "randomly allocated to one of five groups using a random number table", no other details given.

Blinding of outcome assessment: women and investigators were blinded to the treatment allocation, until after the completion of the trial.

Documentation of exclusion: 18 women (9%) were excluded due to anaemia at enrolment, 'defaulting', or being 'mentally subnormal', these women were replaced by other women chosen by an investigator. A further 42 women were excluded before delivery and another 30 failed to attend the postnatal clinic, birth outcomes were available for 160 women (80%).

Use of placebo control: no placebo control.

Participants

228 women met the eligibility criteria; however 200 pregnant women were recruited into the study. Women were allocated to 1 of 5 groups; 40 women were allocated to each group.

Eligible women included:

  1. Hausa women living in Zaria and planning to deliver in Zaria;

  2. pregnant for the first time;

  3. at less than 24 weeks' gestation, as estimated by the height of the fundus uteri;

  4. the wives of unskilled or semiskilled men.

Women were excluded if they had already taken any antimalarial treatment or haematinics during the pregnancy, or had the following complications: hydatiform mole, Hb SC disease, overt anaemia or proteinuria.

The mean gestational age of women at enrolment was 18.5 weeks.

Interventions

Women were allocated to 1 of 5 groups:

  • group 1: no active treatment (control);

  • group 2: antimalarials only (600 mg chloroquine/day + 100 mg proguanil/day);

  • group 3: iron + antimalarials (60 mg iron/day + 600 mg chloroquine/day + 100 mg proguanil/day);

  • group 4: folic acid + antimalarials (1 mg folic acid/day + 600 mg chloroquine/day + 100 mg proguanil/day);

  • group 5: iron + folic acid + antimalarials (1 mg folic acid/day + 60 mg iron/day + 600 mg chloroquine/day + 100 mg proguanil/day).

Outcomes

Maternal outcomes

  1. Anaemia (severe and mild/moderate) before 28 weeks', between 28‐36 weeks', and after 36 weeks' gestation.

  2. Gestation age.

  3. Mode of delivery.

  4. Complications of pregnancy (abortion, hypertension, pre‐eclampsia or eclampsia, hydramnios, abdominal pain).

Infant outcomes

  1. Fetal distress.

  2. Birthweight.

  3. Apgar score at 2 minutes.

  4. Fetal complications.

Laboratory outcomes

  1. Hb concentration, red cell indices and WBC at first attendance, 28 weeks, 36 weeks, at delivery (form mother and infant) and 6 weeks postpartum.

Not all outcomes were reported for each individual treatment group. Miscarriage was reported for the combined groups 4 and 5, therefore for the purpose of this review the groups 4 and 5 are combined (folic acid + iron) and compared with group 2 and group 3 (iron + antimalarials). The authors reported that 8 women had hypertension without other signs, 21 women had pre‐eclampsia and 6 developed eclampsia, with no association between these outcomes and treatment group. No other details were provided, including the breakdown of these outcomes by treatment group.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women were at high risk of anaemia. Information about other nutritional indices was not provided.

Intention‐to‐treat analyses not performed, however, where possible, the review authors included data in the review as intention‐to‐treat.

Compliance: 72 women (36%) were classed as defaulters.

Location: Nigeria.

Timeframe: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

A random number table was used but no details provided of how it was generated.

Allocation concealment (selection bias)

Unclear risk

No details provided about the allocation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Neither the researchers nor the patients were aware of the treatment allocation until after the completion of the study.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Neither the researchers nor the patients were aware of the treatment allocation until after the completion of the study." pg 214.

Incomplete outcome data (attrition bias)
All outcomes

High risk

228 women met the entry criteria, but only 200 were included in the trial. 18 women were excluded and replaced by other women.

Selective reporting (reporting bias)

High risk

Not all outcomes are reported by treatment group. In serial publications up to 70% of the data were excluded.

Other bias

Unclear risk

Limited methodological details provided.

Hans 2010

Methods

Randomisation and allocation concealment: women were randomly assigned to receive either 400 mg of vitamin C daily or not in addition to their standard antenatal vitamin. Randomisation was obtained by a computer‐generated, block design sequence to receive vitamin C or not in a 1:1 ratio. No other methodological details given.

Blinding of outcome assessment: unclear, no details given.

Documentation of exclusion: 16 women (4%) did not complete the trial after randomisation.

Use of placebo control: no placebo control.

Participants

400 women 4 to 12 gestational weeks of pregnancy confirmed serologically by B‐HCG reagent test along with referred last menstrual period not exceeding the past 3 months, aged at least 18. Women with referred pregnancy of more than 3 months by last menstrual period, concomitant HIV infection status, active or recent (< 2 weeks) sexually transmitted disease infection, medical record of any severe organ disease such as heart, liver or renal failure at the time of assessment, diagnosis of pregnancy during inpatient admission for any other reason, recent history of multivitamin supplementation (< 12 weeks) for any reason, except for pregnancy, and patients incapable to read and write.

Interventions

Chewable tablet of synthetic form of L‐ascorbic acid or vitamin C 400 mg administered daily 2 tablet 2 times a day, from first trimester until delivery. Comparison received no vitamin C in addition to their standard antenatal vitamin.

All women received ferrous sulphate 200 mg, folic acid 5 mg and vitamin B‐complex 60 mg once daily tablets. Nutritional counselling was provided to all women.

Outcomes

  1. Prevention of hospitalisations during pregnancy.

  2. Overall hospitalisations rate.

  3. Weight gain during pregnancy (normal < 16 kg).

  4. Term pregnancy (≥ 37 gestational weeks).

  5. Preterm delivery.

  6. miscarriage (< 24 gestational weeks).

  7. Low birthweight (< 2500 g).

  8. Gestational systolic blood pressure.

Notes

Women's risk of spontaneous or recurrent miscarriage is unclear, as is their dietary intake.

Sample‐size calculation based on at least 30% of women not hospitalised during pregnancy in the control group and at least 50% of women not hospitalised in the intervention group.

Analyses were not based on intention‐to‐treat.

Compliance: no details of any compliance assessments were given.

Location: Kyeibuza, Uganda.

Timeframe: August 2007 and January 2009.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Patients presented to the health centre, those who met the inclusion criteria were randomly assigned...randomization was obtained by a computer‐generated, block design sequence to receive vitamin C or not in a 1:1 ratio." pg 3.

Allocation concealment (selection bias)

Unclear risk

No description for allocation concealment in the text. Probably not done.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information on participant or personnel blinding provided.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information on outcome assessor blinding provided.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Drop‐out rates for each group were not clearly described and no information was provided on the reason of exclusion and attrition.

Selective reporting (reporting bias)

Unclear risk

Although expected outcomes were reported, the study protocol was not available to see if all prespecified outcomes were reported as planned.

Other bias

Low risk

The study appears to be free of other sources of bias.

Hemmi 2003

Methods

Randomisation and allocation concealment: unclear, "patients were randomly assigned to the control group or the study group". No other methodological details given.

Blinding of outcome assessment: unclear, no details given.

Documentation of exclusion: 28 women (19%) in the control group were excluded, no details given for the exclusion.

Use of placebo control: no placebo control.

Participants

150 women were recruited into the study. Women with a luteal phase defect, as described by a peak serum P level < 120 mg/mL in the mid‐luteal phase measured at 3 time points, were eligible and invited to participate. Luteal phase defects were ascertained in 2 consecutive menstrual cycles, and the third cycle was the intervention cycle. Women receiving IVF‐ET treatment were excluded. 313 women were considered for enrolment in the study, 150 (48%) were randomised. 28 women were withdrawn from the control group, leaving 122 women in the study, who were allocated to vitamin C (n = 76) or control (n = 46). 5 women in the control group and 19 women in the vitamin C group became pregnant during the study period.

Interventions

Women in the intervention group took 750 mg vitamin C per day from the first day of the third menstrual cycle until a urinary pregnancy test was positive. Pregnancy rate was checked up until 6 months after the study cycle was started. Women in the control group received no supplementation and no treatment was given in the third cycle.

Outcomes

  1. Serum P concentrations.

  2. Serum E2 (oestrogen) concentrations.

  3. Pregnancy rate.

  4. Miscarriage.

Notes

Women's risk of spontaneous or recurrent miscarriage was unclear according to criteria specified in the review.
Their dietary intake of vitamin C is unknown.
No sample‐size calculation was reported.
Analyses were not based on intention to treat.
Compliance: no details of any compliance assessments were given.
Country: Japan.
Time frame: January 1997 to December 2000.
The denominators used for this trials are the number of women randomised and with a confirmed pregnancy (i.e. 19 for the vitamin group and 5 for the control group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Methodological details unclear.

Allocation concealment (selection bias)

Unclear risk

Methodological details unclear.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Methodological details unclear.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No methodological details are given.

Incomplete outcome data (attrition bias)
All outcomes

High risk

28 women (19%) in the control group excluded.

Selective reporting (reporting bias)

Unclear risk

No details of exclusion of women in the control group given.

Other bias

High risk

No placebo control.

ICMR 2000

Methods

Randomisation and allocation concealment: unclear, "containers of vitamin or placebo capsules were given a random number" and "the key to random numbers was kept at the ICMR Headquarters". No other methodological details were given.

Blinding of outcome assessment: "double blind" mentioned in the text, but no details given.

Documentation of exclusion: 187 women (40%) were excluded from the analysis.

Use of placebo control: placebo control.

Participants

466 women were recruited into the study. Women who had previously given birth to a child with an open NTD, and planned to have another child were eligible and invited to participate. This was regardless of their parity, number of previous births with an NTD, age, consanguinity, and socioeconomic status. Women who had previously given birth to a child with closed spina bifida, or with a history of diabetes or abnormal fasting and post‐prandial blood sugar, history of epilepsy, congenital anomalies indicative of a genetic syndrome in the previous NTD, history of vitamin intake in the 3 months prior to enrolment, and pregnancy were excluded. 466 women were enrolled and randomised to either vitamin (n = 231) or placebo (n = 235), of these women, 90 were lost to follow‐up immediately and 71 did not conceive until the final follow‐up. Of the remaining 305 women who were known to become pregnant (vitamin n = 152, placebo n = 153), pregnancy outcomes were unknown for 26 women. In the paper, 279 of the initial 466 women were included in the analysis; however, in this review results are presented for main outcomes on an intention‐to‐treat basis (i.e. n = 466).

Interventions

The folic acid containing multivitamin included 120 mg ferrous sulphate, 240 mg calcium phosphate, 4000 IU vitamin A, 400 IU vitamin D, 2.5 mg vitamin B1, 2.5 mg vitamin B2, 2 mg vitamin B6, 15 mg nicotinamide, 40 mg vitamin C, 4 mg folic acid, 10 mg zinc.
The placebo tablets contained the following trace elements: 120 mg ferrous sulphate and 240 mg calcium phosphate. Both capsules were identical in appearance and women were provided with the tablets from at least 28 days before conception and continuing until at least the second missed menstrual period.

Outcomes

  1. Recurrence of NTDs.

  2. Live births.

  3. Stillbirths.

  4. Spontaneous and induced abortion.

  5. Multiple birth.

Notes

The risk profile of women in the trial for spontaneous and recurrent miscarriage is unclear, as is the dietary intake of participants.
Sample‐size calculation performed, assuming a 20% drop out rate. The trial was terminated after publication of the MRC trial in 1991.
Compliance: compliance was assessed at 3‐monthly visits, by checking a diary card maintained by the woman and the number of capsules returned. If the total number of missed days in 3 months did not exceed 10 days, and the total number of missed days at a stretch did not exceed 3, compliance was taken as satisfactory. Women not meeting the above criteria were excluded if they became pregnant in that particular quarter. No compliance data are specifically reported.
Analyses not based on intention‐to‐treat.
Country: India.
Time frame: 1988 to 1991.
The denominators used for this trial are based on the number of women randomised (i.e. 231 for the vitamin group and 235 for the placebo group). There was not enough information to accurately confirm the number of women that did or did not become pregnant due to the large number of losses to follow‐up.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Containers 'given a random number'.

Allocation concealment (selection bias)

Unclear risk

'Key to random numbers were kept at the ICMR headquarters' but no other details given.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Double‐blind mentioned in the text but no details given.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Unclear of outcome assessors were unaware of treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

High risk

187 (40%) women excluded.

Selective reporting (reporting bias)

Unclear risk

Difficult to assess given the high losses to follow‐up.

Other bias

Unclear risk

Limited methodological details provided.

Jauniaux 2004

Methods

Randomisation and allocation concealment: randomised controlled trial, but no other information provided.

Blinding of outcome assessment: unclear.

Documentation of exclusions: unclear, no information provided.

Use of placebo: placebo control.

Participants

Women with a history of 2 or more early pregnancy losses, with no identifiable cause for the losses.

Interventions

Vitamin C 1000 mg and vitamin E 400 IU versus placebo.

Outcomes

Miscarriage.

Notes

Updated 27/11/2013: the trial was stopped in October 2009 due to poor recruitment and lack of funding.

Women's risk of spontaneous and recurrent miscarriage is unclear.
Sample‐size calculation: not done.
No intention‐to‐treat analyses: not done.
Compliance: unclear.
Location: UK.
Timeframe: recruitment planned from 2000 to 2001, but trial stopped in 2009.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Could not be assessed because the trial was stopped.

Allocation concealment (selection bias)

Unclear risk

Could not be assessed because the trial was stopped.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Could not be assessed because the trial was stopped.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Could not be assessed because the trial was stopped.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Could not be assessed because the trial was stopped.

Selective reporting (reporting bias)

Unclear risk

Could not be assessed because the trial was stopped.

Other bias

Unclear risk

Could not be assessed because the trial was stopped.

Katz 2000

Methods

Randomisation and allocation concealment: cluster‐randomised. 270 centres in the Salarhi district, Nepal, were involved which included 30 subdistricts each with 9 wards. Each ward was assigned to 1 of 3 treatment groups. "Wards were assigned by a random draw of numbered chits, blocked on subdistrict."

Blinding of outcome assessment: women and study investigators were not aware of the treatment codes. Maternal mortality was assessed by study investigators blinded to treatment allocation, no details were given for other outcomes.

Documentation of exclusions: 157 (1%) women were lost to follow‐up and excluded.

Use of placebo: placebo control.

Participants

15,832 women were recruited into the study. All married women of child bearing age in the Salarhi district, Nepal, were eligible and invited to participate in the study. Women migrating into the study area, or women that were never pregnant or refused participation, or women who migrated before being pregnant, were excluded from the analysis. Eligible women were identified from census data and marriage registers. 44,646 women were recruited, of which 1136 (2.5%) were excluded as they either emigrated before becoming pregnant, died or refused consent. During the study period 15,832 women identified themselves as being pregnant, and 157 women were lost to follow‐up in the postpartum period. Results are reported for 17,373 pregnancies, allocated to the following groups: vitamin A (n = 6070), beta‐carotene (n = 5650) or placebo (n = 5653). Denominators for the treatment groups vary for the measures of early infant mortality, due to losses to follow‐up after birth.

Interventions

The 3 treatment groups consisted of a weekly single oral supplement of either:

  1. 23,300 IU preformed vitamin A as retinyl palmitate;

  2. 42 mg of all trans beta‐carotene;

  3. placebo.

All capsules contained mg dl‐alpha‐tocopherol as an antioxidant. Women took the tablets prior to conception, during pregnancy and postpartum, for a total of 3.5 years.

Outcomes

1. Fetal loss, defined as any reported miscarriage, stillbirth or maternal death during pregnancy. The outcomes were based on self‐reports, and women who reported to be pregnant for >= 6 weeks but then no longer reported being pregnant were considered to have had a miscarriage.
Serial publications also reported neonatal death.

Notes

Women's risk profile for spontaneous or recurrent miscarriage was unclear, as was their dietary intake of vitamin A.
Compliance: women were distributed the capsules in their home on a weekly basis, receipt of capsules was noted only if the distributor observed the woman swallowing the capsule. Over half of the women who became pregnant during the study received over 80% of their intended supplements, and 75% of pregnant women received at least half of their eligible doses.
There were serial publications of this study causing the study numerators and denominators to vary between published versions, and multiple pregnancy figures reported did not include higher order pregnancies.
Sample‐size calculation performed.
Partial intention‐to‐treat analyses, and the risk ratios and confidence intervals were adjusted to account for any cluster‐design effect.
Country: Nepal.
Timeframe: April 1994 to September 1997.
The denominators used for this trial are the number of women randomised who identified themselves as pregnant (i.e. 6070 for the vitamin A group, 5650 for the beta‐carotene group and 5653 for the placebo group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Cluster‐randomised, unclear how sequence was generated.

Allocation concealment (selection bias)

Unclear risk

Each ward was assigned to the treatment groups based on 'a random draw of numbered chits, blocked on subdistrict'.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women and investigators blinded to treatment allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"This committee and the data analysts were unmasked to the treatment codes, but the codes were made available to study investigators only at the end of the trial."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

157 women (1%) were lost to follow‐up and excluded, partial intention‐to‐treat analysis performed.

Selective reporting (reporting bias)

Unclear risk

Denominators vary in several publications of this trial.

Other bias

High risk

Some women were pregnant more than once during the study period, however the denominators reported are the total number of pregnancies during the study period, not the total number of women randomised, which incorrectly assumes that each data point included is independent from the next.

Kirke 1992

Methods

Randomisation and allocation concealment: block randomisation, stratified by hospital, using "consecutively numbered, opaque, sealed envelopes".

Blinding of outcome assessment: women and study investigators were initially blinded to the treatment allocation, however the tablet preparations were changed after 55 women were randomised and after this only participants were blinded.

Documentation of exclusion: 3 women (1%) were lost to follow‐up and excluded.

Use of placebo control: 3 treatment regimens were assessed, no placebo control.

Participants

354 women were recruited into the study. Women with a previous NTD defined as anencephalus, iniencephalus, encephalocoele, and spina bifida aperta, who were not pregnant when contacted but were planning a future pregnancy, were eligible and invited to participate. Women were identified from case registers at the participating hospitals. Women with conditions likely to result in impaired absorption from the gastrointestinal tract were excluded.
435 women were approached, of which 354 (84%) consented and were randomised to either F (n = 115 ), MV (n = 119) or MF (n = 120). 16 women did not become pregnant, and 75 women withdrew; however, their pregnancy outcome status was known, and 18 of these women subsequently became pregnant after withdrawing. 3 women were lost to follow‐up. 281 women (93 in the F group, 93 in the MF group and 95 in the MV group) became pregnant in the study period and their pregnancy outcome was known.

Interventions

Indistinguishable trial tablets were initially made by Beecham and Glaxo, however Beecham withdrew their support after 55 women had been randomised. After this time a commercially available pregnavite Forte F was used (MF tablet) and Antigen Pharmaceuticals produced a white multivitamin tablet without folic acid. This was associated with a loss of blinding. Women were randomised to 1 of 3 treatments:

  1. folic acid alone (F);

  2. multivitamin with folic acid (MF);

  3. multivitamin with no folic acid (MV).

The F and MF resulted in a daily dose of 0.3 mg folic acid. The MF and MV resulted in a daily dose of 4000 IU vitamin A, 400 IU calciferol, 1.5 mg thiamine hydrochloride, 1.5 mg riboflavine, 1 mg pyridoxine hydrochloride, 15 mg nicotinamide, 40 mg ascorbic acid, 480 mg calcium phosphate, and 252 mg ferrous sulphate. Women took the tablets for at least 2 months prior to conception and until the date of the 3rd missed period.

Outcomes

  1. Recurrence risk of NTDs.

  2. Spontaneous abortion.

  3. Ectopic pregnancy.

  4. Livebirth.

  5. Stillbirth.

  6. Congenital malformations excluding NTDs.

Notes

The trial was stopped after there were poor recruitment rates and birth rates. A sample‐size calculation required 462 women to show a reduction in NTDs from 5% to 1%. Data from 106 women who were already pregnant at time of recruitment are also included.
The risk profile of women in the trial for spontaneous and recurrent miscarriage is unclear, as is their dietary intake.
Compliance: compliance was assessed on tablet counts and blood tests; however, the results are not presented.
Intention‐to‐treat analyses were performed.
Location: Republic of Ireland.
Timeframe: December 1981 to January 1988.
The denominators used for this trial are the number of women randomised who became pregnant in the study period and their pregnancy outcome was known (i.e. 93 in the F group, 93 in the MF group and 95 in the MV group).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Block randomisation stratified by hospital site.

Allocation concealment (selection bias)

Low risk

Consequtively numbered, opaque sealed envelopes used.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Only participants were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Only participants were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 women (1%) lost to follow‐up and excluded. Intention‐to‐treat analyses performed.

Selective reporting (reporting bias)

Unclear risk

Compliance data not reported.

Other bias

High risk

The trial was stopped after there were poor recruitment rates and birth rates.

Kumwenda 2002

Methods

Randomised controlled trial of vitamin A, iron and folic acid supplementation versus iron and folic acid only, during pregnancy, to improve infant outcomes born to women infected with HIV in Malawi.

Randomisation and allocation concealment: "treatment assignment was determined by use of a computer's random‐number generator" and "mothers were assigned an original study identification number at enrolment and were given the next sequentially numbered opaque bottle with supplements". "Treatment assignment was concealed by pre packing study supplements in sequentially numbered series assigned to study identification numbers."

Blinding of outcome assessment: unclear, not specifically stated, but participants were blind to their treatment allocation.

Documentation of exclusion: 63 (9%) women were lost to follow‐up and 14 (2%) pairs of twins were excluded.

Use of placebo control: control tablets containing iron and folic acid were given.

Participants

Pregnant women between 18 and 29 weeks' gestation and infected with HIV. The average gestation of participants was 23 weeks. 693 women were enrolled and allocated to either vitamin A (n = 340) or control (n = 357), of which pregnancy outcomes were known for 623 women. 63 women were lost to follow‐up and 14 sets of twins were excluded due to their higher risk of low birthweight and infant mortality.

Interventions

All women received orally administered daily doses of 30 mg iron and 400 mcg folic acid during the study. Women in the intervention group received 10,000 IU vitamin A (3 mg retinol equivalent) orally, in addition to the iron and folic acid supplements. Women were asked to take the tablets from enrolments until delivery. Tablet counts were conducted every 4 weeks. All women received 30 mg retinol equivalents at 6 weeks postpartum, according to standard postpartum care in Malawi.

Outcomes

  1. Infant Hb level at 6 weeks and 12 months of age.

  2. Percentage of infants with anaemia at 6 weeks of age and at 12 months, defined as a Hb level of < 110 g/L.

  3. Birthweight.

  4. Percentage of infants < 2500 g at birth.

  5. Weight and length at 6 weeks, 14 weeks and 6 months of age.

  6. Transmission of HIV to the infant, infant mortality at < 6 weeks of age, at 12 months and at 24 months.

  7. Stillbirth and spontaneous abortion (undefined).

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear, although may be increased due to their HIV status.
50% of women in the vitamin A group and 51% of women in the control group had deficient levels of vitamin A (defined as plasma vitamin A < 0.70 umol/L) at trial entry.
Sample‐size calculation performed.
No intention‐to‐treat analyses were performed.
Compliance: more than 95% of women in both groups took > 90% of study supplements, as ascertained by tablet counts.
Location: Malawi.
Timeframe: November 1995 to December 1996.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number list.

Allocation concealment (selection bias)

Low risk

Sequentially number opaque bottles used.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not specifically stated but women were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Unclear of outcome assessors were unaware of treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

63 women (9%) lost to follow‐up and 14 pairs of twins (2%) excluded. No intention‐to‐treat analyses performed.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes appear to be reported.

Other bias

Unclear risk

Insufficient information to assess whether an important risk of other bias exists.

McCance 2010

Methods

Randomisation and allocation concealment: participants were randomly allocated in a 1:1 ratio to receive 1000 mg vitamin C and 400 IU vitamin E. A randomisation sequence generated in advance by Victoria Pharmaceuticals using PRISYM ID software (version1.0009) was used. The randomisation sequence was stratified by centre with balanced blocks of 8 patients and was held by Victoria Pharmaceuticals. Individual sealed envelopes containing treatment allocations were given to trial pharmacists in every centre allowing treatment groups to be revealed in a clinical emergency.

Blinding of outcome assessment: diagnosis was independently confirmed by 3 senior clinicians, who were unaware of treatment allocation.

Documentation of exclusion: only 1 loss to follow‐up was reported.

Use of placebo control: matched placebo control.

Participants

762 pregnant women between 8 and 22 weeks' gestation with type‐1 diabetes attending 25 antenatal metabolic clinics across Northern Ireland, Scotland, and northwest England. Participants were women with type 1 diabetes preceding pregnancy, presentation between 8 weeks' and 22 weeks' gestation, singleton pregnancy, and age 16 years or older. Women with chronic hypertension were included in the trial.

Women were excluded if they did not give consent, were enrolled in another research study, were being treated with warfarin, or were known to misuse drugs Women taking vitamin supplements were excluded only if these contained 500 mg or more vitamin C or 200 IU or more vitamin E daily.

Interventions

1000 mg vitamin C and 400 IU vitamin E versus matched placebo started between 8 and 22 weeks' gestation and taken until delivery.

Outcomes

  1. Pre‐eclampsia.

  2. Placental and endothelial function (established by PAI‐1 to PAI‐2 ratio).

  3. Gestational hypertension.

  4. Birthweight (centile as calculated from customised birthweight charts).

  5. Miscarriage.

  6. Maternal death.

  7. Obstetric complications and other adverse outcomes.

  8. Fetal malformation.

  9. Gestational age at delivery.

  10. Admission to a neonatal care unit.

Notes

Women's risk profile for spontaneous and recurrent miscarriage: women with chronic hypertension were included.

Multivitamin supplementation at randomisation was reported at trial entry. Other information about nutrition status are not provided.

Sample‐size calculation: based on 40% reduction in pre‐eclampsia.

Modified intention to treat was used for analysis of the primary endpoint.

Compliance: unused tablets and capsules were collected during delivery admission or at the 6‐week postnatal trial visit, or were returned in postage prepaid envelopes.

Location: Northern Ireland, Scotland, northwest England.

Tiimeframe: April 2003 to June 2008.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisations by Victoria Pharmaceuticals using PRISYM ID software (version1.0009).

Allocation concealment (selection bias)

Low risk

Supplements were identical in appearance. The randomisation sequence was stratified by centre with balanced blocks of 8 patients, and was held by Victoria Pharmaceuticals.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Treatment allocation was masked from all trial personnel and participants until trial completion.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Diagnosis were independently confirmed by 3 senior clinicians, who were unaware of treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Only 1 loss to follow‐up in placebo group, but the reason is unclear.

Selective reporting (reporting bias)

High risk

Fewer outcomes were stated in the trial registration.

Other bias

Low risk

The study appears to be free of other sources of bias.

MRC 1991

Methods

Randomisation and allocation concealment: third party randomisation, "randomisation was carried out through the Clinical Trials Service Unit in Oxford". Randomisation was stratified by centre.

Blinding of outcome assessment: women, caregivers and study investigators were blinded to the treatment allocation.

Documentation of exclusion: 164 women (9%) excluded.

Use of placebo control: placebo control.

Participants

1817 women were recruited into the study. Women who had a previous pregnancy affected by a NTD, and were planning another pregnancy and not already taking supplements were eligible for the study. Women whose affected child had Meckel's syndrome and those women with epilepsy were excluded. 1817 women were randomised to either F (n = 449), MV (n = 453), MF (n = 461) or P (n = 454), of which, 1195 were informative pregnancies that is, where the outcome of NTD or not was definitely known (F n = 298, MV n = 302, MF n = 295, P n = 300). Results for pregnancy loss are reported for both informative and not informative pregnancies. 164 women were excluded as they may have been pregnant at the time of randomisation.

Interventions

Women were randomised into 1 of 4 groups:

  1. 4 mg, 240 mg di‐calcium phosphate and 120 mg ferrous sulphate (F);

  2. 4000 IU vitamin A, 400 IU calciferol, 1.5 mg thiamine hydrochloride, 1.5 mg riboflavine, 1 mg pyridoxine hydrochloride, 15 mg nicotinamide, 40 mg ascorbic acid, 240 mg di‐calcium phosphate and 120 mg ferrous sulphate (MV);

  3. folic acid combined with the multivitamins specified above (MF);

  4. placebo containing 240 mg di‐calcium phosphate and 120 mg ferrous sulphate only (P).

Women took the tablets prior to conception and attended the site every 3 months to collect additional supplies and again during the 12th week of pregnancy. No special dietary advice was given to women.

Outcomes

  1. NTD and other birth defects.

  2. Spontaneous abortions.

  3. Ectopic pregnancy.

  4. Termination or pregnancy.

  5. Livebirth.

  6. Stillbirth.

  7. Multiple pregnancy.

  8. Subsequent publications report on blood folic acid and zinc concentrations.

Notes

The trial was stopped early after there were 1195 informative pregnancies, according to prespecified stopping rules. The aim of the study was to obtain information on at least 2000 informative pregnancies unless a sufficiently clear result emerged sooner.
Women's risk profile for spontaneous and recurrent miscarriage was unclear, as was their nutritional status.
Compliance: compliance based on self‐reports, and data were available for women with an informative pregnancy only, where 79 (6%) women reported they stopped taking their capsules before their last scheduled visit.
Intention‐to‐treat analyses are reported in this review including not informative pregnancies (i.e. n = 1817).
Location: multi‐national study co‐ordinated from the UK.
Timeframe: July 1983 to April 1991.
The denominators used for this trial are the number of women randomised, i.e. (449 for the F group, 453 for the MV group, 461 for the MF and 454 for the P group). There was no information provided about any women randomised that did not become pregnant in the study period.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Third party randomisation, "randomisation was carried out through the Clinical Trials Service Unit in Oxford".

Allocation concealment (selection bias)

Low risk

Third party randomisation, "randomisation was carried out through the Clinical Trials Service Unit in Oxford".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women, caregivers and investigators blinded to treatment allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No details are given if outcome assessment was blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

164 women (9%) excluded, intention‐to‐treat analyses performed.

Selective reporting (reporting bias)

Unclear risk

No information provided about any women randomised that did not become pregnant in the study period.

Other bias

High risk

The trial was stopped early after there were 1195 informative pregnancies, according to prespecified stopping rules.

Osrin 2005

Methods

Randomisation and allocation concealment: 1 of the authors 'randomly allocated 1200 participant numbers by computer into 2 groups in permuted blocks of 50'. Every identification number was allocated a supplement container, which was then packed by a team member not otherwise involved in the trial. After enrolment, another author allocated participants sequential identification numbers with the corresponding supplement containers.

Blinding of outcome assessment: double‐blind stated but no other details given.

Documentation of exclusion: 61 women (5%) withdrew or were lost to follow‐up, however data on miscarriage were reported for those who withdrew due to miscarriage.

Use of placebo control: control of iron and folic acid supplements given which looked identical to the intervention supplements.

Participants

1200 women were recruited into the study. Women were eligible if they were: less than 20 completed weeks, had a singleton pregnancy, no notable fetal abnormality, no existing maternal illness of a severity that could compromise the outcome of pregnancy, and lived in an area of Dhanusha or the adjoining district of Mahottari accessible for home visits.

Maternal illnesses that led to exclusion were: recently treated recurrent cysticercosis, need for chlorpromazine or anticoagulant drugs with changing doses, and symptomatic mitral stenosis or multivalvular heart disease. Fetal exclusions were: twin pregnancies, anencephaly, occipital meningocele, encephalocele, duodenal atresia and a grossly dilated pelvicalyceal system.

Interventions

Intervention group: vitamin A 800 mcg, vitamin E 10 mg, vitamin D 5 mcg, vitamin B1 1.4 mg, vitamin B2 1.4 mg, niacin 18 mg, vitamin B6 1.9 mg, vitamin B12 2.6 mcg, folic acid 400 mcg, vitamin C 70 mg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 mcg, and iodine 150 mcg.

Control group: iron 60 mg and folic acid 400 mcg.

Supplementation began at a minimum of 12 weeks’ gestation and continued until delivery.

Outcomes

  1. Birthweight.

  2. Gestational duration.

  3. Infant length and head circumference.

  4. Miscarriage defined as cessation of confirmed pregnancy before 23 weeks’ gestation.

  5. Stillbirth defined as delivery of an infant showing no signs of life (movement, breathing, or heartbeat) after 23 weeks’ gestation.

  6. Early neonatal death defined as death of a live born infant in the first 7 days after birth.

  7. Late neonatal death as death of a live born infant after 7 but within 28 days.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear, however, women are presumable at high risk of under‐nutrition as the paper states that in Nepal 'deficiencies of several micronutrients have been well described in individual studies and in a national sample'.

Intention‐to‐treat analyses performed.

Compliance: median 'adherence' was 98% in the control group and 97% in the intervention group.

Location: Nepal.

Timeframe: August 2002 to October 2003.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated in permuted blocks of 50.

Allocation concealment (selection bias)

Unclear risk

1 of the authors allocated participants with sequential identification numbers, but unclear if this person was involved in the recruitment of participants.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Double‐blind stated in the text but no other details given.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The allocation code was broken for the analysis. Pg 956.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

61 women (5%) withdrew or were lost to follow‐up, however data on miscarriage were reported for those who withdrew due to miscarriage. Intention‐to‐treat analyses performed.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes appear to be reported.

Other bias

Low risk

The study appears to be free of other sources of bias.

People's League 1942

Methods

Randomisation and allocation concealment: "women enrolled at the antenatal clinic were divided into two main groups by placing them alternatively on separate lists".

Blinding of outcome assessment: unclear, no information given on blinding of participants, carers or outcome assessors.

Documentation of exclusion: 622 women (11%) were excluded.

Use of placebo control: no placebo given.

Participants

5644 women were recruited into the study. All women attending the antenatal clinics and who were less than or equal to 24 weeks' gestation and who were in 'good health' were eligible for the study. Women who were more than 24 weeks' gestation and women who suffered from any disease or physical abnormality were excluded from the study. After enrolment, women who had twin births and who miscarried at an early stage were also excluded.
5644 women were initially enrolled in the study of which 5022 (89%) remained in the study. Of the 622 (11%) women withdrawn from the trial, 494 were evacuated from the London area (due to World War 2), 39 women had twin births and 89 women miscarried at an early stage. 5022 women remained in the study and were allocated to either multivitamins (n = 2510) or control (n = 2512). Women were further divided into primiparae and multiparae, and various age groups.

Interventions

Women allocated to the treatment group were given daily vitamin C 100 mg, ferrous iron 0.26 g, calcium 0.26 g, minute quantities of iodine, manganese and copper, adsorbate of vitamin B1 containing all factors of the B complex and halibut liver oil 0.36 g containing vitamin A (52,000 IU per g) and vitamin D (2500 IU per g).
Women allocated to the control group received no placebo.

Outcomes

  1. Toxaemia classified into subgroups based on: hypertension only, albuminuria with or without hypertension, or hypertension with albuminuria (pre‐eclampsia).

  2. Maternal sepsis.

  3. Length of gestation (categorised as less than 40 weeks, 40 weeks, and greater than 40 weeks).

  4. Percentage of women breastfeeding.

  5. Stillbirth.

  6. Neonatal mortality (defined as death before 8 days).

  7. Birthweight (pounds) (only reported for primiparae and multiparae separately).

Notes

Women risk status for spontaneous and recurrent miscarriage is unclear.
Dietary intake at trial entry: "vitamin C shortage affected about half the women".
Intention‐to‐treat analyses: not performed.
Compliance: unclear, no information provided.
Sample‐size calculation: unclear. "It was decided that the investigation should include a minimum of 5000 pregnant women". No other details given.
Location: England.
Timeframe: 1938 to 1939.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Quasi‐randomistion using alternate separate lists.

Allocation concealment (selection bias)

High risk

No allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information about blinding provided.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information about blinding provided.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

622 women (11%) excluded, intention‐to‐treat analyses not performed.

Selective reporting (reporting bias)

Unclear risk

Limited methodological details provided.

Other bias

Unclear risk

Limited methodological details provided.

Poston 2006

Methods

Randomisation and allocation concealment: the randomisation (computer‐generated sequence) was blocked—i.e., balanced—by centre in groups of 2 to 10 individuals.

Blinding of outcome assessment: none of the trial staff or any other person involved in the trial knew the allocated treatment of any woman until after completion of the study.

Documentation of exclusion: 9 (0.4%) women were excluded.

Use of placebo control: placebo control.

Participants

2404 women with clinical risk factors for pre‐eclampsia

Inclusion criteria:

gestational age 14+⁰–21+⁶ weeks; one or more of the following risk factors: pre‐eclampsia in the pregnancy preceding the index pregnancy, requiring delivery before 37 completed weeks’ gestation, diagnosis of HELLP syndrome in any previous pregnancy, eclampsia in any previous pregnancy; essential hypertension requiring medication, type 1 or type 2 diabetes, multiple pregnancy; abnormal uterine artery doppler waveform primiparity with BMI at first antenatal appointment of 30 kg/m² or more.

Exclusion criteria:

women unable or unwilling to give written informed consent or women who were being treated with warfarin. Women taking vitamin supplements that contained doses of vitamin C of 200 mg or more or of vitamin E of 40 IU or more daily were excluded.

Interventions

Women were assigned to 1000 mg vitamin C and 400 IU vitamin E (RRR α tocopherol; n = 1199) or matched placebo (n = 1205) daily from the second trimester of pregnancy until delivery.

Outcomes

Primary outcomes

  1. Pre‐eclampsia,

Secondary outcomes:

  1. Low birthweight (<2·5 kg).

  2. Small size for gestational age.

  3. Preterm birth (≤37+⁰ weeks’ gestation).

  4. Gestational age at delivery.

  5. Smaller than 10th centile for gestation.

  6. Use of health‐care resources.

Notes

Women risk status for spontaneous and recurrent miscarriage: history of chronic hypertension, BMI, pre‐eclampsia, multiple pregnancy, diabetes, and other risk factors reported.
Dietary intake at trial entry: use of supplements reported.
Intention‐to‐treat analyses: not performed.
Compliance: 80% (n = 1653) of women took at least 50% of their tablets, 65% (n = 1345) took 80% or more, and 32% (n = 661) took all of their tablets; 6% (n = 125) did not take any tablets.
Sample‐size calculation: expected incidence of pre‐eclampsia in the placebo group of at least 15% and in the treatment group of at least 30%

Location: 25 hospitals, UK.
Timeframe: August 2003 to June 2005.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random sequence Pg 1146

Allocation concealment (selection bias)

Unclear risk

Although paper states that supplementation and placebo looked and tasted the same, (Pg 1146) there is no clear description of how women were allocated to treatment group

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

“none of the trial staff or any other person involved in the trial knew the allocated treatment of any woman until after completion of the study” Pg 1146

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Unclear from text if outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Very low loss to follow‐up rates. In the supplementation group 3 (0.25%) losses to follow‐up and in the placebo group 6 (0.5%).

Selective reporting (reporting bias)

Unclear risk

A large number of outcomes reported in the publication, but not pre‐specified in the registered trial.

Other bias

Low risk

The study appears to be free of other sources of bias.

Prawirohartono 2011

Methods

Randomisation and allocation concealment: community‐based, individually‐randomised, placebo‐controlled and double‐blinded study. Pregnat women were randomly allocated in a 1:1:1:1 ratio in blocks of 12 based on a list of treatment numbers derived from a pseudo‐random number generated with SAS software.

Blinding of outcome assessment: all investigators, field and laboratory staff and participants were blinded to the treatment code until all field data had been collected and preliminary data analysis by coded groups had been completed.

Documentation of exclusions: 75 women (3.5%) were excluded.

Use of placebo control: placebo control.

Participants

2173 women at a gestational age of ,17 weeks were included in the study. Women at a gestational age of >=17 weeks were not eligible.

Interventions

Women were allocated to one of the three intervention groups:

  1. 2400 retinol equivalents of vitamin A as retinyl palmitate,

  2. 20 mg of zinc sulfate, or

  3. the same dose of vitamin A and zinc sulfate.

Comparison group: placebo.

All capsules also contained 2mg dl‐alpha‐tocopherol as antioxidant and 350 mg of soyabean oil, 20 mg of beeswax and 8 mg of lecithin as capsule filler.

Outcomes

  1. Birthweigh.

  2. Birth length.

  3. Neonatal morbidity.

  4. Infant mortality.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is unclear

Intention‐to‐treat analyses not performed.

Sample‐size calculation not performed

Compliance: consumption of 70% of supplements.

Location: Indonesia.

Timeframe: September 1995 to December 1999.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Pregnant women were randomly allocated in a 1:1:1:1 ratio in blocks of 12 based on a list of treatment numbers derived from a computer‐generated pseudo‐random number

Allocation concealment (selection bias)

Unclear risk

Treatment allocations was prepared and held at the University of Newcastle ....Supplements were coded with treatment numbers and women were assigned a treatment number in sequence based on date they consented to participate in the study. However, supplements were packed in plastic strips in identical opaque capsules..page 16 ‐ 17.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All investigators, field and laboratory staff and participants were blinded to the treatment code until all field data had been collected and preliminary data analysis by coded groups had been completed page 17

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All investigators, field and laboratory staff and participants were blinded to the treatment code until all field data had been collected and preliminary data analysis by coded groups had been completed page 17

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Drop‐out rate appears balanced between groups and reasons for loss to follow‐up were provided.

Selective reporting (reporting bias)

Low risk

Study protocol unavailable but outcomes predefined outcomes were reported

Other bias

Unclear risk

Overall, 70% of supplements were consumed, but it is unclear in text where there was more or less compliance.

Roberfroid 2008

Methods

Randomisation and allocation concealment: the randomisation scheme was generated by a computer program in permuted blocks of 4. Randomisation numbers were sealed in opaque envelopes. At each inclusion, the consulting physician opened the next sealed envelope and transmitted the randomisation number to a pharmacist managing the allocation sequence and the packaging of drugs at a central location.

Blinding of outcome assessment: the consulting physicians, pharmacist and women were blinded to allocation.

Documentation of exclusions: 107 women were lost to follow‐up (however their pregnancy outcome was reported). Post randomisation 26 twins were excluded (multivitamin group: 15; iron/folic acid group: 11 twins (including 1 set of triplets). Only singleton pregnancies were included in the analysis because fetal loss and anthropometric measures at birth in multiple pregnancies are not primarily nutrition‐related. 3 women died before delivery and 1 woman underwent a therapeutic abortion.

Use of placebo control: no placebo.

Participants

1374 women were recruited to participate, however 52 women were randomly assigned twice for consecutive pregnancies, resulting in data for 1426 pregnancies. Women had a pregnancy confirmed by urine testing and were randomly assigned to receive either IFA (n = 712) or UNIMMAP (n = 714) daily until 3 months after delivery. Women were recruited between 5 to 36 weeks’ gestation; 34.6% (n = 493) of the participants were recruited in the first trimester of pregnancy, mean gestational age at enrolment was 17.3 weeks (SD 7.8 weeks).

Interventions

UNIMMAP: vitamin A 800 mcg, vitamin D 200 IU, vitamin E 10 mg, vitamin B‐1 1.4 mg, vitamin B‐2 1.4 mg, niacin 18 mg, folic acid 400 mcg, vitamin B‐6 1.9 mg, vitamin B‐12 2.6 mcg, vitamin C 70 mg, zinc 15 mg, iron 30 mg, copper 2 mg, selenium 65 mcg, iodine 150 mcg.

IFA (control): folic acid 400 mcg, Iron 60 mg.

In a case of maternal illness, appropriate treatments were provided according to national guidelines. Severely anaemic women (Hb < 70 g/L, without dyspnoea) received ferrous sulphate (200 mg) + folic acid (0.25 mg) twice daily, for 3 months, regardless of their allocation group. All participants also received 400 mg albendazole in the second and third trimesters. If malaria occurred despite chemoprophylaxis, quinine (300 mg, 3 times/day) was given for 5 days. Vitamin A (200,000 IU) was given to all women after delivery, in accordance with national recommendations.

Outcomes

  1. Gestational duration.

  2. Birthweight, birth length, and Rohrer ponderal index at birth (weight(g)X100/length3(cm)).

  3. Low birthweight (< 2500 g).

  4. Small‐for‐gestational age (birthweight below the 10th percentile).

  5. Large‐for‐gestational age (birthweight above the 90th percentile of the study population).

  6. Thoracic circumference, head circumference, mid upper arm circumference.

  7. Hb concentration in mothers during the third trimester, Hb and sTfR concentrations in cord blood.

  8. Preterm birth (< 37 weeks’ gestation).

  9. Stillbirth (delivery of an infant showing no sign of life after a gestational age of 28 weeks).

  10. Perinatal death.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear. 18% of women in each group had experienced a previous fetal loss.

Women's nutritional status is unclear, although women are presumable at risk as the purpose of the trial is to correct MMN deficiencies.

Intention‐to‐treat analyses not performed, however the review included details of losses to follow‐up where the outcome was known.

Compliance: unclear, states that there was no difference in compliance between the 2 groups.

Location: Burkino Faso.

Timeframe: March 2004 to October 2006.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated with permuted blocks of 4.

Allocation concealment (selection bias)

Low risk

Randomisation numbers were kept in sealed opaque envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Consulting physicians, pharmacist and women were blinded to the intervention.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Authors claim the study had double‐blind design, but it is unclear if the assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Data were reported for singletons only.

Selective reporting (reporting bias)

Unclear risk

As above ‐ data only reported for singletons.

Other bias

High risk

Some women were pregnant more than once during the study period, however the denominators reported are the total number of pregnancies during the study period, not the total number of women randomised, which incorrectly assumes that each data point included is independent from the next.

Roberts 2010

Methods

Randomisation and allocation concealment: women were randomly assigned to receive capsules containing a combination of 1000 mg of vitamin C (ascorbic acid) and 400 IU of vitamin E (RRR‐alpha‐tocopherol acetate) or matching placebo (mineral oil). The simple urn method, with stratification according to clinical centre, was used by the data co‐ordinating centre to create a randomisation sequence. No further methodological details are provided.

Blinding of outcome assessment: medical charts were reviewed by at least 3 reviewers who were unaware of the treatment assignments.

Documentation of exclusions: 183 women (1.8%) were lost to follow‐up and for 2 women had been removed after randomisation.

Use of placebo control: placebo given.

Participants

10,154 pregnant women who had a singleton fetus with a gestational age of less than 16 weeks 0 days at the time of screening attending 16 clinical centres and the independent data coordinating centre of the MFMU Network. Women were eligible for inclusion if they had not had a previous pregnancy that lasted beyond 19 weeks 6 days.

Women were not eligible if they had elevated systolic or diastolic blood pressure, proteinuria, were taking or had taken antihypertensive medication, or were taking more than 150 mg of vitamin C or more than 75 IU of vitamin E daily. Other exclusion criteria were diabetes that was present before the pregnancy, treatment with antiplatelet drugs or non‐steroidal anti‐inflammatory agents, uterine bleeding within the week before recruitment, uterine malformation, serious medical condition, known fetal anomaly or aneuploidy, in vitro fertilisation resulting in the current pregnancy, or abuse of illicit drugs or alcohol.

Interventions

A combination of 1000 mg of vitamin C (ascorbic acid) and 400 IU of vitamin E daily administered from enrolment until delivery. The control group received placebo.

Outcomes

  1. Pregnancy‐associated hypertension.

  2. Serious adverse outcomes in the mother or her fetus or neonate. Pre‐eclampsia.

  3. Other maternal and neonatal outcomes.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Use of prenatal vitamins or multivitamins, daily dose of vitamin C and E were reported at trial entry.

Sample size calculation was based on a 30% reduction in the rate of the primary outcome.

Intention‐to‐treat analysis was performed.

Compliance: monthly, participants returned unused study drugs from the previous month.

Location: UK.

Timeframe: July 2003 to February 2008.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The simple urn method, with stratification according to clinical center, was used by the data coordinating center to create a randomization sequence." pg 1283, last pgh.

Allocation concealment (selection bias)

Unclear risk

Text says participants "were randomly assigned to receive capsules containing...". No details on how participants were allocated to groups. pg 1283 last pgh.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Neither the participants nor the investigators were aware of the treatment assignments." pg 1283, last pgh.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Deidentified medical charts of all women with pregnancy‐associated hypertension were reviewed centrally by at least three reviewers who were unaware of the treatment assignments." pg 1284.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Vitamin C and E = 95/5088 missing and in placebo = 90/5066 missing. Reasons for missing similar between groups.

Selective reporting (reporting bias)

Low risk

Relevant outcomes reported as pre‐specified in the protocol.

Other bias

Low risk

The study appears to be free of other sources of bias.

Rumbold 2006

Methods

Randomisation and allocation concealment: computer‐generated random number list with balanced variable blocks and stratification for collaborating centre and gestational age (< 18 weeks versus 18 weeks or more), allocation occurred via a central telephone randomisation service. The treatment packs contained 4 sealed, opaque, white plastic bottles of either the antioxidants vitamin C and vitamin E or the placebo and were prepared by a researcher not involved in recruitment or clinical care.

Blinding of outcome assessment: women, caregivers and investigators were blinded to allocation.

Documentation of exclusion: no losses to follow‐up.

Use of placebo control: placebo given.

Participants

1877 women were recruited into the study. Eligible women included those: with a nulliparous singleton pregnancy, between 14 and 22 weeks of gestation and with normal blood pressure at the first measurement in pregnancy and again at trial entry.

Women who had any of the following were excluded: known multiple pregnancy, known potentially lethal fetal anomaly, known thrombophilia, chronic renal failure, antihypertensive therapy, or specific contraindications to vitamin C or E therapy such as haemochromatosis or anticoagulant therapy.

Women were allocated to the vitamin C and E group (n = 935) or placebo (n = 935).

Interventions

Women allocated to the vitamin C and E group took 4 coated tablets of a combination of 250 mg of vitamin C (as ascorbic acid) and 100 IU of vitamin E (as d‐alpha‐tocopherol succinate) each day from trial entry until delivery (total daily dose of vitamin C: 1000 mg; vitamin E: 400 IU).

Women were advised not to take any other antioxidant supplements, although a multivitamin preparation that provided a daily intake of no more than 200 mg of vitamin C or 50 IU of vitamin E was permitted.

Outcomes

  1. Pre‐eclampsia.

  2. A composite measure of death or serious outcomes in the infant.

  3. Small‐for‐gestational age.

  4. Serious infant complications occurring before hospital discharge.

  5. For women included a composite of any of the following until 6 weeks postpartum: death, pulmonary edema, eclampsia, stroke, thrombocytopenia, renal insufficiency, respiratory distress syndrome, cardiac arrest, respiratory arrest, placental abruption, abnormal liver function, preterm prelabour rupture of membranes, major postpartum haemorrhage, postpartum pyrexia, pneumonia, deep‐vein thrombosis, or pulmonary embolus requiring anticoagulant therapy.

Notes

Women were at low risk of spontaneous and recurrent miscarriage based on the review criteria.

The majority of women participating had a baseline dietary intake of vitamin C and E above the Australian recommended daily amount.

Intention‐to‐treat analyses performed.

Compliance: there was no difference in compliance between the vitamin group (67%) and the placebo group (70%).

Location: Australia.

Timeframe: December 2001 and January 2005.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number list.

Allocation concealment (selection bias)

Low risk

Allocation occurred via a central telephone randomisation service. Tablets were provided in sealed opaque bottles.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women, caregivers and investigators were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information provided about blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes reported.

Other bias

Low risk

The study appears to be free of other sources of bias.

Rumiris 2006

Methods

Generation of random number sequence: a computer‐generated random number sequence.

Randomisation and allocation concealment: central allocation (randomisation by an independent third party who had no conflict of interest in the study).

Blinding of outcome assessment: treatment allocations were blinded to both the investigator and the patient until the study was finished.

Documentation of exclusion: none reported.

Use of placebo control: no, comparisons were between antioxidants versus iron and folic acid.

Participants

60 women between 8 and 12 weeks' gestation were eligible for randomisation (supplementation group: n = 29; folic acid group: n = 31).

Setting: at the antenatal clinic of the Department of Obstetrics and Gynecology, University of Indonesia between March 2003 and June 2004.

Eligibility criteria: pregnant women with low antioxidant status.

Exclusion criteria:

  1. history or current use of anti‐hypertensive medication or diuretics;

  2. use of vitamins C > 150 mg and/or E > 75 IU per day;

  3. known placental abnormalities;

  4. current pregnancy as a result of in vitro fertilisation;

  5. regular use of platelet active drugs or non‐steroidal anti‐inflammatory drugs;

  6. known fetal abnormalities;

  7. documented uterine bleeding within a week of screening;

  8. uterine malformations;

  9. history of medical complications.

Interventions

Supplementation group: received antioxidant supplements daily ‐ vitamins A (1000 IU), B6 (2.2 mg), B12 (2.2 mcg), C (200 mg), E (400 IU), folic acid (400 mcg), N‐acetylcysteine (200 mg), Cu (2 mg), Zn (15 mg), Mn (0.5 mg), Fe (30 mg), calcium (800 mg), and selenium (100 mcg).

Folic acid group: received Fe 30 mg and folic acid 400 mcg daily.

Timing of the intervention: early pregnancy (8 to 12 weeks).

Outcomes

  1. Pre‐eclampsia.

  2. Abortion.

  3. Hypertension.

  4. Intrauterine growth restriction.

  5. Intrauterine fetal death.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Participating women had low antioxidant status at enrolment, as defined as superoxide dismutase level below 164U/mL. No nutritional information provided.

Intention‐to‐treat analyses performed.

Compliance: unclear, no information reported.

Location: Indonesia.

Timeframe: March 2003 and June 2004.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random number sequence.

Allocation concealment (selection bias)

Low risk

Central allocation (randomisation by an independent third party who had no conflict of interest in the study).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Treatment allocations were blinded to both the investigator and the patient until the study was finished.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Authors claim the study had a double‐blind design, but it is unclear if the assessors were blinded. Treatment allocations were blinded to both the investigator and the patient until the study was finished.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No missing data.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes were reported, no apparent evidence of selective reporting.

Other bias

Unclear risk

At baseline, the control group appears to have a 2 mmHg higher systolic blood pressure than the intervention group, this figure was of borderline statistical significance, P = 0.059.

Rush 1980

Methods

Randomisation and allocation concealment: unclear, women were allocated to groups based on "random assignment". Randomisation was stratified on pre‐pregnancy weight, weight gain during pregnancy, previous low birthweight infant and protein intake. No other methodological details given.

Blinding of outcome assessment: unclear, women were allocated to 2 forms of treatment or control, where both treatments were given as a canned beverage and the control group were given standard oral multivitamins. No information is given on blinding of outcome assessors.

Documentation of exclusion: 237 women (22%) were excluded.

Use of placebo control: no placebo, the control group received standard prenatal multivitamin supplements.

Participants

1051 women were recruited into the study. Women eligible were black, English speaking, and not greater than 30 weeks' gestation. They also had 1 of the following criteria: low pre‐pregnant weight (under 110 pounds at conception); low weight gain at the time of recruitment; at least 1 previous low birthweight infant; a history of protein intake of less than 50 g in the 24 hours preceding recruitment. Women were not eligible if they were known to be seeking a termination, had specific chronic health disorders, if they admitted to recent use of narcotics or heavy use of alcohol, or weighed >= 140 pounds at conception.
The mean gestation at enrolment ranged from 16‐18 weeks for the treatment groups.
1225 women were invited to join the study, of which 1051 (84%) consented. Of these, 237 (22%) were excluded and 814 women (77%) remained active in the study until delivery and were allocated to 1 of 3 groups: supplement (n = 263), complement (n = 272) or control (n = 279).

Interventions

Women were randomised to 1 of 3 groups:

  1. high protein supplement (daily 40 g animal protein, 470 calories, 1000 mg calcium, 100 mg magnesium, 60 mg iron, 4 mg zinc, 2 mg copper, 150 mcg iodine, 6000 IU vitamin A, 400 IU vitamin D, 30 USPU vitamin E, 60 mg vitamin C, 3 mg vitamin B1, 15 mg vitamin B2, 15 mg niacin, 2.5 mg vitamin B6, 1 mg pantothenic acid, 200 mcg biotin, 350 mcg folic acid, 8 mcg vitamin B12);

  2. balanced protein‐energy complement (6 g animal protein, 250 mg calcium, 12 mg magnesium, 40 mg iron, 0.084 mg zinc, 0.15 mg copper, 100 mcg iodine, 4000 IU vitamin A, 400 IU vitamin D, 60 mg vitamin C, 3 mg vitamin B1, 15 mg vitamin B2, 10 mg niacin, 3 mg vitamin B6, 1 mg pantothenic acid, 350 mcg folic acid, 3 mcg vitamin B12);

  3. control (250 mg calcium, 0.15 mg magnesium, 117 mg iron, 0.85 mg zinc, 0.15 mg copper, 100 mcg iodine, 4000 IU vitamin A, 400 IU vitamin D, 60 mg vitamin C, 3 mg vitamin B1, 2 mg vitamin B2, 10 mg niacin, 3 mg vitamin B6, 1 mg pantothenic acid, 350 mcg folic acid, 3 mcg vitamin B12).

Women received the high protein or balanced protein‐energy supplements in the format of a drink. Women in the control group received a standard oral prenatal multivitamin supplement.

Outcomes

  1. Total weight gain, average weight gain and early weight gain during pregnancy.

  2. Duration of gestation (presented as cumulative rates of delivery from life tables for each treatment group).

  3. Preterm birth < 37 weeks.

  4. Fetal death (before < 20 weeks' gestation and >= 20 weeks' gestation).

  5. Neonatal death (according to gestation at delivery).

  6. Birthweight (mean).

  7. Somatic measures of infant growth at 1 year of age.

  8. Psychological measures at 1 year of age.

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear, as there is no information about concurrent medical conditions or other risk factors for miscarriage. Women in the trial had a low caloric intake at trial entry, and unexpectedly, an adequate protein intake. No other specific nutritional information is reported.
Sample‐size calculation reported: 250 women were required in each treatment group to show a 125 g difference in birthweight. A 25% loss to follow‐up was incorporated into the sample size.
Intention‐to‐treat analyses not performed.
There were 9 sets of twins amongst the 3 treatment groups.
Compliance: "on average, about three quarters of the prescribed amount of beverage was probably ingested".
Location: New York City, USA.
Timeframe: 1969 to 1976.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No methodological details given beyond reporting of 'random assignment'.

Allocation concealment (selection bias)

Unclear risk

No methodological details given beyond reporting of 'random assignment'.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information provided about blinding of participants and personnel. Unlikely as participants were given canned beverages or multivitamins.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information provided about blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

237 women (22%) excluded, no intention‐to‐treat analysis.

Selective reporting (reporting bias)

Unclear risk

Unclear if all pre‐specified outcomes reported.

Other bias

Unclear risk

Limited methodological details provided.

Schmidt 2001

Methods

Randomisation and allocation concealment: unclear, women were "randomly assigned on an individual basis, to double‐blind, weekly supplementation until delivery".

Blinding of outcome assessment: unclear, double‐blind stated in text but no details given.

Documentation of exclusion: 42 women (17%) were lost to follow‐up and excluded.

Use of placebo control: control tablets containing iron and folic acid were given.

Participants

243 women were recruited into this study. Pregnant women between 16 and 20 weeks' gestation, aged between 17 and 35 years old, with a parity < 6 and Hb level between 80‐140 g/L, were eligible for this study. Women were randomised to receive either vitamin A plus iron and folic acid (n = 122) or iron and folic acid only (n = 121). Of these 22 (18%) and 20 (17%) women in vitamin A plus iron and folic acid and the iron and folic acid groups respectively, dropped out between enrolment and the follow‐up at 4 months.

Interventions

Women were randomised to a weekly supplementation with 120 mg ferrous sulfate and 500 mcg folic acid, with or without vitamin A (2400 retinol equivalents). Women were asked to take the trial tablets from between 16 and 20 weeks' gestation until birth.

Outcomes

1. Stillbirth.
2. Concentrations of Hb, serum ferritin and serum transferrin receptors, at or near term.
3. Concentrations of iron and vitamin A in breast milk.
4. Hb and serum vitamin A concentrations in the mother and infant at 4 months postpartum.
5. General health, growth and development measures in the first year of life.

Notes

Women risk status for spontaneous and recurrent miscarriage is unclear.
At baseline, between 13% and 17% of women had marginal vitamin A deficiency 44% to 50% of women were anaemic.
Sample‐size calculation performed allowing for a 50% drop‐out during the study period.
Intention‐to‐treat analyses were not performed.
Compliance: adherence to the tablet intake was assessed through interview during a postnatal home visit, which revealed that the median tablet intake was 50 tablets (i.e. 25 weeks), while only 17% of the subjects took more than 90 tablets.
Location: Indonesia.
Serial publications of this data report different denominators.
Time frame: November 1997 to May 1998.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information provided about sequence generation.

Allocation concealment (selection bias)

Unclear risk

Women were 'randomly assigned on an individual basis' but no other details given.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Double‐blind used in the text but no details provided.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Authors claim the study had double‐blind design, but it is unclear who were blinded. No further information was available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

42 women (17%) were lost to follow‐up and excluded, no intention‐to‐treat analyses performed.

Selective reporting (reporting bias)

Unclear risk

Serial publications of this study report different denominators.

Other bias

Unclear risk

Limited methodological details provided.

Spinnato 2007

Methods

Generation of random number sequence: the randomisation sequence was constructed by the data co‐ordinating centre (DCC) as permuted blocks of random size, stratified by clinical centre, and implemented via a program residing on the clinical centres study computer.

Randomisation and allocation concealment: central allocation.

Blinding of outcome assessment: all clinicians and clinical investigators were blinded to group assignment.

Documentation of exclusion: none reported.

Use of placebo control: placebo control.

Participants

739 eligible women between 120/7 and 196/7 weeks of gestation were enrolled in the study (treatment: 371; placebo: 368).

Setting: 4 Brazilian clinical centres: 1 primary clinical centre (Recife) and 3 additional clinical sites (Campinas, Botucatu, and Porto Alegre); each site’s major teaching hospital serves a primarily urban low‐income population.

Eligibility criteria: women between 120/7 and 196/7 weeks of gestation and diagnosed with nonproteinuric chronic hypertension or a prior history of pre‐eclampsia in their most recent pregnancy that progressed beyond 20 weeks' gestation.

Exclusion criteria:multifetal gestation, allergy to vitamin C or vitamin E, requirement for aspirin or anticoagulant medication, 24‐hour urinary protein ≥ 300 mg, pre‐pregnancy diabetes mellitus, known fetal anomaly incompatible with life.

Loss to follow‐up: 32 women (treatment 16; placebo 16).

Interventions

Intervention group: daily treatment with both vitamin C (1000 mg) and E (400 IU) until delivery or until the diagnosis of pre‐eclampsia.

Control group: daily placebo until delivery or until the diagnosis of pre‐eclampsia.

Timing of the intervention: between 120/7 and 196/7 weeks of gestation.

Outcomes

  1. Pre‐eclampsia (women were followed through the 14th day postpartum for the occurrence of pre‐eclampsia).

  2. Severity of pre‐eclampsia.

  3. Gestational hypertension.

  4. Abruptio placentae.

  5. Premature rupture of membranes.

  6. Preterm birth.

  7. Small‐for‐gestational age.

  8. Low birthweight infant.

Notes

25 inclusion/exclusion criteria violations (23 enrolled outside 12‐19 weeks’ gestation; 2 twin gestations ‐ 1 lost to spontaneous abortions, 1 delivered liveborn in treatment group); all 25 women remained in their assigned study groups.

26 women had early treatment terminations (treatment 19; placebo 7), but remained in follow‐up.

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear.

Intention‐to‐treat analyses performed.

Compliance: average compliance was 85%, and similar between treatment groups.

Location: Brazil.

Timeframe: July 2, 2003 and November 23, 2006.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated sequence number.

Allocation concealment (selection bias)

Low risk

Central allocation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All clinicians and clinical investigators were blinded to group assignment.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Authors claim the study had double‐blind design, but it is unclear who was blinded. No further information was available.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Small numbers of missing data, balanced across groups (32 women; treatment 16; placebo 16).

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes were reported, no apparent evidence of selective reporting.

Other bias

Low risk

The study appears to be free of other sources of bias.

Steyn 2003

Methods

Randomisation and allocation concealment: "randomisation was undertaken by computer‐generated numbers". Roche Pharmaceutical supplied numbered containers with either vitamin C or matching placebo, and they retained the study code until completion of the study. No other methodological details given.

Blinding of outcome assessment: "double blind" stated, Roche Pharmaceuticals retained the code until completion of the study.

Documentation of exclusion: none reported.

Use of placebo control: placebo control.

Participants

200 women were recruited into the study. Women with a history of a previous mid‐trimester abortion (defined as spontaneous expulsion of the uterine contents between 13 and 26 weeks' gestational age), or previous preterm labour, and less than 26 weeks' gestation were eligible and invited to participate. Women with iatrogenic causes of their previous preterm labour such as previous induction of labour before term for severe pre‐eclampsia, were excluded. 203 consecutive women were approached, of which 200 (98.5%) consented and were randomised to either vitamin C (n = 100) or placebo (n = 100). No losses to follow‐up were reported.

Interventions

Twice daily tablet of either 250 mg vitamin C or placebo, from trial entry until 34 weeks' gestation. All women were tested for bacterial vaginosis and all women with positive cultures for Mycoplasma hominis (and between 22 and 32 weeks' gestation) were treated with erythromycin for 7 days.

Outcomes

  1. Preterm labour, defined as spontaneous onset of labour and delivery before 37 completed weeks.

  2. The secondary outcome was perinatal outcome, a composite endpoint including birthweight, gestational age at delivery, perinatal mortality, duration of admission in the neonatal intensive care unit and neonatal complications.

The age of fetal viability was considered to be 28 weeks' gestation.

Notes

Results are from an interim analysis performed when 100 participants were recruited into each arm. Recruitment was stopped after the interim analysis revealed few differences between the 2 groups. Unclear if there was a sample‐size calculation performed. Women's risk profile spontaneous and recurrent miscarriage is unclear, although they are clearly at high risk of preterm birth. It is also unclear if multiple births were included.
6% of women had an inadequate dietary intake of vitamin C, defined as an intake < 67% of the recommended dietary allowance (70 mg per day).
Compliance: women were requested to bring the containers to each visit and the remaining tablets were counted to improve and control compliance; however, no compliance data were reported.
Country: South Africa.
Timeframe: unclear.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated sequence number.

Allocation concealment (selection bias)

Low risk

Roche pharmaceuticals supplied numbered study containers and kept the study code until completion of the study.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Authors claim the study had double‐blind design, but it is unclear who was blinded. Allocation was double‐blind and Roche Pharmaceuticals retained the code until completion of the study.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Authors claim the study had double‐blind design, but it is unclear who was blinded. allocation was double‐blind and Roche Pharmaceuticals retained the code until completion of the study.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up reported.

Selective reporting (reporting bias)

Unclear risk

Recruitment stopped after an interim analysis.

Other bias

High risk

Results are from an interim analysis performed when 100 participants were recruited into each arm.

Summit 2008

Methods

Generation of random number sequence: computer‐generated number; 262 clustered unit of randomisation (all pregnant women served by the same midwife received supplements with the same midwife identification number).

Randomisation and allocation concealment: central allocation.

Blinding of outcome assessment: all study scientists and personnel, government staff, and enrollees were unaware of the allocation.

Documentation of exclusion: 1748 loss to follow‐up before delivery (IFA: 853; MMN: 895); 1128 loss to follow‐up after delivery (IFA: 553; MMN: 575). 10,549 pregnant women excluded post‐randomisation because of trial termination (IFA group: 5057; MMN group: 5492).

Use of placebo control: no placebo, comparisons were between multiple micronutrients and iron and folic acid.

Participants

41,839 pregnant women of any gestational age living on Lombok, Nusa Tenggara Barat Province, Indonesia. Women were allocated to IFA (n = 20,543) or MMN (n = 21,296).

Interventions

MMN group: the MMN was the UNIMMAP formulation containing 30 mg iron (ferrous fumarate) and 400 mcg folic acid along with 800 mcg retinol (retinyl acetate), 200 IU vitamin D (ergocalciferol), 10 mg vitamin E (alpha tocopherol acetate), 70 mg ascorbic acid, 1.4 mg vitamin B1 (thiamine mononitrate), 18 mg niacin (niacinanide), 1.9 mg vitamin B6 (pyridoxine), 2.6 mcg vitamin B12 (cyanocobalamin), 15 mg zinc (zinc gluconate), 2 mg copper, 65 mcg selenium, and 150 mcg iodine ‐ 1 capsule daily up to 3 months after birth.

IFA group: the IFA contained 30 mg iron (ferrous fumarate) and 400 mcg folic acid ‐ 1 capsule daily up to 3 months after birth.

Timing of the intervention: any time during pregnancy.

Outcomes

  1. Early infant mortality (deaths until 90 days postpartum).

  2. Neonatal mortality.

  3. Fetal loss (abortions and stillbirths).

  4. Low birthweight.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear. However, 30% of women in each group had an mid upper arm circumference < 23.5cm, which was used as an indicator of women being undernourished.

Intention‐to‐treat analyses performed.

Compliance: median compliance was 85%, there was no difference between treatment groups in compliance.

Location: Indonesia.

Timeframe: July 1, 2001 to April 1, 2004.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated number.

Allocation concealment (selection bias)

Low risk

Central allocation.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All study scientists and personnel, government staff, and enrollees were unaware of the allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The code to indicate which strip was IFA or MMN was known only by the manufacturing production manager and a quality control officer from UNICEF. All study scientists and personnel. government staff, were unaware of the allocation. Blinding is unlikely to be broken.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up: 1748 loss to follow‐up before delivery (IFA: 853; MMN: 895); 1128 loss to follow‐up after delivery (IFA: 553; MMN: 575).

Post‐randomisation exclusion: 10,549 pregnant women excluded because of trial termination (IFA group: 5057; MMN group: 5492).

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes were reported, no apparent evidence of selective reporting.

Other bias

Low risk

The study appears to be free of other sources of bias.

Sunawang 2009

Methods

Randomisation and allocation concealment: 160 clusters were randomly assigned to 4 blocks of 40 clusters each. 2 of the 4 blocks received either MMN of IFA. No details of how blocks were selected. 432 women in 40 clusters were allocated to the group receiving multiple micronutrients and 411 in the other 40 clusters were allocated to the iron–folic acid group. No further details on how allocation was done.

Blinding of outcome assessment: single‐blind design, no further details provided.

Documentation of exclusion: 93 women (11%) were excluded.

Use of placebo control: no placebo, the control group received iron‐folic acid supplementation.

Participants

843 women residing in Indramayu District in the West Java Province of Indonesia who were between 12 to 20 weeks of gestation. Only women intending to remain in the study location until giving birth were recruited. Women suffering from potentially confounding illnesses, including diabetes, coronary heart disease, and tuberculosis, were excluded from the study.

Interventions

MMN supplements containing 15 micronutrients vs IFA (60 mg of elemental iron as ferrous sulfate and 0.25 mg of folic acid). Supplementation was from time of enrolment at 12 to 20 weeks of gestation and continued to 30 days postpartum.

Outcomes

  1. Birthweight.

  2. Anthropometry.

  3. Hb, serum ferritin, serum zinc, and serum retinol.

  4. Compliance.

  5. Side effects of supplementation.

  6. Morbidity.

  7. Fetal loss.

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear.

Women's nutritional status is also unclear.

Sample size calculation not done.

Intention‐to‐treat analysis performed.

Compliance: Data on compliance was collected from weekly visits. Mean adherence in the intervention group 68% and control group 71%.

Location: Indonesia.

Timeframe: May 2001 to December 2002.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

160 clusters were randomly assigned to 4 blocks of 40 clusters each. 2 of the 4 blocks received either MMN of IFA. No details of how blocks were selected. pg s489 pgh 5.

Allocation concealment (selection bias)

Unclear risk

432 women in 40 clusters were allocated to the group receiving multiple micronutrients and 411 in the other 40 clusters were allocated to the iron–folic acid group. No further details on how allocation was done. pg s489, pgh 7.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Authors claim the study had a single‐blind design, but it is unclear who was blinded. Probably not done. pg s489 pgh 8.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No details of blinded outcome assessment provided.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

23/432 missing in MMN and 33/411 missing in IFA. Reasons for drop‐out are similar, but IFA had 5 twin births while MMN cluster had none. Fig. 1.

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes were reported as described.

Other bias

Low risk

The study appears to be free of other sources of bias.

Tofail 2008

Methods

Generation of random number sequence: a computer‐generated register was used for randomisation. Randomisation was performed in blocks of 12 food supplementation was randomly allocated but not blinded. micronutrient capsules looked identical and women were allocated to 1 of 3 types of micronutrient supplements in a 2 by 3 design.

Blinding of outcome assessment: allocation code was not broken until after the analysis.

Documentation of exclusion: 845 losses to follow‐up (19%).

Use of placebo control: no placebo, the control group received IFA (Fe30Fol) supplementation.

Participants

4436 pregnant women from rural Bangladesh within 6‐8 weeks of conception (not more than 14 weeks). Women with Hb < 80 g/L were ineligible for participation.

Interventions

MMNs containing 15 recommended micronutrients (30 mg of iron, 400 μg of folic acid). The micronutrient supplements were offered to the enrolled pregnant women at the 14weeks’ clinic visit up to 3 months after delivery. Intervention was divided into early or late food supplementation.

Early or usual food supplementation plus 1, 2 or 3:

1) 30 mg iron(fumarate) + 400 mcg folic acid (Fe30Fol)

2) 60 mg iron (fumarate) + 400 mcg folic acid (Fe60Fol)

3) 30 mg iron (fumarate), 400 mcg folic acid, 800 mcg RE vitamin A (retinyl acetate), 5 mcg vitamin D (cholecalciferol), 10 mg vitamin E (a‐tocopherol acetate), 70 mg vitamin C, 1.4 mg thiamine (mononitrate), 1.4 mg riboflavin, 18 mg niacin, 1.9 mg vitamin B‐6 (pyridoxine hydrochloride), 2.6 mcg vitamin B‐12 (cyanocobalamin), 15 mg zinc (sulfate), 2 mg copper (sulfate), 65 mcg selenium (sodium selenite), and 150 mcg iodine (potassium iodide) (MMNs).

All women received food supplement which consisted of roasted rice powder, roasted pulse powder, molasses, and soybean oil and had a total energy content of 2500 kJ. Early (immediately after detection of pregnancy, around 9 weeks) enrolment in food supplementation or usual (at the time of their choosing, around 20 weeks).

Outcomes

Infant outcomes:

  1. Blood Hb and plasma ferritin, zinc, retinol, vitamin B‐12, and folate at 6 months.

  2. Low birthweight.

  3. Small‐for‐gestational age.

  4. Morbidities (diarrhoea, lower acute respiratory infections).

  5. Birth anthropometry.

  6. Neonatal survival.

  7. Blood pressure.

  8. Kidney function

  9. Child growth and body composition.

Maternal outcome:

  1. Hb at 30 weeks.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear.

Sample size calculation: not done.

Intention‐to‐treat analysis performed.

Compliance: the number of micronutrient pills taken in the first 30 weeks of pregnancy was 79+/‐34 in the Fe30 group, 78+/‐34 in the Fe60 group, and 75+/‐33 in the MM group.

Location: Bangladesh.

Timeframe: November 2001 to June 2006.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computerised tracking system assigned women to 1 of the 6 groups in blocks of 12 women were randomly allocated. "Computer generated register of study identity numbers with random assignment of food groups (“E” or “U”) and micronutrient groups (from 12 possible pill bottle number codes) was used for randomization.” Randomisation was probably done. Eneroth 2011 pg 221.

Allocation concealment (selection bias)

Low risk

Micronutrient capsules looked identical.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Each micronutrient group had been given 4 different number codes to decrease the risk of unblinding. Pg 2054.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Randomisation codes were safely kept at the administrative office of ICDDR,B and were not broken until after performing the intention‐to‐treat analyses. Pg 2054.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

845 of 4436 losses to follow‐up (19%) before birth; reasons were available. Numbers of women lost to follow‐up did not differ among the treatment groups.

Selective reporting (reporting bias)

Low risk

All the study's pre‐specified outcomes have been reported.

Other bias

Low risk

The study appears to be free of other sources of bias.

Van den Broek 2006

Methods

Generation of random number sequence: using a random‐generation procedure.

Randomisation and allocation concealment: the supplements in vitamin A and placebo treatments allocated were prepared in identical capsules and were packaged in bottles according to the randomisation schedule (sealed envelopes) by midwives who were not involved in the trial conduct.

Blinding of outcome assessment: neither the women nor the midwives involved in treatment allocation revealed the randomisation schedule to anyone involved in the conduct of the trial.

Documentation of exclusion: 77 loss to follow‐up before assessment at 26‐28 weeks (5000 IU vitamin A: 26; 10,000 IU vitamin A: 26; placebo: 25). Additional 93 loss to follow‐up before assessment at 36‐38 weeks (5000 IU vitamin A: 34; 10,000 IU vitamin A: 28; placebo: 31).

Use of placebo control: placebo control.

Participants

700 women with singleton pregnancies at 12‐24 weeks' gestation measured by ultrasound scan (5000 IU vitamin A: 234; 10,000 IU vitamin A: 234; placebo: 232).

Setting: the antenatal clinic at the Namitambo rural Health Centre in southern Malawi, central Africa.

Eligibility criteria: (Hb) < 11.0 g/dL by HemoCue screening method at first antenatal visit, singleton pregnancy with gestational age > 12 weeks and ≤ 24 weeks measured by ultrasound scan, no fetal abnormality detectable by ultrasound at time of booking, residing in the catchment area of the health centre.

Exclusion criteria: women > 24 weeks' gestation, or twin pregnancy.

Interventions

  • Intervention group 1: 5000 IU vitamin A daily until delivery.

  • Intervention group 2: 10,000 IU vitamin A daily until delivery.

  • Comparison group: placebo daily until delivery.

Timing of the intervention: supplementation started as early as possible after 12 weeks of pregnancy.

All women received iron tablets daily (60 mg elemental iron as ferrous sulphate with 0.25 mg folic acid).

Outcomes

  1. Anaemia status (no anaemia ([Hb] ≥ 11.0 g/dL), anaemia ([Hb] < 11.0 g/dL) or severe anaemia ([Hb] < 8.0 g/dL).

  2. Hb concentration (Coulter counter value), iron status (determined by serum ferritin and serum transferring receptor concentration).

  3. Evidence of infection (assessed by serum CRP, peripheral malaria parasitaemia and HIV status).

  4. Vitamin A status (determined by serum retinol and the MRDR).

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status is also unclear.

Intention‐to‐treat analyses performed.

Compliance: unclear, no information provided.

Location: Malawi.

Timeframe: April 1997 and July 1999.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random‐generation procedure used.

Allocation concealment (selection bias)

Low risk

The vitamin A and placebo treatments allocated were prepared in identical capsules and packaged in bottles according to the randomisation schedule (sealed envelopes) by midwives who were not involved in the trial conduct.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Neither the women nor the midwives involved in treatment allocation revealed the randomisation schedule to anyone involved in the conduct of the trial.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information provided about blinding of outcome assessment.

Incomplete outcome data (attrition bias)
All outcomes

High risk

77 loss to follow‐up before assessment at 26‐28 weeks (5000 IU vitamin A: 26; 10,000 IU vitamin A: 26; placebo: 25). Additional 93 loss to follow‐up before assessment at 36‐38 weeks (5000 IU vitamin A: 34; 10,000 IU vitamin A: 28; placebo: 31).

Selective reporting (reporting bias)

Low risk

All pre‐specified outcomes were reported, no apparent evidence of selective reporting.

Other bias

Low risk

The study appears to be free of other sources of bias.

Villar 2009

Methods

Generation of random number sequence: no sequence generation details available.

Randomisation and allocation concealment: central allocation (randomisation was performed by the statisticians of the British VIP Trial).

Blinding of outcome assessment: "double blind" stated.

Documentation of exclusion: 10 women (treatment 6; placebo 4), and 29 infants (treatment 13, placebo 16) were lost to follow‐up.

Use of placebo control: placebo control.

Participants

1365 women between 14‐22 gestational age agreed to participate and were randomised (vitamins group: 687; placebo group: 678).

Setting: antenatal clinics located in Nagpur, India; Lima and Trujillo, Peru; Cape Town, South Africa; and Ho Chi Minh City, Viet Nam which served populations with low social‐economic status and had evidence of overall low nutritional status, between October 2004 and December 2006.

Eligibility criteria: pregnant women considered high risk for pre‐eclampsia (chronic hypertension, renal disease, pre‐eclampsia‐eclampsia in the pregnancy preceding the index pregnancy requiring delivery before 37 weeks’ gestation, HELLP syndrome in any previous pregnancy, pre‐gestational diabetes, primiparous with a BMI > 30 kg/m2, history of medically‐indicated preterm delivery, abnormal uterine artery Doppler waveforms and women with antiphospholipid syndrome), multifetal gestation. Women ingesting medications with aspirin‐like compounds were not excluded.

Exclusion criteria: women ingesting vitamin supplements that contained ≥ 200 mg of vitamin C and/or ≥ 50 IU of vitamin E and women receiving warfarin.

Interventions

Intervention group: received 1000 mg vitamin C and 400 IU of vitamin E daily until delivery.

Comparison group: received placebo daily until delivery.

Timing of the intervention: between 14 and 22 weeks' gestation.

Outcomes

  1. Pre‐eclampsia.

  2. Eclampsia.

  3. Placental abruption.

  4. Low birthweight (< 2500 g).

  5. Small‐for‐gestational age (< 10th centile of the WHO recommended standard).

  6. Intrauterine or neonatal death before hospital discharge.

  7. Preterm delivery (< 37 weeks).

  8. Early preterm delivery (< 34 weeks).

  9. Very low birthweight (< 1500 g).

  10. ≥ 7 days in the neonatal intensive care unit.

  11. Congenital malformations.

Pre‐eclampsia information was unavailable for 14 women in the vitamins and 9 in the placebo group.

There were data from 81 supplemented (11.8%) and 100 placebo‐treated (14.7%) women with multiple pregnancies, for whom newborn outcomes were considered separately.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear. Women at high risk of pre‐eclampsia were included but data on fetal loss was not reported separately for this group.

No specific information on women's nutritional status is included; however, the paper states that the trial was conducted in populations with 'documented low nutritional status'.

Intention‐to‐treat analyses performed.

Compliance: median compliance was 87%, and was similar between the treatment groups.

Location: Antenatal clinics in India, Peru, South Africa and Vietnam.

Timeframe: October 2004 and December 2006.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation sequence blocked by centre in groups of 2 to 10 individuals.

Allocation concealment (selection bias)

Low risk

Central allocation (randomisation was performed by the statisticians of the British VIP Trial).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Women and investigators blinded to allocation.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Identifying characteristics and randomisation code were kept in a secure and separate database in the server unavailable to the research team, until all data analyses were completed.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Small numbers of missing data, balanced across groups.

Women: 10 (treatment 6; placebo 4).

Infants: 29 (treatment 13; placebo 16).

Selective reporting (reporting bias)

Unclear risk

Perinatal death was reported instead of pre‐specified neonatal death.

Other bias

Low risk

The study appears to be free of other sources of bias.

West 2011

Methods

Generation of random number sequence: sectors were used as the unit of randomisations for supplement allocation, 3 sets of 3 identical coins on which the numbers 1, 2 or 3 were written were placed into a container, mixed and removed randomly, without replacement, and the 3‐digit code of each sector was read aloud sequentially. Study supplements were identical in colour, taste and external appearance. Treatment codes were assigned by the Nutrilite Health Institute and were kept in a sealed envelope in a locked cabinet at both Nutrilite and Johns Hopkins University. Masking was further ensured by having a senior administrative staff (not involved in field activities) recode the supplement bottles with sector‐specific permanent stickers bearing codes from 001 to 596.

Blinding of outcome assessment: investigators were all blinded to the allocation codes until the end of the parent trial.

Documentation of exclusion: 628 women (1%) were excluded.

Use of placebo control: placebo control.

Participants

102,769 women from 596 sectors (60,294 pregnancy identified and 59,666 pregnancies included) 19 rural unions in the northwest Districts of Gaibandha and Rangpur in rural Bangladesh. Women were recruited from the first trimester of pregnancy through 12 weeks (84th day) after pregnancy termination. Eligible women included pregnant or postpartum, lactationally amenorrhoeic women were placed on a 'waiting list', and only became eligible for pregnancy surveillance once their menses resumed. Married women, women entering the study area within 4 months of marriage were also eligible to join the cohort under pregnancy surveillance. And when identified as pregnant, enrolled. Women who never got pregnant during the study period, permanently moved from the study area, were sterilised, reported menopause, divorce or death of husband, refused to participate or participation status unknown, died before detecting a pregnancy , had a pregnancy outcome after October 12, 2006, reported a last menstrual period after January 5, 2006 or had an unknown date of a last menstrual cycle were excluded.

Interventions

1. Vitamin A (consisting of 7000 mcg retinol equivalents, or 23,300 IU, of VA palmitate in soybean oil with a small amount of vitamin E as an antioxidant).

2. β‐carotene at 42 mg—an amount equivalent to 7000 mcg REs administered weekly from the time of pregnancy enrolment until 3 months postpartum.

3. Control group received placebo (consisting of soybean oil with a small amount of vitamin E as an antioxidant).

All 3 supplements contained 5 IU vitamin E in oil.

Outcomes

  1. All‐cause pregnancy‐related mortality.

  2. Fetal loss due to miscarriage or stillbirth.

  3. Infant mortality under 3 months of age.

  4. Maternal obstetric and infectious morbidity.

  5. Infant infectious morbidity.

  6. Maternal and infant micronutrient status.

  7. Fetal and infant growth.

  8. Prematurity.

  9. External birth defects.

  10. Postnatal infant growth to 3 months of age.

Notes

Women's risk of spontaneous and recurrent miscarriage was unclear.

Women's nutritional status: a 1‐week history of diet at trial entry and 12 weeks after pregnancy was reported.

Sample size estimation: based on a 35% or greater reduction in all‐cause mortality.

Primary outcomes were compared on an intent‐to‐treat basis.

Compliance: adherence to supplementation was comparable across groups, with approximately 80% of women having directly consumed (under staff supervision) at least 64% of eligible supplements.

Location: Bangladesh.

Timeframe: August 2001 to January 2007.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sectors were randomised in blocks of 9. 3 sets of 3 identical coins on which the numbers 1, 2 or 3 were written were placed into a container, mixed and removed randomly, without replacement, and the 3‐digit code of each sector was read aloud sequentially. Pg 7 (Labrique).

Allocation concealment (selection bias)

Low risk

Study supplements were identical in colour, taste and external appearance. Supplements were originally shipped in identically‐labelled, 100‐count white opaque plastic bottles distinguished only by the code number‐1, 2 or 3‐listed on the label. A senior administrative staff (not involved in field activities) recode the supplement bottles with sector‐specific permanent stickers bearing codes from 001 to 596. Treatment codes were assigned by the Nutrilite Health Institute and were kept in a sealed envelope in a locked cabinet at both Nutrilite and Johns Hopkins University. Pg 7‐8 (Labrique).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study participants, interviewers, field supervisors and investigators remained masked to treatment assignments until the end of the trial. Pg 8 (Labrique).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Investigators remained masked to treatment assignments until the end of the trial. Pg 8 (Labrique).

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Number of missing data among each group are small and balanced with detailed reason.

Selective reporting (reporting bias)

Low risk

Registration of trial and outcomes reported as described previously.

Other bias

Low risk

The study appears to be free of other sources of bias.

West 2014

Methods

Generation of random number sequence: 596 sectors of comparable size were used as units of randomisations. "We stratified the contiguous list of 596 sectors into 74 blocks of 8 each (for the first 592 sectors), plus a 75th block of 4 sectors. A sector‐supplement code key with A or B was created by flip of a coin, reflecting assignment to iron–folic acid or MM supplementation, and duplicated, and each of 2 copies was sealed into an envelope by an uninvolved colleague at Johns Hopkins. Computer program randomised sectors within blocks to 1 of 2 codes such that each permutation had an equal probability of being chosen. The resulting 2 lists of sectors were securely transmitted to field headquarters. 1 envelope with the code key was securely transmitted to the supplement producer and the other sealed in an envelope and secured at Johns Hopkins. At no time during the trial did study investigators or field or data management staff have access to the key."

Blinding of outcome assessment: outcome assessors were blinded to the treatment allocation.

Documentation of exclusion: 1351 pregnant women (3%) were excluded.

Use of placebo control: no placebo, the control group received IFA supplementation.

Participants

Participants in the study included 44,567 pregnant women and 28,518 infants in rural setting in Bangladesh. Pregnant women were recruited around ˜ 10 weeks' gestation. All women under 45 years of age who are married and living with their husbands as residents of the JiVitA study area at the time of an initial population enumeration, and those who enter the cohort as newlyweds, were eligible for pregnancy surveillance and, when identified as pregnant, enrolled. Women who permanently moved, were sterilised or menopausal, died, and did not get pregnant were excluded.

Interventions

Weekly supplementation from enrolment (early pregnancy) to 3 months postpartum.

Multiple‐micronutrient: vitamin A (770 mcg retinol equivalents), vitamin D (5 mcg), vitamin E (15 mg), thiamin (1.4 mg), riboflavin (1.4 mg), niacin (1.4 mg), vitamin B12 (2.5 mg), vitamin B6 (1.9 mg), vitamin C (85 mg), zinc (12 mg), iodine (220 mcg), copper (1000 mcg), and selenium (60 mcg). The control group received IFA supplement (standard care).

Outcomes

1. Infant survival: determine the efficacy of a standard MMN supplement given to women daily during pregnancy through 12 weeks postpartum in lowering neonatal and infant mortality through 6 months of age by > 15% compared to the mortality of infants whose mothers receive daily iron + folic acid.

2. Fetal and newborn outcomes: assess the efficacy of the MM intervention in reducing the:

a) stillbirth rate by 23% or more, from an expected 30 to 24 or fewer stillbirths per 1000 births (i.e. live + still births);

b) rate of preterm birth (live birth delivered < 37 weeks’ gestation) by 10% or more, from an expected 20% to 18% or fewer of all live births;

c) prevalence of low birthweight (< 2500 g) by 5% or more, from an expected 40% to 38% or fewer of all live births; and

d) neonatal morbidity related to sepsis, birth asphyxia, hypothermia and diarrhoea.

3. Other infant outcomes (to 6 months of age): assess the efficacy of the MM supplement intervention in improving:

a) linear and ponderal growth, including its ability to protect lean body mass, that could lead to reduced prevalences of stunting, wasting and underweight status in infancy;

b) infant morbidity, including diarrhoea and acute lower respiratory infection, in the first 3 months of life;

c) micronutrient intake, represented by measured breast milk micronutrient concentrations;

d) micronutrient status, and reducing prevalences of multiple deficiencies.

4. Maternal outcomes: assess the efficacy of either MM supplement intervention in influencing among mothers the:

a) prevalence of infectious morbidity, based on history, testing and signs, during pregnancy and in the 1st 6 months postpartum;

b) rates of potentially fatal (“near miss”) obstetric complications.

Notes

Women's risk of spontaneous and recurrent miscarriage: previous fetal loss and infant death reported.

Women's nutritional status is unclear.

Sample size estimation: live‐born infants based on a 15% or greater reduction in 6‐month mortality; pregnancies based on a 30% loss from induced abortion, miscarriage, and stillbirth.

Intent‐to‐treat analysis of all outcomes.

Compliance: adherence was high, with half the women in both groups estimated to consume a median of approximately 95% of all distributed supplements; 80% in both groups consumed more than 80% of their intended tablets.

Location: Bangladesh.

Timeframe: 2008 to 2012.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"We used an in‐house program (VBScript, Microsoft) that recognized 70 possible permutations for n = 8 sectors and k = 2 supplement allocations and 6 for the last block of n = 4sectors. Using this program, we randomised sectors within blocks to 1 of 2 codes such that each permutation had an equal probability of being chosen". Pg 2650.

Allocation concealment (selection bias)

Low risk

"Supplements were identical in appearance. Tablets were packed into opaque plastic bottles, affixed with codes AorB representing supplement content, and shipped to the field where logistics staff, uninvolved in the study, relabeled bottles with sector numbers(001‐596) according to the random allocation list." Pg 2652.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded and blinding of the participants is unlikely to have been broken.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

At no time during the trial did study investigators or field or data management staff have access to the key. Pg 2651.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Numbers of missing outcome data in both group are small and balanced with similar reasons. Pg 2651, fig 1.

Selective reporting (reporting bias)

Low risk

Study protocol was available and all of the study's pre‐specified outcomes were reported in studies.

Other bias

Low risk

The study appears to be free of other sources of bias.

Wibowo 2012

Methods

Generation of random number sequence: participants were randomised according to a computer‐generated random number sequence. "Participants were assigned on an individual basis to antioxidant or placebo supplementation and remained in the same allocation group throughout the pregnancy and 2 weeks postpartum." No details about how allocation concealment was done.

Blinding of outcome assessment: unclear.

Documentation of exclusion: 6 women (5.5%) were excluded.

Use of placebo control: no placebo, the control group received non‐antioxidant multiple micronutrients.

Participants

110 women residing in Cipto Mangunkusumo National Hospital, Jakarta, Indonesia between 8 and 12 weeks of gestation. To be eligible, women had to have normal blood pressure at their first visit in pregnancy and again at trial entry. Women with multiple pregnancy, fetal anomaly, thrombophilia, infections, mola hydatidosa, chronic renal failure, uncontrolled hypertension, placental abnormalities, documented uterine bleeding within a week of screening, uterine malformation and history of medical and metabolic complication, such as heart disease or diabetes were excluded.

Interventions

Antioxidant multiple micronutrient (MMN) supplement mixed into milk administered from trial entry until 2 weeks postpartum. Control received non‐antioxidant (MMN) supplement and all women received 40 g of milk powder.

Outcomes

  1. Pre‐eclampsia.

  2. Fetal growth restriction.

  3. HELLP syndrome.

  4. Biochemical markers.

Notes

Women's risk of spontaneous and recurrent miscarriage: history of pre‐eclampsia reported.

Women's nutritional status is unclear.

Sample size calculation: based on an expected incidence of pre‐eclampsia in the control group of at least 29% and in the treatment group of at least 30%.

Analyses were performed on an intention‐to‐treat basis.

Compliance: unclear, no information reported.

Location: Jakarta, Indonesia.

Timeframe: June 2001 to December 2009.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were "..randomized according to a computer‐generated random number sequence" pg 1153, pgh 2.

Allocation concealment (selection bias)

Unclear risk

"Participants were assigned on an individual basis to antioxidant or placebo supplementation." No details of how allocation was done. pg 1153, pgh 2.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Treatment allocations were blinded to both investigator and the patient..." pg 1153, pgh 2.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Investigators blinded to the sample background" but not sure if they blinded outcomes of interest in current review.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3/52 drop‐out from supplementation group and 3/58 drop‐out from control group. drop‐out rate balanced in both groups.

Selective reporting (reporting bias)

Low risk

Primary and secondary outcomes reported as planned in the protocol.

Other bias

Low risk

The study appears to be free of other sources of bias.

Xu 2010

Methods

Generation of random number sequence: double‐blinded, multicentre trial. Randomisation was performed through an electronic data management platform, which enabled randomisation and data entry over the Internet. They were randomly allocated at a ratio of 1:1

to antioxidant supplementation (vitamins C and E) group or to placebo group through an electronic data management platform.

Blinding of outcome assessment: outcome assessors were blinded to the treatment allocation.

Documentation of exclusion: 277 women (10.5%) were excluded.

Use of placebo control: placebo control.

Participants

2460 women participated in the study. Women were eligible for the trial if they were between 12 and 18 completed weeks of pregnancy on the basis of last menstrual period and confirmed by early ultrasound examination. The exclusion criteria were:

(1) women who regularly consumed supplements200 mg/day for vitamin C and/or 50 IU/day for vitamin E;

(2) women who took warfarin;

(3) women who had known fetal abnormalities,

(4) women who had a history of medical complications,

(5) women with repeated spontaneous abortion,

(6) women who used an illicit drug during the current pregnancy.

Interventions

Women were provided either with vitamins C and E or placebo. Total daily dose of vitamin C was 1000 mg, and that of vitamin E was 400 IU.

Outcomes

Primary outcomes:

  1. Gestational hypertension and its adverse conditions.

Other maternal outcomes:

  1. Death.

  2. Severe gestational hypertension.

  3. Severe pre‐eclampsia.

  4. Prelabour rupture of membranes (PROM).

  5. Preterm PROM (PPROM).

  6. Hospitalisation prior to giving birth.

Fetal and neonatal outcomes:

  1. Fetal loss or perinatal death (defined as any fetal loss at 20 weeks),

  2. Stillbirth.

  3. Neonatal death.

  4. Preterm birth (before 37 weeks of gestational age; gestational age corrected by early ultrasound scan).

  5. Preterm birth (before 34 weeks of gestational age.

  6. Small for gestational age (defined as 5th or 10th centile).

  7. Perinatal mortality.

  8. Spontaneous abortion.

  9. Neonatal morbidity indicators.

Notes

Women's risk of spontaneous and recurrent miscarriage: history of pre‐eclampsia and gestational hypertension reported as well as obstetric history (abortion, stillbirth, low birthweight, preterm birth).

Women's nutritional status: use of supplements reported .

Sample size calculation: based on an expected 4% and 15% incidence of the primary outcome in the low‐ and high‐risk strata, respectively.

Analyses were performed on an intention‐to‐treat basis.

Compliance: 85.5% in the vitamin group, 86.5% in the placebo group.

Location: multicentre trial in Canada (17 centres) and Mexico (10 centres).

Timeframe: January 2004 to March 2006.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

They [women] were randomly allocated at a ratio of 1:1 to antioxidant supplementation (vitamins C and E) group or to placebo group through an electronic data management platform.”Pg 239.e3

Allocation concealment (selection bias)

Unclear risk

Although paper states that "Women in the placebo group were advised to take capsules that were identical in appearance to the active treatment capsules", no details were provided on how they were allocated to treatment groups

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

None of the trial staff or any other person involved in the trial knew the treatment allocation for any women until after completion of the trial analysis.” Pg 239.e3 and 4

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

“None of the trial staff or any other person involved in the trial knew the treatment allocation for any women until after completion of the trial analysis.”Pg 239.e4

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

A higher loss to follow‐up was seen in the Mexican centres although the loss was balanced between treatment and placebo groups

Selective reporting (reporting bias)

Low risk

Outcomes reported according to the trial registration.

Other bias

Low risk

The study appears to be free of other sources of bias.

Zagre 2007

Methods

Generation of random number sequence: cluster‐randomised study wherin villages‐not individuals‐were randomly assigned to 1 treatment group or the other. The 2 supplements looked different but a coding system was adopted. “…packaged the supplements in boxes with identical labelling except for the supplement code”… "the code letter did not distinguish which supplement was used".

Blinding of outcome assessment: unclear if outcome assessors were unaware of participants' allocation to treatment or control group.

Documentation of exclusion: 768 women (20.9%) were excluded.

Use of placebo control: no placebo, the control group received iron‐folic acid supplementation.

Participants

3670 women from Maradi, rural Niger. Women who lived in 1 of the selected villages and who had experienced amenorrhoea for less than 12 weeks were eligible for participation. Exclusion criteria included women with night blindness and/or clinical signs of severe anaemia.

Interventions

Daily multiple micronutrients consisting vitamin A 800 mcg,vitamin D 200 IU, vitamin E 10 mg, vitamin C 70 mg, vitamin B1 1.4 mg, vitamin B2 1.4 mg, vitamin B3 18 mg, vitamin B6 1.9, vitamin B12 2.6 mg, folic acid 400 mcg, iron 30 mg, zinc 15 mg, copper 2 mg, selenium 65 mcg, and iodine 150 mcg from enrolment until delivery. The control group received iron/folic acid.

Outcomes

Maternal outcomes:

  1. Birth assistance.

  2. Conditions of delivery.

  3. Breastfeeding practices.

  4. Miscarriage.

  5. Stillbirths.

  6. Maternal deaths.

Infant outcome:

  1. Birthweight.

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear.

Women's nutritional status is unclear.

Sample size calculation: based on reduction of 25% in low birthweight.

Intention‐to‐treat analysis not performed.

Compliance: at subsequent visits, the remaining capsules were counted, and the number of missing capsules was replenished for another month and noted in the particular booklet. Compliance with treatment in the intervention group was 79.2% ± 18.1% and in the control group 78.4% ± 18.5%.

Location: Maradi, Niger.

Timeframe: January 2004 to March 2005.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Villages‐not individuals‐were randomly assigned to one treatment group or the other." No details on how randomisation was done.

Allocation concealment (selection bias)

Low risk

"Packaged the supplements in boxes with identical labeling except for the supplement code."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Health workers and midwives did not distinguish which supplement was used.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Data collectors were informed that each supplement came in two sizes and colors, so that the code letter did not distinguish which supplement was used."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Proportion of women lost to follow‐up was significantly different across groups 335/1777 in IFA and 290/L ,893 in MMN. Detailed reasons for missing data not provided.

Selective reporting (reporting bias)

Unclear risk

Many outcomes were assessed but report was limited to only 2 outcomes.

Other bias

High risk

There were differences in the baseline characteristics of participants. Women in control group tended to be poorer and less educated and more women in intervention group used more preventive measures against malaria and had larger households.

Zeng 2008

Methods

Generation of random number sequence: randomisation of villages was stratified by county with a fixed ratio of treatments (1:1:1) and blocking of 15. The randomisation schedule was generated off site with a pseudo‐random number generator. Allocation concealment was described “a treatment colour code was assigned to each village based on the treatment allocation schedule. The treatment codes were opened only once all data had been collected”.

Blinding of outcome assessment: unclear.

Documentation of exclusion: 133 women (2.3%) were lost to follow‐up, 279 women (4.8%) stopped taking the supplement and refused to continue to participate, and 601 women (10.3%) experienced fetal loss.

Use of placebo control: no placebo, the control group received folic acid alone.

Participants

5828 women from Shaanxi Province of north west China between < 12 – 28 weeks' gestational age. Eligibility included all women resident in the counties who became pregnant between August 2002 and January 2006.

Women were ineligible if they:

1. were already taking supplements;

2. had a serious illness;

3. had an abnormal reproductive history;

4. were planning;

5. to work outside the area; or

were more than 28 weeks pregnant.

Interventions

Supplementation with MMN; IFA (60 mg of iron and 400 mcg of folic acid) or folic acid alone (400 mcg of folic acid) from enrolment until delivery.

Outcomes

  1. Birthweight.

  2. Duration of gestation.

  3. Maternal Hb concentration.

Notes

Women's risk of spontaneous and recurrent miscarriage is unclear.

Women's nutritional status is unclear.

Sample size calculation: based on a 25% reduction in low birthweight between either iron‐folic acid or multiple micronutrient and folic acid (control) groups.

Compliance: the number of remaining capsules was reported by the village doctor who visited the women every 2 weeks. The level of compliance with the supplementation was high in all treatment groups.

Location: Shaanxi Province, China.

Timeframe: August 2002 to January 2006.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomisation of villages was stratified by county with a fixed ratio of treatments (1:1:1) and blocking of 15 ....... The randomisation schedule was generated off site with a pseudo‐random number generator....." pg 2, pgh 3.

Allocation concealment (selection bias)

Low risk

"A treatment colour code was assigned to each village based on the treatment allocation schedule. The treatment codes were opened only once all data had been collected." pg 2, pgh 3.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"A treatment colour code was assigned to each village based on the treatment allocation schedule. The treatment codes were opened only once all data had been collected." pg 2, pgh 3.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information provided about blinding of outcome assessors.

Incomplete outcome data (attrition bias)
All outcomes

High risk

121/1666 missing in folic acid, 67/1537 missing in iron‐folic acid, 88/1494 missing in multiple micronutrients in birthweight analysis. No reasons for missing data. Amount of missing data from other outcomes unknown. Fig 1; table 4.

Selective reporting (reporting bias)

Low risk

Study protocol is available and all primary outcomes were reported as described in the protocol.

Other bias

Unclear risk

From the 531 clusters, 13 clusters were excluded due to no birth outcomes in the excluded clusters. The number of clusters excluded was unbalanced across the intervention groups which may have been due to important baseline differences.

B‐HCG: Beta human chorionic gonadotropin
BMI: body mass index
F: folic acid
Hb: haemoglobin
HbCC: haemoglobin C disease
HbSC:haemoglobin SC disease
HbSS: haemoglobin sickle cell disease
HELLP syndrome: haemolysis, elevated liver enzymes, low platelet count syndrome
HIV‐1: Human Immunodeficiency Virus‐1
HOFPP: Hungarian Optimal Family Planning Programme
IQR: interquartile range
IFA: iron and folic acid
IU: international units
IVF‐ET: in vitro fertilization and embryo transfer
mcg: micrograms
mg/mL: milligrams per millilitre
MF: multivitamins with folic acid
mg: milligrams
MMN: multiple micronutrient
MRDR: modified relative dose‐response
MV: multivitamins without folic acid
MRC: Medical Research Council
NTD: neural tube defect
P: progesterone
PAI‐1: plasminogen activator inhibitor‐1
PAI‐2: plasminogen activator inhibitor‐2
PCV: packed cell volume
sTfR: Soluble transferrin receptor
UK: United Kingdom
UNIMMAP: United Nations International Multiple Micronutrient Preparation
USA: United States of America
WBC: white blood cell

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Baumslag 1970

Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with either iron, iron and folic acid or iron, folic acid and vitamin B12 from "after the 24th week of pregnancy".

Biswas 1984

Unclear of the gestational age at which women entered the trial.

Blot 1981

Onset of supplementation was > 20 weeks' gestation.
Supplementation with either iron and folic acid or iron alone occurred "at the end of the 6th month of pregnancy". Unclear if women were randomised to the treatment groups.

Chanarin 1968

Onset of supplementation was > 20 weeks' gestation.
Women were given a folic acid supplement after the 20th week of pregnancy. Abortion was reported according to folic acid status at 15 weeks, prior to supplementation.

Chelchowska 2004

No relevant clinical outcomes, reports biochemical markers of antioxidant status only.

Christian 2003

Data for main outcomes of interest were not reported in a form that could be included in the analysis. Perinatal death was reported which included stillbirths (gestational age >= 28 weeks) and death among infants in the first 7 days of life. Miscarriage data (defined as fetal loss < 28 weeks' gestation age) was not provided.

Colman 1974

Onset of supplementation was > 20 weeks' gestation.
Women were supplemented "during the final month of pregnancy". Outcomes reported included folic acid red cell and serum folic acid concentration and haemoglobin concentration.

Correia 1982

No main outcomes of interest reported. Outcomes presented in the study were fetal weight (birthweight) and placental weight. Women's risk of spontaneous and recurrent miscarriage is unclear.

Coutsoudis 1999

Onset of supplementation was > 20 weeks' gestation.
Women were given vitamin A and beta‐carotene "during the third trimester of pregnancy".

Dawson 1962

Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with folic acid "on or after the 28th week". Group allocation was not done randomly. Reported outcomes include incidence of folic acid deficiency and megaloblastic anaemia, and haemoglobin concentration.

Edelstein 1968

Onset of supplementation was > 20 weeks' gestation.
Supplementation was started at the 28th week of pregnancy. Outcomes reported included serum folate activity and serum folate, urinary formiminoglutamic acid, serum vitamin B12, mean haemoglobin and haematocrit values.

Ferguson 1955

Only 24 (9%) of the 269 women in the trial began to participate before 15 weeks' gestation and outcomes not reported separately according to gestation at enrolment.

Feyi‐Waboso 2005

Onset of supplementation was 20 or more weeks' gestation.

Fletcher 1971

No inclusion/exclusion criteria reported, unclear of gestational age at enrolment to the study, reports combined outcomes for "antepartum and threatened or complete abortion" and "stillbirth or neonatal death or congenital malformation" (not reported separately).

Giles 1971

Onset of supplementation was > 20 weeks' gestation for a large proportion of the participants.
4 groups in the study, 2 of which involved supplementation after 20 weeks' gestation. Results were not reported separately between groups.

Hampel 1974

Unclear of the gestational age at which women entered the trial.

Hankin 1966

No main outcomes reported.
Supplementation was from "approximately 20 weeks", no clinically relevant outcomes, outcomes relating to vitamin C status in plasma and breast milk reported.

Hekmatdoost 2011

The intervention assessed the effectiveness of different forms of the same vitamin ‐ folate (folic acid vs 5‐methylenetetrahydrofolate (MTHF)) against each other. There was no placebo or control group.

Hibbard 1969

No main outcomes reported.
Biochemical measures of blood folate status reported.

Hunt 1984

All women received a multivitamin in addition to the zinc supplement or placebo.

Huybregts 2009

Both groups received a multivitamin supplement (same vitamin content in each group).

Kaestel 2005

Women were recruited until late pregnancy and onset of supplementation occurred after 20 weeks.

Laurence 1981

No main outcomes or pregnancy loss outcomes reported. Miscarriage reported in those women where there was a neural tube defect, but not in all women according to treatment group.

Lin 2010

Intervention assessed effect of nutritional supplement besides vitamins. No main outcomes reported.

Lira 1989

No main outcomes reported.
Biochemical measures of iron and folate status reported.

Lumeng 1976

Unclear gestational age at enrolment, 5 women were excluded due to abortion, premature labour, inadequate dietary records or missing more than 3 prenatal visits. Exclusions were not reported by group allocation. Outcomes related to maternal and fetal plasma levels of pyridoxal 5'‐phosphate and coenzyme saturation of aspartate aminotransferase and alanine aminotransferase in maternal erthrocytes were reported.

Marya 1981

Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with vitamin D "throughout the 3rd trimester".

Meirinho 1987

No clinical outcomes reported.
Maternal plasma concentrations of trophoblastic protein SP1 were reported.

Metz 1965

Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with either iron or iron and folic acid, or iron, folic acid and vitamin B12. Supplementation was started after the 24th week of pregnancy.

Mock 2002

No main outcomes reported.
Women were enrolled in either early or late pregnancy. Biochemical measures of biotin status reported.

Moldenhauer 2002

No main outcomes reported.
Unclear if this is a cohort study or randomised trial. Women in this study were participating in a randomised placebo‐controlled trial of calcium supplementation, and completed a dietary assessment at 12‐21 weeks' gestation and 29‐31 weeks' gestation. Unclear whether all women took a standard prenatal multivitamin or just women in the placebo group. Results are presented according to "teens", "twins" and "singleton" pregnancies, not according to whether women took the supplement or not. Outcomes reported included dietary intakes of vitamin C and E (with and without the contribution of the prenatal vitamin supplement).

Owen 1966

Onset of supplementation was > 20 weeks' gestation.
Women supplemented with oral vitamin K1 "several days before delivery".

Potdar 2014

Study was a food intervention trial.

Ross 1985

Unclear about content of vitamin supplements.
Women were supplemented with high or low 'bulk' dietary supplements with vitamins added; however, the vitamin supplements added were not specified.

Schuster 1984

Unclear of gestation at enrolment to the trial.
No pregnancy loss outcomes reported.

Semba 2001

No main outcomes reported.
Women enrolled between 18 and 28 weeks' gestation, no clinical outcomes reported, only haemoglobin and plasma erythropoietin concentrations.

Shu 2002

Both groups received a multivitamin (same vitamin content in both groups).

Smithells 1981

Non‐randomised study of periconceptional multivitamin supplementation for the prevention of neural tube defects.

Suharno 1993

No main outcomes reported.
Anaemic pregnant women were enrolled between 16 and 24 weeks' gestation. The only clinical outcome reported was the percentage of women with anaemia following treatment with a combination of vitamin A and iron or placebo.

Tanumihardjo 2002

No main outcomes reported.
Mean gestation at enrolment was 17.6 weeks, no clinical outcomes reported, markers of vitamin A and iron status reported.

Taylor 1982

No main outcomes reported. Haematological features and serum ferritin were determined. No reports on pregnancy loss.

Thauvin 1992

No main outcomes reported.
Women were supplemented from 3 months' gestation, data on pregnancy outcomes including spontaneous abortion were collected but not reported.

Trigg 1976

Unclear of gestation at enrolment to the trial.

Ulrich 1999

Non‐randomised study.
Observational cohort study of folic acid users, randomised to different doses of folic acid, but no controls.

Villamor 2002

No main outcomes reported.
Women enrolled between 12 and 27 weeks' gestation, no pregnancy loss or main outcomes reported, only reports measures of weight gain during pregnancy.

Vutyavanich 1995

No main outcomes reported.
Women were enrolled in the study if they were less than 17 weeks' gestation; however, no pregnancy loss or main outcomes were reported, only measures of nausea and vomiting.

Wehby 2012

This trial involved only one vitamin compared at different doses.

Young 2015

No relevant outcomes were reported in this study.

Characteristics of studies awaiting assessment [ordered by study ID]

Adu‐Afarwuah 2015

Methods

Partially double‐blind, individually‐randomised controlled trial.

Participants

1320 pregnant women around 20 gestational weeks.

Interventions

Women received 1 of 3 supplements daily until delivery:

60 mg Fe + 400 μg folic acid (IFA), or

1‐2 recommended dietary allowances of 18 micronutrients including 20 mg Fe (MMN), or

SQ‐LNS with the same nutrient levels as in MMN, plus 4 additional minerals as well as macronutrients contributing 118 kcal (LNS).

Outcomes

Haemoglobin concentration (g/L) and 2 markers of iron status, zinc protoporphyrin (ZPP, μmol/mol heme) and transferrin receptor (TfR, mg/L) were assessed.

Notes

Only study abstract available and the composition of the supplement is not clear. Need to see full text.

Agarwal 2012a

Methods

Individually‐randomised controlled trial.

Participants

50 women of recurrent of abortions (more than 2).

Interventions

Women received Vitamin B12 1500 mcg, Vitamin B6 10 mg and folic acid 5 mg daily throughout pregnancy.

Outcomes

  1. Abortion.

  2. Pre‐eclampsia.

  3. IUGR.

  4. Preterm labour.

Notes

Only study abstract available, comparison group also received same intervention but duration is different.

Frenzel 1956

Methods

Unclear.

Participants

Unclear.

Interventions

Unclear.

Outcomes

Unclear.

Notes

A copy of the paper could not be located.

Prado 2015

Methods

Randomised cohorts.

Participants

Pregnant women and infants.

Interventions

Various formulations of lipid‐based nutrient supplements (LNS) during pregnancy and infancy or infancy alone.

Outcomes

  1. Association between linear growth and language development

  2. Association between 18‐month language scores and

  3. 18‐month length‐for‐age z‐score (LAZ)

  4. LAZ at age 6 or 9 months and

  5. The change in LAZ between infancy (6 or 9 months) and 18 months

Notes

Abstract only, no specification what LNS is in abstract.

IFA: iron and folic acid
IUGR: Intrauterine growth restriction
MMN: multiple micronutrient

Characteristics of ongoing studies [ordered by study ID]

Johns 2004

Trial name or title

The effect of antioxidant supplementation on women with threatened miscarriage.

Methods

Randomised controlled trial.

Participants

580 women who present with first trimester bleeding.

Interventions

Vitamin C 1000 mg and Vitamin E 400 IU versus placebo.

Outcomes

  1. Incidence of miscarriage.

  2. Late miscarriage.

  3. Preterm labour.

  4. Preterm pre‐labour rupture of the membranes.

  5. Fetal growth restriction.

  6. Pre‐eclampsia.

Starting date

01/03/2004.

Contact information

Dr  Jemma  Johns

UCLH/UCL Research & Development Governance Committee
Research and Development Directorate
University College London Hospitals NHS Trust
1st Floor, Maple House
149 Tottenham Court Road

Notes

Listed as completed.

IU: internation unit(s)

Data and analyses

Open in table viewer
Comparison 1. Vitamin C plus vitamin E versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

7

18949

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.92, 1.40]

Analysis 1.1

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 1 Total fetal loss.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

4

13346

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.65, 1.26]

Analysis 1.2

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 2 Early or late miscarriage.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

7

21442

Risk Ratio (M‐H, Fixed, 95% CI)

1.31 [0.97, 1.76]

Analysis 1.3

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 3 Stillbirth.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

5

8334

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.84, 1.62]

Analysis 1.4

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 4 Congenital malformations.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 4 Congenital malformations.

5 Any adverse effects of vitamin supplementation sufficient to stop supplementation Show forest plot

1

739

Risk Ratio (M‐H, Fixed, 95% CI)

1.16 [0.39, 3.41]

Analysis 1.5

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 5 Any adverse effects of vitamin supplementation sufficient to stop supplementation.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 5 Any adverse effects of vitamin supplementation sufficient to stop supplementation.

Open in table viewer
Comparison 2. Vitamin C versus no supplement/placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

224

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [0.58, 2.83]

Analysis 2.1

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 1 Total fetal loss.

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

2

224

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.52, 2.65]

Analysis 2.2

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 2 Early or late miscarriage.

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

200

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.12, 72.77]

Analysis 2.3

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 3 Stillbirth.

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 3 Stillbirth.

Open in table viewer
Comparison 3. Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

406

Risk Ratio (M‐H, Fixed, 95% CI)

1.32 [0.63, 2.77]

Analysis 3.1

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 1 Total fetal loss.

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

2

790

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.79, 1.79]

Analysis 3.2

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 2 Early or late miscarriage.

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 2 Early or late miscarriage.

Open in table viewer
Comparison 4. Vitamin A plus iron and folate versus iron and folate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

1640

Risk Ratio (Fixed, 95% CI)

1.01 [0.61, 1.66]

Analysis 4.1

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 1 Total fetal loss.

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

2

1397

Risk Ratio (Fixed, 95% CI)

0.86 [0.46, 1.62]

Analysis 4.2

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 2 Early or late miscarriage.

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

3

1640

Risk Ratio (Fixed, 95% CI)

1.29 [0.57, 2.91]

Analysis 4.3

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 3 Stillbirth.

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 3 Stillbirth.

Open in table viewer
Comparison 5. Vitamin A versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

52480

Risk Ratio (Random, 95% CI)

1.05 [0.90, 1.23]

Analysis 5.1

Comparison 5 Vitamin A versus placebo, Outcome 1 Total fetal loss.

Comparison 5 Vitamin A versus placebo, Outcome 1 Total fetal loss.

2 Early of late miscarriage Show forest plot

1

39668

Risk Ratio (Fixed, 95% CI)

0.98 [0.92, 1.04]

Analysis 5.2

Comparison 5 Vitamin A versus placebo, Outcome 2 Early of late miscarriage.

Comparison 5 Vitamin A versus placebo, Outcome 2 Early of late miscarriage.

3 Stillbirth Show forest plot

1

39668

Risk Ratio (Fixed, 95% CI)

0.95 [0.86, 1.06]

Analysis 5.3

Comparison 5 Vitamin A versus placebo, Outcome 3 Stillbirth.

Comparison 5 Vitamin A versus placebo, Outcome 3 Stillbirth.

Open in table viewer
Comparison 6. Beta‐carotene versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

51163

Risk Ratio (Fixed, 95% CI)

1.02 [0.98, 1.07]

Analysis 6.1

Comparison 6 Beta‐carotene versus placebo, Outcome 1 Total fetal loss.

Comparison 6 Beta‐carotene versus placebo, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

39860

Risk Ratio (Fixed, 95% CI)

1.00 [0.94, 1.06]

Analysis 6.2

Comparison 6 Beta‐carotene versus placebo, Outcome 2 Early or late miscarriage.

Comparison 6 Beta‐carotene versus placebo, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

39860

Risk Ratio (Fixed, 95% CI)

1.09 [0.98, 1.20]

Analysis 6.3

Comparison 6 Beta‐carotene versus placebo, Outcome 3 Stillbirth.

Comparison 6 Beta‐carotene versus placebo, Outcome 3 Stillbirth.

Open in table viewer
Comparison 7. Vitamin A or beta‐carotene versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

17373

Risk Ratio (Fixed, 95% CI)

1.05 [0.91, 1.21]

Analysis 7.1

Comparison 7 Vitamin A or beta‐carotene versus placebo, Outcome 1 Total fetal loss.

Comparison 7 Vitamin A or beta‐carotene versus placebo, Outcome 1 Total fetal loss.

Open in table viewer
Comparison 8. Vitamin A (with/without multivitamins) versus multivitamins or placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1074

Risk Ratio (Fixed, 95% CI)

0.80 [0.53, 1.21]

Analysis 8.1

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 1 Total fetal loss.

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

1075

Risk Ratio (Fixed, 95% CI)

0.76 [0.37, 1.55]

Analysis 8.2

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 2 Early or late miscarriage.

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

1075

Risk Ratio (Fixed, 95% CI)

1.04 [0.60, 1.79]

Analysis 8.3

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 3 Stillbirth.

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 3 Stillbirth.

Open in table viewer
Comparison 9. Multivitamin plus iron and folic acid versus iron and folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

10

94948

Risk Ratio (Fixed, 95% CI)

0.96 [0.93, 1.00]

Analysis 9.1

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 1 Total fetal loss.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

10

94948

Risk Ratio (Fixed, 95% CI)

0.98 [0.94, 1.03]

Analysis 9.2

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 2 Early or late miscarriage.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

10

79851

Risk Ratio (Fixed, 95% CI)

0.92 [0.85, 0.99]

Analysis 9.3

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 3 Stillbirth.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 3 Stillbirth.

4 Congenital malformation Show forest plot

1

1200

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.14, 7.08]

Analysis 9.4

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 4 Congenital malformation.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 4 Congenital malformation.

Open in table viewer
Comparison 10. Multivitamin without folic acid versus no multivitamin/folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

907

Risk Ratio (Fixed, 95% CI)

0.49 [0.34, 0.70]

Analysis 10.1

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

907

Risk Ratio (Fixed, 95% CI)

0.89 [0.59, 1.34]

Analysis 10.2

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

907

Risk Ratio (Fixed, 95% CI)

0.14 [0.01, 2.77]

Analysis 10.3

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

1

907

Risk Ratio (M‐H, Fixed, 95% CI)

1.60 [0.53, 4.86]

Analysis 10.4

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 11. Multivitamin with/without folic acid versus no multivitamin/folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1368

Risk Ratio (Fixed, 95% CI)

0.91 [0.65, 1.27]

Analysis 11.1

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

1368

Risk Ratio (Fixed, 95% CI)

0.95 [0.67, 1.34]

Analysis 11.2

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

1368

Risk Ratio (Fixed, 95% CI)

0.33 [0.06, 1.98]

Analysis 11.3

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

1

1368

Risk Ratio (M‐H, Fixed, 95% CI)

1.99 [0.75, 5.26]

Analysis 11.4

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 12. Multivitamin plus folic acid versus folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

5012

Risk Ratio (Fixed, 95% CI)

1.04 [0.88, 1.23]

Analysis 12.1

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 1 Total fetal loss.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

3

5012

Risk Ratio (Fixed, 95% CI)

0.97 [0.80, 1.18]

Analysis 12.2

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 2 Early or late miscarriage.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

3

4316

Risk Ratio (Fixed, 95% CI)

1.32 [0.93, 1.88]

Analysis 12.3

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 3 Stillbirth.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

1096

Risk Ratio (M‐H, Fixed, 95% CI)

1.71 [0.72, 4.04]

Analysis 12.4

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 4 Congenital malformations.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 13. Multivitamin without folic acid versus folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1090

Risk Ratio (Fixed, 95% CI)

0.90 [0.62, 1.30]

Analysis 13.1

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 1 Total fetal loss.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

2

1090

Risk Ratio (Fixed, 95% CI)

0.89 [0.61, 1.31]

Analysis 13.2

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 2 Early or late miscarriage.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

2

1090

Risk Ratio (Random, 95% CI)

0.99 [0.04, 22.90]

Analysis 13.3

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 3 Stillbirth.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.61 [0.67, 3.85]

Analysis 13.4

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 4 Congenital malformations.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 14. Multivitamin with/without folic acid versus folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1644

Risk Ratio (Fixed, 95% CI)

0.96 [0.70, 1.33]

Analysis 14.1

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 1 Total fetal loss.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 1 Total fetal loss.

2 Early of late miscarriage Show forest plot

2

1644

Risk Ratio (Fixed, 95% CI)

0.96 [0.70, 1.33]

Analysis 14.2

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 2 Early of late miscarriage.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 2 Early of late miscarriage.

3 Stillbirth Show forest plot

2

1644

Risk Ratio (Fixed, 95% CI)

0.79 [0.15, 4.10]

Analysis 14.3

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 3 Stillbirth.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

1644

Risk Ratio (M‐H, Fixed, 95% CI)

1.66 [0.76, 3.63]

Analysis 14.4

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 4 Congenital malformations.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 15. Multivitamin with/without vitamin A versus vitamin A or placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1074

Risk Ratio (Fixed, 95% CI)

0.60 [0.39, 0.92]

Analysis 15.1

Comparison 15 Multivitamin with/without vitamin A versus vitamin A or placebo, Outcome 1 Total fetal loss.

Comparison 15 Multivitamin with/without vitamin A versus vitamin A or placebo, Outcome 1 Total fetal loss.

Open in table viewer
Comparison 16. Multivitamin versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

5021

Risk Ratio (Fixed, 95% CI)

0.83 [0.58, 1.17]

Analysis 16.1

Comparison 16 Multivitamin versus control, Outcome 1 Total fetal loss.

Comparison 16 Multivitamin versus control, Outcome 1 Total fetal loss.

2 Stillbirth Show forest plot

1

5021

Risk Ratio (Fixed, 95% CI)

0.83 [0.58, 1.17]

Analysis 16.2

Comparison 16 Multivitamin versus control, Outcome 2 Stillbirth.

Comparison 16 Multivitamin versus control, Outcome 2 Stillbirth.

Open in table viewer
Comparison 17. Multivitamin plus vitamin E versus multivitamin without vitamin E or control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

823

Risk Ratio (Fixed, 95% CI)

0.92 [0.46, 1.83]

Analysis 17.1

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 1 Total fetal loss.

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

823

Risk Ratio (Fixed, 95% CI)

1.04 [0.26, 4.13]

Analysis 17.2

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 2 Early or late miscarriage.

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

823

Risk Ratio (Fixed, 95% CI)

0.88 [0.39, 1.98]

Analysis 17.3

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 3 Stillbirth.

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 3 Stillbirth.

Open in table viewer
Comparison 18. Multivitamin plus folic acid versus no multivitamin/folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

6883

Risk Ratio (Random, 95% CI)

1.00 [0.75, 1.34]

Analysis 18.1

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

3

6883

Risk Ratio (Random, 95% CI)

0.99 [0.72, 1.38]

Analysis 18.2

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

3

6883

Risk Ratio (Fixed, 95% CI)

1.04 [0.51, 2.10]

Analysis 18.3

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

5777

Risk Ratio (M‐H, Fixed, 95% CI)

1.69 [0.81, 3.53]

Analysis 18.4

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 19. Folic acid plus multivitamin versus no folic acid/multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

6883

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.75, 1.34]

Analysis 19.1

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

3

6883

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.72, 1.38]

Analysis 19.2

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

3

6883

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.51, 2.09]

Analysis 19.3

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

5777

Risk Ratio (M‐H, Fixed, 95% CI)

1.69 [0.81, 3.53]

Analysis 19.4

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 20. Folic acid without multivitamin versus no folic acid/multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.64, 1.40]

Analysis 20.1

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.65, 1.44]

Analysis 20.2

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.11, 4.02]

Analysis 20.3

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

1.42 [0.45, 4.43]

Analysis 20.4

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 21. Folic acid with/without multivitamin versus no folic acid/multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.69, 1.35]

Analysis 21.1

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.70, 1.39]

Analysis 21.2

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.15, 2.96]

Analysis 21.3

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

1.90 [0.71, 5.04]

Analysis 21.4

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 22. Folic acis plus multivitamin versus multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1102

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [0.80, 1.67]

Analysis 22.1

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 1 Total fetal loss.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

2

1102

Risk Ratio (M‐H, Fixed, 95% CI)

1.16 [0.80, 1.69]

Analysis 22.2

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

2

1102

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.04, 22.55]

Analysis 22.3

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 3 Stillbirth.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

1102

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.28, 3.12]

Analysis 22.4

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 23. Folic acid without multivitamin versus multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.77, 1.62]

Analysis 23.1

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.77, 1.64]

Analysis 23.2

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

4.97 [0.58, 42.29]

Analysis 23.3

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 3 Stillbirth.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.26, 1.49]

Analysis 23.4

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 24. Folic acid with or without multivitamin versus multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1644

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.82, 1.57]

Analysis 24.1

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

2

1642

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.79, 1.51]

Analysis 24.2

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

2

1644

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.02, 28.39]

Analysis 24.3

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 3 Stillbirth.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 3 Stillbirth.

4 Congenital malformations Show forest plot

2

1644

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.19, 2.51]

Analysis 24.4

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Open in table viewer
Comparison 25. Folic acid plus iron versus iron

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.23 [0.01, 4.59]

Analysis 25.1

Comparison 25 Folic acid plus iron versus iron, Outcome 1 Total fetal loss.

Comparison 25 Folic acid plus iron versus iron, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.02, 9.03]

Analysis 25.2

Comparison 25 Folic acid plus iron versus iron, Outcome 2 Early or late miscarriage.

Comparison 25 Folic acid plus iron versus iron, Outcome 2 Early or late miscarriage.

3 Stillbirth Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.02, 9.03]

Analysis 25.3

Comparison 25 Folic acid plus iron versus iron, Outcome 3 Stillbirth.

Comparison 25 Folic acid plus iron versus iron, Outcome 3 Stillbirth.

Open in table viewer
Comparison 26. Folic acid plus iron and antimalarials versus iron and antimalarials

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

160

Risk Ratio (M‐H, Fixed, 95% CI)

13.0 [0.74, 226.98]

Analysis 26.1

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 1 Total fetal loss.

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 1 Total fetal loss.

2 Early or late miscarriage Show forest plot

1

160

Risk Ratio (M‐H, Fixed, 95% CI)

13.0 [0.74, 226.98]

Analysis 26.2

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 2 Early or late miscarriage.

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 2 Early or late miscarriage.

Open in table viewer
Comparison 27. Antioxidant vitamin supplementation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Early or late miscarriage Show forest plot

1

110

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.24, 5.29]

Analysis 27.1

Comparison 27 Antioxidant vitamin supplementation, Outcome 1 Early or late miscarriage.

Comparison 27 Antioxidant vitamin supplementation, Outcome 1 Early or late miscarriage.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figuras y tablas -
Figure 1

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

'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

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.1 Total fetal loss.
Figuras y tablas -
Figure 3

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.1 Total fetal loss.

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.2 Early or late miscarriage.
Figuras y tablas -
Figure 4

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.2 Early or late miscarriage.

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.3 Stillbirth.
Figuras y tablas -
Figure 5

Funnel plot of comparison: 9 Multivitamin plus iron and folic acid versus iron and folic acid, outcome: 9.3 Stillbirth.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 1.1

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 1 Total fetal loss.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 1.2

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 2 Early or late miscarriage.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 1.3

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 3 Stillbirth.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 1.4

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 4 Congenital malformations.

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 5 Any adverse effects of vitamin supplementation sufficient to stop supplementation.
Figuras y tablas -
Analysis 1.5

Comparison 1 Vitamin C plus vitamin E versus placebo, Outcome 5 Any adverse effects of vitamin supplementation sufficient to stop supplementation.

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 2.1

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 1 Total fetal loss.

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 2.2

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 2 Early or late miscarriage.

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 2.3

Comparison 2 Vitamin C versus no supplement/placebo, Outcome 3 Stillbirth.

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 3.1

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 1 Total fetal loss.

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 3.2

Comparison 3 Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone, Outcome 2 Early or late miscarriage.

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 4.1

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 1 Total fetal loss.

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 4.2

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 2 Early or late miscarriage.

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 4.3

Comparison 4 Vitamin A plus iron and folate versus iron and folate, Outcome 3 Stillbirth.

Comparison 5 Vitamin A versus placebo, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 5.1

Comparison 5 Vitamin A versus placebo, Outcome 1 Total fetal loss.

Comparison 5 Vitamin A versus placebo, Outcome 2 Early of late miscarriage.
Figuras y tablas -
Analysis 5.2

Comparison 5 Vitamin A versus placebo, Outcome 2 Early of late miscarriage.

Comparison 5 Vitamin A versus placebo, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 5.3

Comparison 5 Vitamin A versus placebo, Outcome 3 Stillbirth.

Comparison 6 Beta‐carotene versus placebo, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 6.1

Comparison 6 Beta‐carotene versus placebo, Outcome 1 Total fetal loss.

Comparison 6 Beta‐carotene versus placebo, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 6.2

Comparison 6 Beta‐carotene versus placebo, Outcome 2 Early or late miscarriage.

Comparison 6 Beta‐carotene versus placebo, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 6.3

Comparison 6 Beta‐carotene versus placebo, Outcome 3 Stillbirth.

Comparison 7 Vitamin A or beta‐carotene versus placebo, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 7.1

Comparison 7 Vitamin A or beta‐carotene versus placebo, Outcome 1 Total fetal loss.

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 8.1

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 1 Total fetal loss.

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 8.2

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 2 Early or late miscarriage.

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 8.3

Comparison 8 Vitamin A (with/without multivitamins) versus multivitamins or placebo, Outcome 3 Stillbirth.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 9.1

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 1 Total fetal loss.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 9.2

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 2 Early or late miscarriage.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 9.3

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 3 Stillbirth.

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 4 Congenital malformation.
Figuras y tablas -
Analysis 9.4

Comparison 9 Multivitamin plus iron and folic acid versus iron and folic acid, Outcome 4 Congenital malformation.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 10.1

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 10.2

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 10.3

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 10.4

Comparison 10 Multivitamin without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 11.1

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 11.2

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 11.3

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 11.4

Comparison 11 Multivitamin with/without folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 12.1

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 1 Total fetal loss.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 12.2

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 2 Early or late miscarriage.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 12.3

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 3 Stillbirth.

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 12.4

Comparison 12 Multivitamin plus folic acid versus folic acid, Outcome 4 Congenital malformations.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 13.1

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 1 Total fetal loss.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 13.2

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 2 Early or late miscarriage.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 13.3

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 3 Stillbirth.

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 13.4

Comparison 13 Multivitamin without folic acid versus folic acid, Outcome 4 Congenital malformations.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 14.1

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 1 Total fetal loss.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 2 Early of late miscarriage.
Figuras y tablas -
Analysis 14.2

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 2 Early of late miscarriage.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 14.3

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 3 Stillbirth.

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 14.4

Comparison 14 Multivitamin with/without folic acid versus folic acid, Outcome 4 Congenital malformations.

Comparison 15 Multivitamin with/without vitamin A versus vitamin A or placebo, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 15.1

Comparison 15 Multivitamin with/without vitamin A versus vitamin A or placebo, Outcome 1 Total fetal loss.

Comparison 16 Multivitamin versus control, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 16.1

Comparison 16 Multivitamin versus control, Outcome 1 Total fetal loss.

Comparison 16 Multivitamin versus control, Outcome 2 Stillbirth.
Figuras y tablas -
Analysis 16.2

Comparison 16 Multivitamin versus control, Outcome 2 Stillbirth.

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 17.1

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 1 Total fetal loss.

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 17.2

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 2 Early or late miscarriage.

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 17.3

Comparison 17 Multivitamin plus vitamin E versus multivitamin without vitamin E or control, Outcome 3 Stillbirth.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 18.1

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 1 Total fetal loss.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 18.2

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 2 Early or late miscarriage.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 18.3

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 3 Stillbirth.

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 18.4

Comparison 18 Multivitamin plus folic acid versus no multivitamin/folic acid, Outcome 4 Congenital malformations.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 19.1

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 19.2

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 19.3

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 19.4

Comparison 19 Folic acid plus multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 20.1

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 20.2

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 20.3

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 20.4

Comparison 20 Folic acid without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 21.1

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 1 Total fetal loss.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 21.2

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 2 Early or late miscarriage.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 21.3

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 3 Stillbirth.

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 21.4

Comparison 21 Folic acid with/without multivitamin versus no folic acid/multivitamin, Outcome 4 Congenital malformations.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 22.1

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 1 Total fetal loss.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 22.2

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 22.3

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 3 Stillbirth.

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 22.4

Comparison 22 Folic acis plus multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 23.1

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 23.2

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 23.3

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 3 Stillbirth.

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 23.4

Comparison 23 Folic acid without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 24.1

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 1 Total fetal loss.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 24.2

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 2 Early or late miscarriage.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 24.3

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 3 Stillbirth.

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 4 Congenital malformations.
Figuras y tablas -
Analysis 24.4

Comparison 24 Folic acid with or without multivitamin versus multivitamin, Outcome 4 Congenital malformations.

Comparison 25 Folic acid plus iron versus iron, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 25.1

Comparison 25 Folic acid plus iron versus iron, Outcome 1 Total fetal loss.

Comparison 25 Folic acid plus iron versus iron, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 25.2

Comparison 25 Folic acid plus iron versus iron, Outcome 2 Early or late miscarriage.

Comparison 25 Folic acid plus iron versus iron, Outcome 3 Stillbirth.
Figuras y tablas -
Analysis 25.3

Comparison 25 Folic acid plus iron versus iron, Outcome 3 Stillbirth.

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 1 Total fetal loss.
Figuras y tablas -
Analysis 26.1

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 1 Total fetal loss.

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 2 Early or late miscarriage.
Figuras y tablas -
Analysis 26.2

Comparison 26 Folic acid plus iron and antimalarials versus iron and antimalarials, Outcome 2 Early or late miscarriage.

Comparison 27 Antioxidant vitamin supplementation, Outcome 1 Early or late miscarriage.
Figuras y tablas -
Analysis 27.1

Comparison 27 Antioxidant vitamin supplementation, Outcome 1 Early or late miscarriage.

Summary of findings for the main comparison. Vitamin C and vitamin E versus placebo for preventing miscarriage

Vitamin C plus vitamin E versus control for preventing miscarriage

Population: pregnant women
Setting: Australia, Brazil, Canada, Scotland, UK, USA
Intervention: vitamin C and vitamin E
Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with Vitamin C plus vitamin E

Total fetal loss

Study population

RR 1.14
(0.92 to 1.40)

18,949
(7 RCTs)

⊕⊕⊕⊕
HIGH 1

17 per 1000

20 per 1000
(16 to 24)

Moderate

14 per 1000

16 per 1000
(13 to 20)

Early or late miscarriage

Study population

RR 0.90
(0.65 to 1.26)

13,346
(4 RCTs)

⊕⊕⊕⊝
MODERATE 2

9 per 1000

9 per 1000
(7 to 12)

Moderate

8 per 1000

8 per 1000
(6 to 11)

Stillbirth

Study population

RR 1.31
(0.97 to 1.76)

21,442
(7 RCTs)

⊕⊕⊕⊝
MODERATE 2

8 per 1000

10 per 1000
(7 to 13)

Moderate

7 per 1000

9 per 1000
(7 to 12)

Any adverse effects of vitamin supplementation sufficient to stop supplementation

Study population

RR 1.16
(0.39 to 3.41)

739
(1 RCT)

⊕⊕⊕⊝
MODERATE 2 3

16 per 1000

19 per 1000
(6 to 56)

*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; 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 Not effective but 95% CI is narrow and precise.

2 Non significant with wide 95% CI.

3 Small sample size.

Figuras y tablas -
Summary of findings for the main comparison. Vitamin C and vitamin E versus placebo for preventing miscarriage
Summary of findings 2. Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage

Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage

Population: pregnant women
Settings: Indonesia, Malawi
Intervention: vitamin A plus iron plus folate
Comparison: iron plus folate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with Vitamin A

Total fetal loss (including miscarriages or combined miscarriages and stillbirths) ‐ Vitamin A + iron + folate versus iron + folate

Study population

RR 1.01
(0.61 to 1.66)

1640
(3 RCTs)

⊕⊕⊝⊝
LOW 1 2

37 per 1000

37 per 1000
(22 to 61)

Moderate

59 per 1,000

60 per 1,000

(36 to 98)

Early or late miscarriage ‐ Vitamin A + iron + folate versus iron + folate

Study population

RR 0.86
(0.46 to 1.62)

1397
(2 RCTs)

⊕⊕⊝⊝
LOW 1 2

31 per 1000

26 per 1000
(14 to 50)

Moderate

50 per 1,000

43 per 1,000

(23 to 80)

Stillbirth ‐ Vitamin A + iron + folate versus iron + folate

Study population

RR 1.29
(0.57 to 2.91)

1640
(3 RCTs)

⊕⊕⊝⊝
LOW 1 2

13 per 1000

16 per 1000
(7 to 37)

Moderate

21 per 1,000

27 per 1,000

(12 to 61)

Any adverse effects

See comments.

No studies reported this outcome.

*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; 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 High and unclear risk of attrition bias.

2 Wide 95% CI.

Figuras y tablas -
Summary of findings 2. Vitamin A plus iron plus folate versus iron plus folate for preventing miscarriage
Summary of findings 3. Multivitamin plus iron plus folate versus iron plus folate for preventing miscarriage

Multivitamin plus iron plus folate versus iron plus folate for preventing miscarriage

Population: pregnant women
Settings: Bangladesh, Barkino Faso, Indonesia, Nepal, Niger, Pakistan, Tanzania
Intervention: vitamin A plus iron plus folate
Comparison: iron plus folate

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with Multivitamin

Total fetal loss (including miscarriages or combined miscarriages and stillbirths) ‐ Multivitamins + iron + folic acid versus iron + folic acid

Study population

RR 0.96
(0.93 to 1.00)

94,948
(10 RCTs)

⊕⊕⊕⊕
HIGH

136 per 1000

130 per 1000
(126 to 136)

Moderate

218 per 1,000

209 per 1,000

(202 to 218)

Early or late miscarriage ‐ Multivitamin + iron + folic acid versus iron + folic acid

Study population

RR 0.98
(0.94 to 1.03)

94948
(10 RCTs)

⊕⊕⊕⊝
MODERATE 1,2

84 per 1000

83 per 1000
(79 to 87)

Moderate

134 per 1,000

132 per 1,000

(126 to 138)

Stillbirth ‐ Multivitamin + iron + folic acid versus iron + folic acid

Study population

RR 0.92
(0.85 to 0.99)

79,851
(10 RCTs)

⊕⊕⊕⊕
HIGH

29 per 1000

26 per 1000
(24 to 28)

Moderate

46 per 1,000

43 per 1,000

(39 to 46)

Any adverse effects

See comments

No studies reported this outcome

*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; 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 Publication bias detected by funnel plot.

2 Wide confidence interval crossing the line of no effect.

Figuras y tablas -
Summary of findings 3. Multivitamin plus iron plus folate versus iron plus folate for preventing miscarriage
Comparison 1. Vitamin C plus vitamin E versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

7

18949

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.92, 1.40]

2 Early or late miscarriage Show forest plot

4

13346

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.65, 1.26]

3 Stillbirth Show forest plot

7

21442

Risk Ratio (M‐H, Fixed, 95% CI)

1.31 [0.97, 1.76]

4 Congenital malformations Show forest plot

5

8334

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.84, 1.62]

5 Any adverse effects of vitamin supplementation sufficient to stop supplementation Show forest plot

1

739

Risk Ratio (M‐H, Fixed, 95% CI)

1.16 [0.39, 3.41]

Figuras y tablas -
Comparison 1. Vitamin C plus vitamin E versus placebo
Comparison 2. Vitamin C versus no supplement/placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

224

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [0.58, 2.83]

2 Early or late miscarriage Show forest plot

2

224

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.52, 2.65]

3 Stillbirth Show forest plot

1

200

Risk Ratio (M‐H, Fixed, 95% CI)

3.0 [0.12, 72.77]

Figuras y tablas -
Comparison 2. Vitamin C versus no supplement/placebo
Comparison 3. Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

406

Risk Ratio (M‐H, Fixed, 95% CI)

1.32 [0.63, 2.77]

2 Early or late miscarriage Show forest plot

2

790

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.79, 1.79]

Figuras y tablas -
Comparison 3. Vitamin C plus multivitamins versus placebo plus multivitamins or multivitamins alone
Comparison 4. Vitamin A plus iron and folate versus iron and folate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

1640

Risk Ratio (Fixed, 95% CI)

1.01 [0.61, 1.66]

2 Early or late miscarriage Show forest plot

2

1397

Risk Ratio (Fixed, 95% CI)

0.86 [0.46, 1.62]

3 Stillbirth Show forest plot

3

1640

Risk Ratio (Fixed, 95% CI)

1.29 [0.57, 2.91]

Figuras y tablas -
Comparison 4. Vitamin A plus iron and folate versus iron and folate
Comparison 5. Vitamin A versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

52480

Risk Ratio (Random, 95% CI)

1.05 [0.90, 1.23]

2 Early of late miscarriage Show forest plot

1

39668

Risk Ratio (Fixed, 95% CI)

0.98 [0.92, 1.04]

3 Stillbirth Show forest plot

1

39668

Risk Ratio (Fixed, 95% CI)

0.95 [0.86, 1.06]

Figuras y tablas -
Comparison 5. Vitamin A versus placebo
Comparison 6. Beta‐carotene versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

51163

Risk Ratio (Fixed, 95% CI)

1.02 [0.98, 1.07]

2 Early or late miscarriage Show forest plot

1

39860

Risk Ratio (Fixed, 95% CI)

1.00 [0.94, 1.06]

3 Stillbirth Show forest plot

1

39860

Risk Ratio (Fixed, 95% CI)

1.09 [0.98, 1.20]

Figuras y tablas -
Comparison 6. Beta‐carotene versus placebo
Comparison 7. Vitamin A or beta‐carotene versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

17373

Risk Ratio (Fixed, 95% CI)

1.05 [0.91, 1.21]

Figuras y tablas -
Comparison 7. Vitamin A or beta‐carotene versus placebo
Comparison 8. Vitamin A (with/without multivitamins) versus multivitamins or placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1074

Risk Ratio (Fixed, 95% CI)

0.80 [0.53, 1.21]

2 Early or late miscarriage Show forest plot

1

1075

Risk Ratio (Fixed, 95% CI)

0.76 [0.37, 1.55]

3 Stillbirth Show forest plot

1

1075

Risk Ratio (Fixed, 95% CI)

1.04 [0.60, 1.79]

Figuras y tablas -
Comparison 8. Vitamin A (with/without multivitamins) versus multivitamins or placebo
Comparison 9. Multivitamin plus iron and folic acid versus iron and folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

10

94948

Risk Ratio (Fixed, 95% CI)

0.96 [0.93, 1.00]

2 Early or late miscarriage Show forest plot

10

94948

Risk Ratio (Fixed, 95% CI)

0.98 [0.94, 1.03]

3 Stillbirth Show forest plot

10

79851

Risk Ratio (Fixed, 95% CI)

0.92 [0.85, 0.99]

4 Congenital malformation Show forest plot

1

1200

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.14, 7.08]

Figuras y tablas -
Comparison 9. Multivitamin plus iron and folic acid versus iron and folic acid
Comparison 10. Multivitamin without folic acid versus no multivitamin/folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

907

Risk Ratio (Fixed, 95% CI)

0.49 [0.34, 0.70]

2 Early or late miscarriage Show forest plot

1

907

Risk Ratio (Fixed, 95% CI)

0.89 [0.59, 1.34]

3 Stillbirth Show forest plot

1

907

Risk Ratio (Fixed, 95% CI)

0.14 [0.01, 2.77]

4 Congenital malformations Show forest plot

1

907

Risk Ratio (M‐H, Fixed, 95% CI)

1.60 [0.53, 4.86]

Figuras y tablas -
Comparison 10. Multivitamin without folic acid versus no multivitamin/folic acid
Comparison 11. Multivitamin with/without folic acid versus no multivitamin/folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1368

Risk Ratio (Fixed, 95% CI)

0.91 [0.65, 1.27]

2 Early or late miscarriage Show forest plot

1

1368

Risk Ratio (Fixed, 95% CI)

0.95 [0.67, 1.34]

3 Stillbirth Show forest plot

1

1368

Risk Ratio (Fixed, 95% CI)

0.33 [0.06, 1.98]

4 Congenital malformations Show forest plot

1

1368

Risk Ratio (M‐H, Fixed, 95% CI)

1.99 [0.75, 5.26]

Figuras y tablas -
Comparison 11. Multivitamin with/without folic acid versus no multivitamin/folic acid
Comparison 12. Multivitamin plus folic acid versus folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

5012

Risk Ratio (Fixed, 95% CI)

1.04 [0.88, 1.23]

2 Early or late miscarriage Show forest plot

3

5012

Risk Ratio (Fixed, 95% CI)

0.97 [0.80, 1.18]

3 Stillbirth Show forest plot

3

4316

Risk Ratio (Fixed, 95% CI)

1.32 [0.93, 1.88]

4 Congenital malformations Show forest plot

2

1096

Risk Ratio (M‐H, Fixed, 95% CI)

1.71 [0.72, 4.04]

Figuras y tablas -
Comparison 12. Multivitamin plus folic acid versus folic acid
Comparison 13. Multivitamin without folic acid versus folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1090

Risk Ratio (Fixed, 95% CI)

0.90 [0.62, 1.30]

2 Early or late miscarriage Show forest plot

2

1090

Risk Ratio (Fixed, 95% CI)

0.89 [0.61, 1.31]

3 Stillbirth Show forest plot

2

1090

Risk Ratio (Random, 95% CI)

0.99 [0.04, 22.90]

4 Congenital malformations Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.61 [0.67, 3.85]

Figuras y tablas -
Comparison 13. Multivitamin without folic acid versus folic acid
Comparison 14. Multivitamin with/without folic acid versus folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1644

Risk Ratio (Fixed, 95% CI)

0.96 [0.70, 1.33]

2 Early of late miscarriage Show forest plot

2

1644

Risk Ratio (Fixed, 95% CI)

0.96 [0.70, 1.33]

3 Stillbirth Show forest plot

2

1644

Risk Ratio (Fixed, 95% CI)

0.79 [0.15, 4.10]

4 Congenital malformations Show forest plot

2

1644

Risk Ratio (M‐H, Fixed, 95% CI)

1.66 [0.76, 3.63]

Figuras y tablas -
Comparison 14. Multivitamin with/without folic acid versus folic acid
Comparison 15. Multivitamin with/without vitamin A versus vitamin A or placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1074

Risk Ratio (Fixed, 95% CI)

0.60 [0.39, 0.92]

Figuras y tablas -
Comparison 15. Multivitamin with/without vitamin A versus vitamin A or placebo
Comparison 16. Multivitamin versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

5021

Risk Ratio (Fixed, 95% CI)

0.83 [0.58, 1.17]

2 Stillbirth Show forest plot

1

5021

Risk Ratio (Fixed, 95% CI)

0.83 [0.58, 1.17]

Figuras y tablas -
Comparison 16. Multivitamin versus control
Comparison 17. Multivitamin plus vitamin E versus multivitamin without vitamin E or control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

823

Risk Ratio (Fixed, 95% CI)

0.92 [0.46, 1.83]

2 Early or late miscarriage Show forest plot

1

823

Risk Ratio (Fixed, 95% CI)

1.04 [0.26, 4.13]

3 Stillbirth Show forest plot

1

823

Risk Ratio (Fixed, 95% CI)

0.88 [0.39, 1.98]

Figuras y tablas -
Comparison 17. Multivitamin plus vitamin E versus multivitamin without vitamin E or control
Comparison 18. Multivitamin plus folic acid versus no multivitamin/folic acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

6883

Risk Ratio (Random, 95% CI)

1.00 [0.75, 1.34]

2 Early or late miscarriage Show forest plot

3

6883

Risk Ratio (Random, 95% CI)

0.99 [0.72, 1.38]

3 Stillbirth Show forest plot

3

6883

Risk Ratio (Fixed, 95% CI)

1.04 [0.51, 2.10]

4 Congenital malformations Show forest plot

2

5777

Risk Ratio (M‐H, Fixed, 95% CI)

1.69 [0.81, 3.53]

Figuras y tablas -
Comparison 18. Multivitamin plus folic acid versus no multivitamin/folic acid
Comparison 19. Folic acid plus multivitamin versus no folic acid/multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

3

6883

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.75, 1.34]

2 Early or late miscarriage Show forest plot

3

6883

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.72, 1.38]

3 Stillbirth Show forest plot

3

6883

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.51, 2.09]

4 Congenital malformations Show forest plot

2

5777

Risk Ratio (M‐H, Fixed, 95% CI)

1.69 [0.81, 3.53]

Figuras y tablas -
Comparison 19. Folic acid plus multivitamin versus no folic acid/multivitamin
Comparison 20. Folic acid without multivitamin versus no folic acid/multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.64, 1.40]

2 Early or late miscarriage Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.65, 1.44]

3 Stillbirth Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.11, 4.02]

4 Congenital malformations Show forest plot

1

903

Risk Ratio (M‐H, Fixed, 95% CI)

1.42 [0.45, 4.43]

Figuras y tablas -
Comparison 20. Folic acid without multivitamin versus no folic acid/multivitamin
Comparison 21. Folic acid with/without multivitamin versus no folic acid/multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

0.97 [0.69, 1.35]

2 Early or late miscarriage Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

0.99 [0.70, 1.39]

3 Stillbirth Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

0.67 [0.15, 2.96]

4 Congenital malformations Show forest plot

1

1364

Risk Ratio (M‐H, Fixed, 95% CI)

1.90 [0.71, 5.04]

Figuras y tablas -
Comparison 21. Folic acid with/without multivitamin versus no folic acid/multivitamin
Comparison 22. Folic acis plus multivitamin versus multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1102

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [0.80, 1.67]

2 Early or late miscarriage Show forest plot

2

1102

Risk Ratio (M‐H, Fixed, 95% CI)

1.16 [0.80, 1.69]

3 Stillbirth Show forest plot

2

1102

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.04, 22.55]

4 Congenital malformations Show forest plot

2

1102

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.28, 3.12]

Figuras y tablas -
Comparison 22. Folic acis plus multivitamin versus multivitamin
Comparison 23. Folic acid without multivitamin versus multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.77, 1.62]

2 Early or late miscarriage Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.77, 1.64]

3 Stillbirth Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

4.97 [0.58, 42.29]

4 Congenital malformations Show forest plot

2

1090

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.26, 1.49]

Figuras y tablas -
Comparison 23. Folic acid without multivitamin versus multivitamin
Comparison 24. Folic acid with or without multivitamin versus multivitamin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

2

1644

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.82, 1.57]

2 Early or late miscarriage Show forest plot

2

1642

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.79, 1.51]

3 Stillbirth Show forest plot

2

1644

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.02, 28.39]

4 Congenital malformations Show forest plot

2

1644

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.19, 2.51]

Figuras y tablas -
Comparison 24. Folic acid with or without multivitamin versus multivitamin
Comparison 25. Folic acid plus iron versus iron

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.23 [0.01, 4.59]

2 Early or late miscarriage Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.02, 9.03]

3 Stillbirth Show forest plot

1

75

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.02, 9.03]

Figuras y tablas -
Comparison 25. Folic acid plus iron versus iron
Comparison 26. Folic acid plus iron and antimalarials versus iron and antimalarials

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total fetal loss Show forest plot

1

160

Risk Ratio (M‐H, Fixed, 95% CI)

13.0 [0.74, 226.98]

2 Early or late miscarriage Show forest plot

1

160

Risk Ratio (M‐H, Fixed, 95% CI)

13.0 [0.74, 226.98]

Figuras y tablas -
Comparison 26. Folic acid plus iron and antimalarials versus iron and antimalarials
Comparison 27. Antioxidant vitamin supplementation

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Early or late miscarriage Show forest plot

1

110

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.24, 5.29]

Figuras y tablas -
Comparison 27. Antioxidant vitamin supplementation