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Supplement: Nutrition as a Preventive Strategy against Adverse Pregnancy Outcomes

Characteristics of Randomized Controlled Trials Included in Systematic Reviews of Nutritional Interventions Reporting Maternal Morbidity, Mortality, Preterm Delivery, Intrauterine Growth Restriction and Small for Gestational Age and Birth Weight Outcomes ^{1 ,2}

José Villar^*,3, Mario Merialdi^*, A. Metin Gülmezoglu^*, Edgardo Abalos, Guillermo Carroli, Regina Kulier^** and Mercedes de Onis

^* UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO, CH–1211 Geneva 27, Switzerland, Centro Rosarino de Estudios Perinatales (CREP), WHO Collaborative Center in Maternal and Child Health, Rosario 2000, Argentina, ^** Geneva Foundation for Medical Education and Research, Geneva, Switzerland and Department of Nutrition, WHO, CH–1211 Geneva 27, Switzerland

³ To whom correspondence should be addressed. E-mail: villarj{at}who.int.

This table presents supplementary data for manuscripts by Villar et al. (1) and Merialdi et al. (2), published in this issue.
ANNEX TABLE 1

Trial No. Trial reference Description of intervention Participants and settings Comments NUTRITIONAL ADVICE 1 Hankin & Symonds (3) Advice to improve quality (primarily to increase protein content) of diet versus no dietary advice 149 primigravidas and secundigravidas at first antenatal care visit (all <20 weeks gestation) Allocation by day of week 2 Kafatos et al. (4) Nutrition counseling to improve "quality" of diet ("high nutrient value") versus no counseling 568 pregnant women in rural area of northern Greece before 27 weeks' gestation 20 clinics randomized using computer-generated random tables, but analyzed based on individual women rather than clinics. Dietary intake unblinded. Discrepancies in sample size for different outcomes PROTEIN/ENERGY 3 Adair & Pollitt (5) Pre-pregnancy and pregnancy supplement containing 40 g protein and 800 kcal energy + vitamins & minerals versus supplement containing vitamin & minerals only 213 rural Taiwanese women with "marginal" diets (estimated daily protein intake <40 g) Allocation concealment method not specified. More than 20% missing data for some outcomes 4 Atton & Watney (6) Supplement containing 407 kcal energy + 14.6 g protein versus unsupplemented diet 148 non-obese Asian women. Noncompliers excluded from analysis. No data on total intake, which does not allow for detecting cases of substitution or redistribution in the family 5 Campbell Brown (7) Supplement containing 300 kcal energy + 15–20 g protein versus normal (unsupplemented) diet 180 Aberdeen primiparous women at high risk of low birth weight delivery starting approximately at 27 wk gestation Strict alternate allocation 6 Ceesay et al. (8) Two supplement biscuits containing 1017 kcal energy, 22 g protein, 56 g fat, 47 mg calcium and 1.8 mg iron consumed daily in presence of birth attendant versus no supplement 2082 rural Gambian women from 28 villages with "chronic" marginal nutritional status Cluster randomization by village using "a stratified design according to the village size". No details on method of random allocation or concealment 7 Elwood et al. (9) Tokens for free milk versus no intervention 1251 pregnant women in two small Welsh towns at first reporting of pregnancy Allocation concealment with sealed envelopes. 24% of subjects lost to follow-up (higher in the control group). Non-adjusted higher proportion of smokers in the control group 8 Girija et al. (10) Supplement containing 417 kcal energy + 30 g protein versus normal (unsupplemented) diet 20 poor Indian women in last trimester Alternate allocation 9 Iyenger (11) Hospitalization with hospital diet plus supplementation with 350 kcal energy, 35 g protein, iron and vitamins versus same treatment with no protein. 25 low socio economic status Indian women with low protein and energy intakes at 36 wk gestation Allocation method not reported 10 Kardjiati et al. (12) Supplement containing 465 kcal energy + 7.1 g protein versus supplement containing 52 kcal energy + and 6.2 g protein. 747 women in rural East Java at 26–28 wk gestation Blind randomization based on household numbers using random numbers table 11 Mardones-Santander et al. (13) High protein (22% of energy content) powdered milk supplement versus normal protein (12% of energy content) powdered milk supplement 782 low income Chilean women <20 wk gestation with low weight-for-height at 1st visit Alternated allocation 12 Mora et al. (14) Supplement containing 865 kcal energy + 38.4 g protein beginning in 3rd trimester versus normal (unsupplemented) diet 456 poor women from Bogota at 1st and 2nd trimester of pregnancy Allocation method not reported 13 Ross et al. (15) Supplement containing 700–800 kcal energy + 36–44 g protein versus placebo 127 black South African women <20 wk gestation Allocation method not reported 14 Ross et al. (16) Supplement containing 580 kcal energy + 60 g protein + vitamins and minerals versus regular institution diet ("barely adequate") 56 poor primiparous women from rural North Carolina with "marginal" (in quantity/quality of proteins) previous diet Alternate allocation 15 Rush et al. (17) Supplement containing 40 g protein + 470 kcal energy + vitamins & minerals versus supplement containing 6 g protein + 322 kcal energy + vitamin & minerals 1051 low-income black women in Harlem, New York City, at risk of low birth weight delivery Almost no data for 25% of women randomized due to lack of compliance, or lost to follow-up 16 Rush et al. (18) Supplement containing 6 g protein + 322 kcal energy + vitamins & minerals versus supplement containing vitamin & minerals only 530 low-income black women in Harlem, New York City, at risk of low birth weight delivery Stratified randomization based on a table of random numbers 17 Viegas et al. (19) Supplement containing 273 kcal energy + vitamins 18–28 wk gestation versus vitamins only 153 Asian women <20 wk gestation in Birmingham, Alabama Allocation method not reported 18 Viegas et al. (20) Supplement containing 425 kcal energy + vitamins 28–38 wk gestation versus vitamins only. 130 Asian women <20 wk gestation in Birmingham, Alabama Allocation method not reported ENERGY AND PROTEIN RESTRICTION 19 Badrawi et al. (21) Balanced low-energy diet (1500–2000 kcal/d) versus normal diet (2300–3000 kcal/d) 100 obese multiparous Egyptian women Allocation method not reported 21 Campbell (22) Low energy (1250 kcal/d) diet versus no intervention 13 obese primiparous Scottish women Allocation method not reported 20 Campbell & MacGillivray (23) Low energy (<1200 kcal/d) low carbohydrate diet versus no intervention 153 Scottish primiparous with high gestational weight gain Allocation method not reported SALT RESTRICTION 22 Knuist et al. (24) Low sodium diet (<50 mmol sodium/d) versus no changes in the usual diet 361 nulliparous before 20 wk gestation, DBP <90 mmHg Written dietary instructions given by a midwife. Allocation by sealed numbered opaque envelopes 23a van Buul et al. (25) Low sodium diet (20 mmol sodium/d) versus normal diet 270 nulliparous with singleton pregnancies after 12 wk gestation Oral and written instructions by dietician in the experimental arm. Allocation by "closed envelope system" no further information 23b Steegers et al (26) CALCIUM 24 Belizan et al. (27) 2 g/d calcium versus placebo 1194 healthy nulliparous women in Argentina at 20 wk gestation. Low calcium intake Overall trial well-designed and conducted. Double-blind placebo-controlled 25 Crowther et al. (28) 1.8 g/d calcium versus placebo Nulliparous with singleton pregnancies and blood pressure <140/90 mmHg Trial stopped prematurely for financial reasons. Estimated sample size 948. Data from 456 women 26 Levine et al. (29) 2 g/d calcium versus placebo All women in both groups took 50 mg calcium per day as normal supplementation 4589 primigravid women, from 13 to 21 wk, 5 centers in USA Compliance was 64% in the calcium group and 67% in the placebo group. 20% of women took >90% of the allocated treatment 27 Lopez-Jaramillo et al. (30) 2 g/d calcium versus placebo <24 wk pregnant, primigravid women in Ecuador. Low calcium intake Overall trial well-designed and conducted. Double-blind placebo-controlled 28 Lopez-Jaramillo et al. (31) 2 g/d calcium versus placebo Women at 18–30 wk of gestation at high risk of developing pregnancy hypertension. Low calcium intake Overall trial well-designed and conducted. Double-blind placebo-controlled 29 Lopez-Jaramillo et al. (32) 2 g/d calcium versus placebo 360 women <20 wk gestation in Ecuador. Low calcium intake Overall trial well-designed and conducted. Double-blind placebo-controlled 30 Niromanesh et al. (33) 2 g/d calcium versus placebo 30 women at high risk for preeclampsia recruited between at 28–32 wk 31 Purwar et al. (34) 2 g/d calcium versus placebo 201 healthy primigravid women <20 wk gestation. Low calcium intake Overall trial well-designed and conducted. Double-blind placebo-controlled 32 Sanchez-Ramos et al. (35) 2 g/d calcium versus placebo 63 angiotensin-sensitive nulliparous women in U.S., 20–24 wk gestation. Low calcium intake. Overall trial well-designed and conducted. Double-blind placebo-controlled 33 Villar & Repke (36) 2 g/d calcium versus placebo 190 healthy pregnant adolescents (17 years) in U.S., 23 wk 34 Villar et al. (37) 2 g/d calcium versus placebo 52 healthy nulliparous or primiparous women (34 black in U.S. and 18 white in Argentina) 18–30 y, 26 wk IRON AND FOLATE Iron and folate versus placebo/no treatment 35 Harrison (38) Iron (60 mg/d) and folic acid (1 mg/d) versus no treatment 228 adolescents before 24 wk, without hemoglobinopathy Double blind. This arm of comparison includes only 39 women (Exp. group:16 women, Control group:23 women) 36 Taylor et al. (39) Ferrous sulfate (325 mg) plus folic acid (350 µg) versus no treatment 48 women before 12 wk gestation, singleton pregnancies, without medical problems Alternate allocation Routine iron versus placebo/no treatment 37 Batu et al. (40) 60 mg elemental iron daily versus placebo 55 women <25 wk gestation Low serum iron (50 µg/L). Allocation method not clear 38 Chisholm (41) 30 mg iron three times a day + folic acid versus folic acid 120 women with Hb 102 g/L Randomization method not clear. Double blind 39 De Benaze et al. (42) Iron versus placebo 191 women recruited at first antenatal visit at 3 mo gestation Allocation method not clear. Double blind 40 Holly (43) Iron 300 mg/three times a day versus no treatment 149 women with Hb >100 g/L <26 wk gestation Randomization method not clear 41 Menon & Rayan (44) Iron + folic acid versus folic acid 185 women recruited between 16–24 wk gestation with no disease and Hb 10.5 g/dl 42 Milman et al. (45) 66 mg/d iron versus placebo 207 women with singleton and uncomplicated pregnancy <16 wk gestation Allocation method not clear. Double blind 43 Morgan (46) 100 mg elemental iron/d versus no treatment 356 participants with no previous hematinicsupplement. Treatment for at least 6 wk. Hb 10.5 g prior to supplementation Allocation according to day of week. Patients in the iron group who did not take iron were excluded from the analysis, thus the discrepancy in the treatment and the control group 44 Paintin et al. (47) 35 mg iron three times a day versus placebo 99 primigravid women >20 wk gestation. Hb >100 g/L 45 Preziosi et al. (48) 100 mg/d iron versus placebo 197 women at 28 wk gestation attending the first antenatal visit. No complications 46 Pritchard & Hunt (49) Ferrous sulfate 300 mg three times a day versus placebo 90 women in late second trimester. Hb >100 g/L 47 Romslo et al. (50) 200 mg iron versus placebo 55 women with normal singleton pregnancy recruited <10 wk gestation Allocation method not clear. Double blind 48 Willoughby & Jewell (51) 105 mg/d iron versus no iron 124 women with Hb >100 g/L Allocation according to hospital number Routine versus selective iron 49 Hemminki & Rimpela (52) 100 mg elemental iron/d if Hb <100 g/L or Hct <30 on 2 consecutive visits with low iron versus routine 100 mg iron to all from 17th wk Women with singleton pregnancy from 21 health centers and 51 midwives. No chronic illness and Hb >110 g/L or Hct >32 from 17th wk gestation Allocation method not clear. Double blind Routine folate (see also Trials No. 37, 38, 41) 50 Baumslang et al. (53) Folic acid 5 mg versus no folate 128 South African women with singleton recruited at 24–28 wk. All received 200 mg/day iron Low birth weight defined as 5 lb 51 Blot et al. (54) 350 µg folic acid/d versus placebo 109 women. All received iron and vitamin C daily Randomization method not clear. Double blind. 52 Fleming et al. (55) 5 mg folic acid fortnightly then weekly versus placebo 53 primigravid <23 wk gestation. Sickle cell disease excluded. All receiving iron Alternate allocation. Double blind 53 Fletcher et al. (56) 5 mg folic acid versus no folate 643 women at their first antenatal visit, all receiving ferrous sulfate 200 mg Randomization method not clear 54 Giles & Burton (57) 15 mg/d folic acid versus no folic acid 1479 women with singleton pregnancies <28 wk gestation Alternate allocation 55 Giles et al. (58) 5 mg/d folic acid versus placebo 620 women at first antenatal visit 56 Rae & Robb (59) 500 µg folic acid/3 times a day versus placebo 698 women from a low socioeconomic population. All received iron Randomization by day of week 57 Rolschau et al. (60) 500 ug folic acid/d versus no folic acid 40 Danish women 21–25 wk gestation (Hemoglobin 105 g/L) Randomization method not clear. Double blind. 58 Trig et al. (61) 0.5 mg folic acid/d versus no folic acid 158 women at first prenatal visit. All women received iron supplementation Alternate allocation Iron plus folate (see also Trials No. 35) 59 Fleming et al. (62) 60 mg/d iron + 1 mg/d folic acid versus no treatment 80 primiparous women <24 wk gestation 60 Foulkes & Goldie (63) 100 mg iron + 350 µg folic acid/d versus no treatment 501 women with singleton pregnancy attending antenatal clinic <16 wk gestation with serum ferritin >12 µg/L Randomization method not clear 61 Taylor et al. (64) 100 mg/day iron + 350 µg/d folic acid versus no treatment 501 women with singleton pregnancy recruited before 16 wk. Serum ferritin <12 µg/L Randomization method not clear Treatment of anemia 62 Singh et al. (65) Intravenous versus oral iron 100 pregnant women with iron deficiency anemia MAGNESIUM 63 Arikan et al. (66) 15 mmol magnesium citrate/d 530 women with low-risk pregnancies Only abstract available. Recruitment method not clear 64 D'Almeida et al. (67) 500 mg magnesium oxide daily from 4 mo gestation versus polyunsaturated fatty acid (placebo) 100 women completed the trial–total number randomized unknown Randomization by ‘random number table. Placebo group had significantly better dietary intake 65 Kovacs et al. (68) 15 mmol magnesium aspartate/d versus placebo 985 women with single pregnancies. Subjects recruited 6–21 wk gestation 66 Martin et al. (69) 4 g magnesium gluconate/d versus placebo 54 women with risk factors for preterm delivery recruited at 23 wk gestation Randomization method not given 67 Sibai et al. (70) Magnesium aspartate hydrochloride in a daily dose of 365 elemental magnesium versus placebo 400 normotensive primigravid women in USA Double-blind with coded drugs 68 Spatling & Spatling (71) 15 mmol magnesium-aspartate-hydrochloride/d versus placebo containing 13.5 mmol aspartic acid 568 low- and high-risk women attending outpatient clinic, Department of Obstetrics, University of Zurich, Switzerland Quasirandom allocation (birth date) FISH OIL 69 Bulstra-Ramakers et al. 1 (72) Eicosapentaenoic acid (0.25 mg) or placebo three times daily 63 pregnant women with history of IUGR, with or without history of pregnancy induced hypertension Double-blind placebo-controlled 70a Olsen et al. 1 (73) 2.3 g/d n–3 fatty acids versus placebo (olive oil) in the prophylactic trials; and 6.1 g/d n–3 fatty acids versus placebo (olive oil) in the therapeutic trials 4 prophylactic trials: EARL–PD: 232 pregnant with history of preterm delivery, EARL–IUGR: 280 women with history of IUGR, EARL–PIH: 386 women with history of pregnancy-induced hypertension, and TWINS trial: 579 women with uncomplicated twin pregnancies; and 2 therapeutic trials: TREAT–PE: 79 women with pre-eclampsia, and SUSP–IUGR: 63 women with suspected IUGR in the current pregnancy Randomized, double blind, placebo-controlled trial. 19 Centers in Denmark, Scotland, Sweden, England, Italy, The Netherlands, Norway, Belgium and Russia. Pregnant women were eligible if they belonged to one of the trial groups. All centers recruited for the six trials. All six trials were mutually exclusive 70b Olsen et al. 1 (74) 71 Onwude et al. 1 (75) 2.7 g MaxEpa daily (1.62 g eicosapentaenoic acid and 1.08 g Docosahexaenoic acid) versus placebo 233 pregnant women at high risk of developing pregnancy hypertension or IUGR Double-blind placebo-controlled trial 72 People's League of Health (76) Experimental group received 0.36 g/d halibut liver oil, vitamins, and minerals Large, multicenter trial conducted in London, UK Alternate allocation, no blinded assessment of outcomes 73 Salvig et al. 1 (77) Random assignment at a ratio of 2:1:1 to fish oil [four 1 g Pikasol capsules (containing 2.7 g n–3 fatty acids) per day], olive oil (four 1 g capsules/d), or no supplement 533 healthy women at 30 wk gestation attending the main midwife clinic in Aarhus, Denmark Well designed trial but evidence that women allocated to olive oil were less likely to increase their fish consumption than women allocated to no oil; olive oil may also have effects so far not reported ZINC 74 Caulfield 1 et al. (78) 30 mg zinc/d versus placebo 1016 pregnant women in urban shantytown in Peru. Recruited 10–24 wk pregnant. All women received iron and folic acid Fetal neurobehavioral development assessed in a subsample of 55 women 75 Christian 1 et al. (79) 25 mg zinc/d versus placebo 202 Nepalese women with reported night blindness and enrolled in vitamin A supplementation trial 76 Dijkhuizen & Wieringa 2 (80) 30 mg zinc/d versus placebo 229 women in West Java. 77 Goldenberg et al. (81) 25 mg zinc/d versus placebo 580 Afro American women in the US <19 wk gestation with low plasma zinc levels. All women received non zinc multivitamin. No medical problems reported 78 Hunt et al. (82) 20 mg zinc/d versus placebo 213 Hispanic low-income women attending a prenatal clinic in Los Angeles, USA. All women received vitamins Double-blind with few exclusions after entry. Sample size inadequate to confirm or reject an effect on any specific pregnancy outcome 79 Jonsson et al. (83) 44 mg zinc/d versus placebo 2000 healthy middle-class women Danish women <20 wk pregnant. Gestational age confirmed by sonography Excluded 40% of participants due to for poor compliance 80 Mahomed et al. (84) 20 mg daily/d versus placebo 494 women <20 wk pregnant booking for delivery in Bristol, UK Double-blind with few exclusions after entry. Sample size inadequate to confirm or reject an effect on any specific pregnancy outcome 81 Merialdi2 (85) 25 mg zinc/d versus placebo 242 women in an urban shantytown in Peru. Recruited 10–16 wk gestation. All women received iron and folic acid 82 Osendarp 1 et al. (86) 30 mg zinc/d versus placebo 559 urban poor Bangladeshi women recruited 12–16 wk gestation 83 Robertson et al. (87) 62 mg zinc/d versus no zinc 134 women <18 wk gestation. All women received iron and folate 84 Ross et al. (15) 30–90 mg zinc/d versus placebo 55 women South African Zulu women <20 wk pregnant attending a prenatal clinic 90% of the study subjects followed up to term. Analysis includes only the comparison between the groups receiving zinc and placebo 85 Simmer et al. (88) 22.5 mg zinc/d versus placebo 56 pregnant women at risk of delivering a SGA baby in London, UK Double-blind with few exclusions after entry. Sample size inadequate to confirm or reject an effect on any specific pregnancy outcome VITAMINS 86 Brooke (89) 1000 IU/day vitamin D versus placebo in the third trimester until delivery First generation Asian women in London Method of random allocation not specified 87 Chappell et al. 3 (90) 1000 mg/d vitamin C + 400 IU/d vitamin E versus placebo 283 women at high risk of pre-eclampsia Double-blind placebo-controlled trial. 88 Howells et al. 3 (91) 8000 IU/d vitamin A (retinyl palmitate) + vitamin D versus vitamin D 29 Asian women attending an antenatal clinic in London with serum retinol levels <1.24 µmol/l. Subjects recruited at 28 wk Randomized trial 89 Mallet (92) 29 women received 1000 IU/day vitamin E in the last trimester, 27 women received a single dose of 200,000 IU vitamin E, and 29 women were controls (no placebo). French women pregnant during the winter months in the northern region of the country 90 Semba et al. (93) 3000 µg vitamin A/d + iron and folate versus iron and folate 115 women attending an antenatal clinic 91 Suharno et al. 3 (94) Vitamin A (2.4 mg retinol) versus 60 mg elemental iron versus vitamin A + iron versus placebo 251 women recruited at 16–24 wk in rural West Java Randomized double masked trial 92 West et al. 3 (95) 7000 µg retinol equivalent vitamin A versus 7000 µg retinol equivalent beta-carotene versus placebo all weekly 44,646 married women of childbearing age living with their husbands in 270 wards in Sarlahi district, Nepal. Cluster randomized, double-blind trial

¹ published after the last update of the Cochrane library systematic review

² published as doctoral dissertation

³ trial identified separately not from published systematic review. IUGR, intrauterine growth restriction; Hb, hemoglobin; Hct, hematocrit

	FOOTNOTES

 
¹ Manuscript prepared for the USAID-Wellcome Trust workshop on "Nutrition as a preventive strategy against adverse pregnancy outcomes," held at Merton College, Oxford, July 18–19, 2002. The proceedings of this workshop are published as a supplement to The Journal of Nutrition. The workshop was sponsored by the United States Agency for International Development and The Wellcome Trust, UK. USAID's support came through the cooperative agreement managed by the International Life Sciences Institute Research Foundation. Supplement guest editors were Zulfiqar A. Bhutta, Aga Khan University, Pakistan, Alan Jackson (Chair), University of Southampton, England, and Pisake Lumbiganon, Khon Kaen University, Thailand.

² The views expressed in this document are solely the responsibility of the authors and do not necessarily represent the views of the World Health Organization or its member states.

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