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Vitamin supplementation for preventing miscarriage

  1. Alice Rumbold1,*,
  2. Philippa Middleton2,
  3. Caroline A Crowther3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 20 APR 2005

Assessed as up-to-date: 1 FEB 2005

DOI: 10.1002/14651858.CD004073.pub2


How to Cite

Rumbold A, Middleton P, Crowther CA. Vitamin supplementation for preventing miscarriage. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD004073. DOI: 10.1002/14651858.CD004073.pub2.

Author Information

  1. 1

    Menzies School of Health Research, Casuarina, NT, Australia

  2. 2

    The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

  3. 3

    The University of Adelaide, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

*Alice Rumbold, Menzies School of Health Research, PO BOX 41096, Casuarina, NT, 0820, Australia. alice.rumbold@menzies.edu.au.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 20 APR 2005

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This is not the most recent version of the article. View current version (19 JAN 2011)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Miscarriage or pregnancy loss within the first 20 weeks of gestation is a frequent complication of pregnancy, with 12% to 16% of all clinically recognised pregnancies ending in miscarriage (Everett 1997; Regan 1989). Recurrent miscarriage, defined as the occurrence of three or more consecutive spontaneous miscarriages, affects one to two per cent of women of reproductive age (Coulam 1991). Miscarriage is associated with significant maternal morbidity including haemorrhage and infection and, in some cases, maternal death (NHMRC 2001), with maternal death more common in countries that are resource-poor (Goyaux 2001). Women experiencing miscarriage may suffer significant psychological and emotional stress. Grief experienced by women and their families can be complicated by feelings of self-blame, anxiety and depression, and social withdrawal and marital disturbances may result (Lee 1996). This emotional distress may be further compounded when women experience recurrent miscarriage.

Care of women suffering miscarriage is complicated by different definitions, disagreement on its validity as a clinical disorder and poor quality data on women not requiring hospital or outpatient treatment. Miscarriage can be caused by a wide range of factors and determining the aetiology of miscarriage is often difficult, with a variety of underlying mechanisms being potentially responsible. Up to two thirds of early pregnancy losses (miscarriage before 12 weeks' gestation), are associated with chromosomal abnormalities (Stern 1996). While early miscarriages are more likely to be associated with chromosomal abnormalities and defective placental development, late miscarriage (miscarriage occurring between 12 and 20 weeks' gestation) may be more likely due to structural problems of the uterus and/or cervix, such as cervical incompetence. Women experiencing recurrent miscarriage may often have an underlying medical condition such as autoimmune disease, i.e. systemic lupus erythematosus and antiphospholipid syndrome, or other blood clotting disorders such as hyperhomocysteinemia (high levels of homocysteine in the blood) or another thrombophilia (Preston 1996) . Recurrent miscarriage is thought to involve an underlying placental vascular pathology seen also in pre-eclampsia, intrauterine growth restriction and placental abruption (Ray 1999). Current therapies being considered for the prevention of miscarriage include progesterone and immunotherapy and these topics are covered in other Cochrane reviews (Oates-Whitehead 2003; Scott 2003).

Vitamins are essential nutrients required for a range of functions in the body. Vitamins are either water soluble, such as vitamin C and the B group vitamins (including folate) or fat soluble such as vitamin A, D, E and K. Vitamins are obtained from the diet and also from dietary supplements of either individual vitamin preparations or a multivitamin preparation. Multivitamins contain a range of vitamins and minerals usually in doses similar to the recommended dietary intakes. Folate, vitamin B6 and vitamin B12 have been recommended for women with hyperhomocysteinemia, and therefore supplementation may influence the risk of spontaneous miscarriage in these women. Similarly, oxidative stress, where there is overproduction of reactive oxygen molecules leading to decreased levels of antioxidants, has been linked to spontaneous and recurrent miscarriage (Jauniaux 2000; Simsek 1998). Therefore, intake of antioxidant vitamins such as vitamin C and vitamin E may be an important factor associated with the risk of miscarriage. One observational study has demonstrated an association between the risk of spontaneous early miscarriage and dietary factors, with a high risk associated with poor intake of green vegetables, fruit and dairy products coupled with a high intake of fat (Di Cintio 2001). Little information is available about the impact of vitamins on the risk of early versus late miscarriage, however, dietary factors could theoretically influence structural abnormalities such as cervical incompetence. There is a growing body of research investigating the relationship between nutrition and placental development, fetal growth, pregnancy outcomes and adult diseases (Godfrey 1996; Morris 2001; NRC 1989). Therefore, adequate maternal nutrition, particularly vitamin intake, may be an important factor in preventing spontaneous miscarriage. There is currently little information about the most appropriate vitamin type or combination; therefore, this review will cover all vitamin types. Similarly, many commercially available vitamin preparations contain a range of combinations of vitamins; therefore, this review will pool all vitamin types together initially to determine overall if any vitamins and any improvement in maternal nutrition helps to prevent miscarriage. Individual vitamin types will also be discussed separately.

The use of any vitamin supplements in pregnancy needs to be carefully monitored and evaluated for safety and efficacy. This is particularly true for early pregnancy use, where there is the potential for teratogenicity. High maternal levels of preformed vitamin A (retinoic acid) are known to induce spontaneous miscarriage and malformations involving the central nervous systems and cardiac development (WHO 1998). Potential teratogenic effects of other vitamins have not been reported. In contrast, folate supplementation and multivitamin supplementation have been associated with a decreased risk of neural tube defects (Lumley 2001b). Periconceptional folate and multivitamin supplementation for the prevention of neural tube defects has been covered in another Cochrane review (Lumley 2001b). Concerns have been raised about the impact of folate and multivitamin supplementation on the rate of multiple births (Lumley 2001a; Lumley 2001b); however, further research is needed to establish a direct causal relationship. Potential side-effects of vitamins can occur with hypervitaminosis (excessive ingestion of one or more vitamins). Hypervitaminosis A (vitamin A poisoning) has been associated with irritability, fatigue, changes in the skin, hair loss, headache, and abdominal discomfort (Olsen 1999). Similarly hypervitaminosis D (vitamin D poisoning) has been associated with nausea, vomiting, weakness, disturbed digestion, and elevated blood and tissue calcium levels (Olsen 1999). For vitamin E, non-randomised controlled clinical trials of vitamin E supplementation in a variety of doses have failed to demonstrate any consistent side-effects (Bendich 1993). However, there has been limited evaluation of the use of these and other vitamins in pregnancy. While water soluble vitamins such as vitamin C and the B group vitamins are easily excreted by the body, the fat soluble vitamins A, D, E and K may accumulate in the body and in the developing fetus. The safety of using these vitamins needs to be clearly demonstrated before they can be recommended for routine antenatal care.

The aims of this review are to identify all published and unpublished randomised controlled trials that investigate vitamins for the prevention of miscarriage and to assess the benefits and hazards of women using vitamins for the prevention of miscarriage.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

The objectives of this review are:
(1) to determine the effectiveness and safety of any vitamin supplementation taken by women prior to conception, periconceptionally and in early pregnancy on the risk of:
(a) spontaneous miscarriage;
(b) maternal adverse outcomes;
(c) fetal and infant adverse outcomes.

(2) If vitamins are effective, to determine which of these agents are best and to compare vitamins with other interventions.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All randomised trials and quasi-randomised trials comparing one or more vitamins with either placebo, other vitamins, no vitamins or other interventions, prior to conception, periconceptionally or in early to mid-pregnancy.

 

Types of participants

Pregnant women (less than 20 weeks' gestation) or women in the reproductive age group planning on becoming pregnant in the near future, regardless of whether they are at low or high risk of having a miscarriage.

 

Types of interventions

Comparisons of any vitamin(s) alone or in combination with other agents with either placebo, other vitamin(s), no vitamin(s) or other interventions for the prevention of miscarriage, either in areas where there is inadequate dietary intake or where there is presumed adequate intake of that vitamin(s).

 

Types of outcome measures

 

Main outcomes

 
For the woman

  1. Fetal loss, incidence of early and late miscarriage (early miscarriage defined as spontaneous pregnancy loss less than 12 weeks' gestation, late miscarriage defined as spontaneous pregnancy loss greater than or equal to 12 and less than 20 weeks).
  2. Placental abruption.
  3. Pre-eclampsia.
  4. Psychological effects (anxiety and depression).

 
For the infant

  1. Stillbirth, perinatal or neonatal death.
  2. Preterm birth (defined as birth less than 37 weeks' gestation).
  3. Birthweight.
  4. Small-for-gestational age (birthweight less than the third centile or the most extreme centile reported).
  5. Congenital malformations.

 

Other outcomes

  1. Multiple pregnancy (including only trials supplementing women prior to or around the time of conception).
  2. Very preterm birth (defined as less than 34 weeks' gestation).
  3. Apgar score less than seven at five minutes.
  4. Use of blood transfusion for the mother.
  5. Anaemia (maternal and infant).
  6. Placental weight.
  7. Methods of feeding: breastfeeding, formula or both.
  8. Subsequent fertility (subsequent pregnancy rate per couple or as defined by the authors).
  9. Poor growth at childhood follow up.
  10. Disability at childhood follow up.
  11. Adverse effects of vitamin supplementation sufficient to stop supplementation, such as manifestations of hypervitaminosis, headache, nausea, vomiting, diarrhoea.
  12. Maternal views of care.

 

Use of health service resources

  1. Gynaecological hospital admission.
  2. Admission to neonatal intensive care unit.
  3. Healthcare costs.

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group Trials Register by contacting the Trials Search Co-ordinator (8 September 2004).

The Cochrane Pregnancy and Childbirth Group's Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
  2. monthly searches of MEDLINE;
  3. handsearches of 30 journals and the proceedings of major conferences;
  4. weekly current awareness search of a further 37 journals.

Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via
the current awareness service can be found in the 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co-ordinator searches the register for each review using these codes rather than keywords.

In addition, we searched CENTRAL (The Cochrane Library Issue 2, 2003) for the following terms: miscarriage*, spontaneous abortion, recurrent abortion, spontaneous pregnancy loss, recurrent pregnancy loss, fetal death, vitamin*, folate, folic acid.

We searched MEDLINE (1966 to May 2003), Current Contents (1998 to May 2003) and EMBASE (1980 to May 2003) for potentially eligible studies, using the search strategy in Appendix 1.

We did not apply any language restrictions.

 

Data collection and analysis

Two review authors assessed potentially eligible trials found after the literature search for their suitability for inclusion in the review. Decisions regarding inclusion were made separately and results compared. Any disagreement was resolved through discussion. Trials that supplemented women in early and mid pregnancy were considered eligible for inclusion. Supplementation occurring in mid pregnancy was not specified in the original protocol for this review, however, this was amended to be in line with other miscarriage reviews such as 'Progestogen for preventing miscarriage' (Oates-Whitehead 2003). Similarly, we specified in the original protocol that we would exclude studies reporting greater than 20% losses to follow up. In this review we have included studies that reported more than 20% losses to follow up and undertaken further analyses based on various aspects of trial quality, including the percentage of losses to follow up reported.

The authors deemed it important to include any supplementation trials, where supplementation began prior to 20 weeks' gestation, and where at least one main outcome as specified in the review was reported, even if the intervention was not specifically for the prevention of miscarriage. We excluded trials where the onset of supplementation occurred definitely after 20 weeks' gestation. We included trials where the onset of supplementation occurred both prior to and after 20 weeks' gestation, and when it could not be established whether the majority of the women started supplementation prior to 20 weeks' gestation. Where trials recruited women prior to becoming pregnant, we reported the denominators for each trial as all women randomised; or where there was accurate information about the number of women in each trial who became pregnant, we reported the denominators as the number of women randomised and with a confirmed pregnancy. Two authors extracted data using an agreed format, and again we resolved discrepancies through discussion. We entered and double checked the data.

We assessed the validity of each included trial according to the criteria outlined in the Cochrane Reviewers' Handbook (Alderson 2004). We assessed trials with a grade allocated to each trial on the basis of allocation concealment: A (adequate), B (unclear) or C (inadequate). Where the method of allocation concealment was unclear, we attempted to contact authors to provide further details.

We assessed blinding, completeness of follow up and placebo control for each outcome using the following criteria.

For completeness of follow up:
A. less than three per cent of participants excluded;
B. three per cent to 9.9 per cent of participants excluded;
C. ten per cent to 19.9 per cent of participants excluded;
D. greater than or equal to 20 per cent of participants excluded.

For blinding of assessment of outcome:
A. double blind, neither investigator nor participant knew or were likely to guess the allocated treatment;
B. single blind, either the investigator or the participant knew the allocation. Or, the trial is described as double blind, but side-effects of one or other treatment mean that it is likely that for a significant proportion (equal to or greater than 20 per cent) of participants the allocation could be correctly identified;
C. no blinding, both investigator and participant knew (or were likely to guess) the allocated treatment;
D. unclear.

For use of placebo control:
A. placebo controlled;
B. unclear whether placebo controlled;
C. no placebo control.

We carried out statistical analyses using the Review Manager software (RevMan 2004), with results presented as summary relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes. We adopted a generic inverse variance approach for the meta-analyses for dichotomous outcomes where trials using cluster-randomisation techniques were included (Alderson 2004). We applied tests of heterogeneity between trials to assess the significance of any differences between trials (I2 greater than or equal to 50%) and we explored possible causes of heterogeneity. We calculated summary relative risks using a fixed-effect model. If heterogeneity was detected, we performed subgroup analyses for the main outcomes by risk of miscarriage, time of trial entry, type of vitamin used, vitamin dosage, use of placebo, adequacy of prior dietary intake of vitamins. We modelled heterogeneity that was not explained by subgroup analyses using a random-effects analysis.

Where possible, women were classified into subgroups based on:

  1. their risk of spontaneous miscarriage (high risk defined as the presence of medical conditions associated with miscarriage such as hyperhomocysteinemia, thrombophilia, antiphospholipid syndrome, systemic lupus erythematosus; low risk defined as none of the above conditions);
  2. their risk of recurrent miscarriage (high risk defined as two or more previous consecutive spontaneous miscarriages, and or the presence of medical conditions associated with miscarriage such as hyperhomocysteinemia, thrombophilia, antiphospholipid syndrome, systemic lupus erythematosus; low risk defined as none of the above conditions);
  3. the dose of vitamin(s) (below or above the recommended dietary intake);
  4. the duration of vitamin usage;
  5. low or adequate dietary vitamin intake at trial entry (low intake defined as less than the recommended daily intake for each vitamin in that setting, as measured by dietary questionnaire).

All included trials were included in the initial analyses which were performed by any vitamin to include all vitamin combinations and then by individual vitamin type. We carried out sensitivity analyses to explore the effect of trial quality. This involved analysis based on an A, B or C rating of allocation concealment, blinding of assessment of outcome and placebo control. We compared the results of high-quality studies with those of poorer quality studies, where studies rated A were compared with those rated B or C.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

See tables 'Characteristics of included studies' and 'Characteristics of excluded studies' for details of individual studies.

 

Excluded studies

Thirty-five trials were excluded, of which twelve reported no clinically meaningful data in a format suitable for inclusion (Hibbard 1968; Laurence 1981; Lira 1989; Meirinho 1987; Mock 2002; Moldenhauer 2002; Semba 2001; Suharno 1993; Tanumihardjo 2002; Thauvin 1992; Villamor 2002; Vutyavanich 1995). Eight trials did not clearly report the gestational age when supplementation was started (Biswas 1984; Fletcher 1971; Hampel 1974; Lumeng 1976; Schuster 1984; Trigg 1976 ) or did not report outcomes separately for women starting supplementation prior to 20 weeks (Ferguson 1955; Giles 1971). Eleven trials (Baumslag 1970; Blot 1981; Chanarin 1968; Colman 1974; Coutsoudis 1999; Dawson 1962; Edelstein 1968; Hankin 1966; Marya 1981; Metz 1965; Owen 1966) reported supplementation after 20 weeks' gestation. One trial (Ross 1985) did not specify the contents of the supplements, while one trial was excluded as all women were given the supplement and there was no appropriate control (Hunt 1984) and two were non-randomised (Smithells 1981; Ulrich 1999).

Three other trials (Beazley 2002; Chaudhuri 1969; Rivas 2000) supplemented women for the prevention of pre-eclampsia, and did not report any outcomes related to pregnancy loss. These trials are covered in the Cochrane review 'Antioxidants for preventing pre-eclampsia' (Rumbold 2003).

 

Included studies

We identified seventeen trials assessing supplementation with any vitamin(s) starting prior to 20 weeks' gestation. The included trials involved 35,812 women, and some of these women were pregnant more than once in the study period, resulting in data being contributed for 37,353 pregnancies in total. Many of the trials assessed interventions not specifically for the prevention of miscarriage. Four of the included studies were assessing folic acid supplementation for the prevention of neural tube defects (Czeizel 1994; ICMR 2000; Kirke 1992; MRC 1991). For the purpose of this review however, the authors deemed it important to include any supplementation trials, where supplementation began prior to 20 weeks' gestation, and where at least one main outcome as specified in the review was reported.

 

Participants

The demographic and obstetric characteristics of women varied widely between the trials (See table 'Characteristics of included studies'), as did the gestational age at trial entry and the type of supplements. Some trials enrolled women prior to conception (Czeizel 1994; Hemmi 2003; ICMR 2000; Kirke 1992; MRC 1991) and asked women to continue taking the supplements up until the second or third missed menstrual period. One trial (Katz 2000) supplemented women from before to conception, through pregnancy and up to 3.5 years postpartum. Other trials enrolled women in the first trimester (Briscoe 1959) or in early to mid pregnancy (Chappell 1999; Correia 1982; Fawzi 1998; Fleming 1968; Kumwenda 2002; People's League 1942; Rush 1980; Schmidt 2001; Steyn 2003). Two trials (Fawzi 1998; Kumwenda 2002) involved vitamin A supplementation in women seropositive for the Human Immunodeficiency Virus. The trials were conducted in both resource-rich and resource-poor countries including the United States (Briscoe 1959; Rush 1980), United Kingdom (Chappell 1999; People's League 1942), Portugal (Correia 1982), Hungary (Czeizel 1994), Tanzania (Fawzi 1998), Nigeria (Fleming 1968), Japan (Hemmi 2003), India (ICMR 2000), Nepal (Christian 2003; Katz 2000), the Republic of Ireland (Kirke 1992), Malawi (Kumwenda 2002), Indonesia (Schmidt 2001), South Africa (Steyn 2003) and one trial involved 33 international centres (MRC 1991).

 

Interventions

The seventeen trials assessed a range of vitamin supplements, alone or in combination with other supplements. The vitamins included vitamin A, alone or with iron, folate, zinc or multivitamins (Christian 2003; Fawzi 1998; Katz 2000; Kumwenda 2002; Schmidt 2001), vitamin C with or without multivitamins or vitamin E (Briscoe 1959; Chappell 1999; Hemmi 2003; Steyn 2003), folate with or without multivitamins and/or iron (Correia 1982; Czeizel 1994; Fleming 1968; ICMR 2000; Kirke 1992; MRC 1991) and multivitamins alone (People's League 1942; Rush 1980). The doses of vitamins were similar for the vitamin C supplementation trials (range 400 mg to 1000 mg). However, they varied widely between trials for the folate (range 0.3 mg to 10 mg), multivitamins and vitamin A trials (range 5000 international units (IU) to 23,300 IU).

Data from six trials could not be included in the analysis of 'any vitamins versus no or minimal vitamins' because the trials either had more than two treatment arms or compared one or more vitamin interventions with each other. For example, one trial (Fawzi 1998) using a 2 x 2 factorial design compared vitamin A supplements with or without multivitamins versus multivitamins (excluding vitamin A) or placebo. However, results were not explicitly presented for each group. Similarly, two trials (Kumwenda 2002; Schmidt 2001) compared vitamin A supplements with iron and folate versus iron and folate alone, and one trial with five treatment arms (Christian 2003) compared multivitamins with iron, folate and vitamin A verus iron, folate and vitamin A alone. Other trials compared folic acid alone with multivitamins plus folic acid or multivitamins excluding folic acid (Kirke 1992) or multivitamins with vitamin E compared with multivitamins without vitamin E (Rush 1980). Data from these trials were used only in the subanalyses according to vitamin type as none of the treatment arms were comparable to the control groups used in the trials included in the 'any vitamins versus no or minimal vitamins' comparisons.

 

Outcomes

 

Main outcomes

Fifteen trials reported either pregnancy loss as miscarriage or stillbirth. Two trials (Christian 2003; Correia 1982) were included as they reported main outcomes (perinatal death, neonatal death, infant death, preterm birth, birthweight, small-for-gestational age), however, information on miscarriage or stillbirth was either not reported separately or at all. The outcome 'total fetal loss' included both miscarriage or stillbirth, and overcame problems with different definitions of miscarriage and stillbirth. For some trials, miscarriage was considered to occur up until 26 or 28 weeks' gestation, while other studies reported miscarriage as pregnancy loss prior to 20 weeks' gestation, and stillbirth as pregnancy loss greater or equal to 20 weeks' gestation. Other studies did not specify their definition of miscarriage or stillbirth. For the other main outcomes for the mother, one trial reported placental abruption (Chappell 1999), and another trial (Steyn 2003) reported antepartum haemorrhage including placental abruption. Four trials (Chappell 1999; Fleming 1968; People's League 1942; Steyn 2003) reported pre-eclampsia or 'toxaemia', no trials reported any psychological effects. For the infant, perinatal death was reported in two trials (Christian 2003; Steyn 2003), neonatal death in six trials (Christian 2003; Czeizel 1994; Katz 2000; People's League 1942; Rush 1980; Steyn 2003), preterm birth in seven trials (Chappell 1999; Christian 2003; Czeizel 1994; Fleming 1968; Katz 2000; Rush 1980; Steyn 2003), birthweight in four trials (Christian 2003; Correia 1982; Czeizel 1994; Kumwenda 2002), small-for-gestational age in six trials (Chappell 1999; Christian 2003; Czeizel 1994b; Fawzi 1998; Fleming 1968; ICMR 2000) and congenital malformations in three trials (Czeizel 1994; Kirke 1992; MRC 1991). In this review, congenital malformations covered malformations excluding neural tube defects, as these are covered in the Cochrane review 'Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects' (Lumley 2001b).

 

Other outcomes

Five trials reported multiple pregnancy (Czeizel 1994b; Fleming 1968; ICMR 2000; Katz 2000; Kumwenda 2002), one trial reported very preterm birth (Steyn 2003), one trial reported infant anaemia at six weeks and 12 months (Kumwenda 2002), one trial reported placental weight (Correia 1982) and another trial reported on weight and length at six weeks and four months (Kumwenda 2002). One trial also reported on mode of feeding as the number of women breastfeeding (People's League 1942). The following outcomes were not reported by any of the trials: Apgar score less than seven at five minutes, use of blood transfusion for the mother, maternal anaemia, subsequent fertility, disability at childhood follow up, adverse effects of supplementation, and maternal views of care. One trial (Steyn 2003) reported on the duration of admission to the neonatal intensive care unit, however, no trials reported any other measures of use of health service resources.

 

Additional outcomes

One trial (Steyn 2003) reported birthweight as the median birthweight and range; however, these data were not in a format suitable for inclusion in the birthweight comparisons (see  Table 1). One trial (Christian 2003) reported infant death and this outcome has been included in the 'other outcomes reported' for the multivitamin and folic acid comparisons .

 

Risk of bias in included studies

 

Randomisation

Two trials (Fleming 1968; People's League 1942) used quasi-random allocation methods involving alternate allocation of participants. Similarly, two trials (Christian 2003; Katz 2000) used cluster randomisation to allocate subdistricts within Nepal to each treatment arm and randomised women by "drawing numbered identical chits from a hat, blocked on subdistrict".

 

Allocation concealment

Concealment of allocation was reported in five trials by either the use of opaque sealed envelopes (Kirke 1992) or third party randomisation, where participants were randomly allocated to each group either by an individual not directly involved in the research or via telephone or computer allocation (Chappell 1999; Kumwenda 2002; MRC 1991; Steyn 2003). Of the remaining twelve trials, the degree of concealment was unclear for ten trials including the two cluster trials (Briscoe 1959; Christian 2003; Correia 1982; Czeizel 1994; Fawzi 1998; Hemmi 2003; ICMR 2000; Katz 2000; Rush 1980; Schmidt 2001) and for two trials was inadequate (Fleming 1968; People's League 1942).

 

Losses to follow up

Two trials did not report on losses to follow up (Briscoe 1959; Steyn 2003). Where reported, losses to follow up were less than three per cent for four trials (Chappell 1999; Czeizel 1994; Katz 2000; Kirke 1992), three to 9.9 per cent for two trials (Fawzi 1998; MRC 1991) and ten to 19.9 per cent for five trials (Christian 2003; Hemmi 2003; Kumwenda 2002; People's League 1942; Schmidt 2001). Four trials (Correia 1982; Fleming 1968; ICMR 2000; Rush 1980) had greater than 20 per cent of participants excluded.

 

Blinding

Seven trials reported that women and their carers and/or study investigators were blinded to the treatment allocation (Briscoe 1959; Chappell 1999; Christian 2003; Fawzi 1998; Fleming 1968; Katz 2000; MRC 1991); however, few studies explicitly reported that outcome assessors were blind to the treatment allocation. Four trials used the term "double blinded" but gave no details (Correia 1982; ICMR 2000; Schmidt 2001, Steyn 2003); for two trials participants were blinded (Kirke 1992; Kumwenda 2002); and for four trials it was unclear who, if any, was blinded (Czeizel 1994; Hemmi 2003; People's League 1942; Rush 1980).

 

Use of placebo

A placebo was given in eight trials (Briscoe 1959; Chappell 1999; Correia 1982; Fawzi 1998; ICMR 2000; Katz 2000; MRC 1991; Steyn 2003); seven trials gave a control tablet containing either trace elements, iron, zinc or other vitamins (Christian 2003; Czeizel 1994; Fleming 1968; Kirke 1992; Kumwenda 2002; Rush 1980; Schmidt 2001); and two trials used no placebo (Hemmi 2003; People's League 1942).

 

Effects of interventions

Seventeen trials are included, involving 35,812 women and 37,353 pregnancies.

 

Any vitamins versus no vitamins (or minimal vitamins)

 

Primary outcomes

For the outcomes of miscarriage and stillbirth, ten trials contributed data which included 31,167 pregnancies (Briscoe 1959; Chappell 1999; Czeizel 1994; Fleming 1968; Hemmi 2003; ICMR 2000; Katz 2000; MRC 1991; People's League 1942; Steyn 2003). No difference was seen between women given any type of vitamin(s) compared with controls for total fetal loss (relative risk (RR) 1.05, 95% confidence interval (CI) 0.95 to 1.15), early or late miscarriage (RR 1.08, 95% CI 0.95 to 1.24) or stillbirth (RR 0.85, 95% CI 0.63 to 1.14), using fixed-effect models. These findings occurred regardless of whether the trials started supplementation prior to pregnancy, in the first twelve weeks of pregnancy, before 20 weeks' gestation or both prior to and after 20 weeks' gestation. For the other primary outcomes, women given any type of vitamin(s) compared with controls were less likely to develop pre-eclampsia (RR 0.68, 95% CI 0.54 to 0.85, four trials, 5580 women (Chappell 1999; Fleming 1968; People's League 1942; Steyn 2003)). No significant difference was seen between women given any type of vitamin(s) compared with controls for placental abruption (RR 0.34, 95% CI 0.04 to 3.19, one trial, 283 women (Chappell 1999)), antepartum haemorrhage including placental abruption (RR 7.00, 95% CI 0.88 to 55.86, one trial, 200 women (Steyn 2003)), perinatal death (RR 0.51, 95% CI 0.05 to 5.54, one trial, 182 women (Steyn 2003)), neonatal death (RR 1.12, 95% CI 0.95 to 1.32, four trials, 25,121 women (Czeizel 1994b; Katz 2000;People's League 1942; Steyn 2003)), preterm birth (RR 1.06 95% CI 0.95 to 1.18, five trials, 23,433 women (Chappell 1999; Czeizel 1994; Fleming 1968; Katz 2000; Steyn 2003)), small-for-gestational-age infants (RR 1.02 95% CI 0.82 to 1.27, four trials, 5406 women (Chappell 1999; Czeizel 1994; Fleming 1968; ICMR 2000)) or congenital malformations (RR 1.50, 95% CI 0.73 to 3.06, two trials, 6679 women (Czeizel 1994; MRC 1991)). Significant heterogeneity was found for birthweight. No significant difference was seen between women given any type of vitamin(s) compared with controls for birthweight (weighted mean difference (WMD) 140.37 g, 95% CI -160.58 to 441.32, two trials, 4891 women (Correia 1982; Czeizel 1994b)) using a random-effects model.

 

Secondary outcomes

Women given any type of vitamin(s) compared with controls were more likely to have a multiple pregnancy (RR 1.38, 95% CI 1.12 to 1.70, three trials, 20,986 women (Czeizel 1994b; ICMR 2000; Katz 2000)) and greater placental weight (WMD 96.00 g, 95% CI 30.73 to 161.27, one trial, 29 women (Correia 1982)). No overall difference was seen between women given any vitamin(s) compared with controls for the outcomes very preterm birth (RR 1.30, 95% CI 0.78 to 2.17, one trial, 200 women (Steyn 2003)), the number of women breastfeeding (RR 0.98, 95% CI 0.96 to 1.01, one trial, 4878 women (People's League 1942)) or the duration of admission to the neonatal intensive care unit (WMD 1.30 days, 95% CI -0.28 to 2.88, one trial, 181 women (Steyn 2003)). No other secondary outcomes were reported.

 

Further analyses by quality rating

Five trials had an allocation concealment rating of 'A' (Chappell 1999; Kirke 1992; Kumwenda 2002; MRC 1991; Steyn 2003), ten trials had a rating of 'B' (Briscoe 1959; Christian 2003; Correia 1982; Czeizel 1994; Fawzi 1998; Hemmi 2003; ICMR 2000; Katz 2000; Rush 1980; Schmidt 2001) and two trials had a rating of 'C' (Fleming 1968; People's League 1942). A total of ten trials involving 31,167 women were included in the sensitivity analyses of primary outcomes based on allocation concealment (Briscoe 1959; Chappell 1999; Czeizel 1994; Fleming 1968; Hemmi 2003; ICMR 2000; Katz 2000; MRC 1991; People's League 1942; Steyn 2003). No difference was seen in total fetal loss between women supplemented with any vitamins compared with controls for those trials with an allocation concealment rating of 'A' (RR 0.98, 95% CI 0.84 to 1.14, three trials, 2300 women (Chappell 1999; MRC 1991; Steyn 2003)), a rating of 'B' (RR 1.03, 95% CI 0.98 to 1.09, five trials, 23,771 women (Briscoe 1959; Czeizel 1994; Hemmi 2003; ICMR 2000; Katz 2000)) or those rated 'C' (RR 0.92, 95% CI 0.77 to 1.10, two trials, 5096 women (Fleming 1968; People's League 1942)). Similarly, no difference was seen between women supplemented with any vitamins compared with controls for early or late miscarriage or stillbirth for any of the comparisons based on allocation rating.

 

Further analyses by use of placebo

Ten trials used a placebo or trace element control (Briscoe 1959; Chappell 1999; Correia 1982; Czeizel 1994; Fawzi 1998; Fleming 1968; ICMR 2000; Katz 2000; MRC 1991; Steyn 2003), five trials compared different combinations of vitamins (Christian 2003; Fawzi 1998; Kumwenda 2002; Rush 1980; Schmidt 2001) and two trials used no placebo control (Hemmi 2003; People's League 1942). No difference was seen between women given any vitamins compared with controls for total fetal loss for those trials using a placebo (RR 1.03, 95% CI 0.98 to 1.08, eight trials, 26,122 women (Briscoe 1959; Chappell 1999; Czeizel 1994; Fleming 1968; ICMR 2000; Katz 2000; MRC 1991; Steyn 2003)) and for those trials with no placebo (RR 0.92, 95% CI 0.77 to 1.10, two trials, 5045 women (Hemmi 2003; People's League 1942)). Similarly no difference was seen between women given any vitamins compared with controls for early or late miscarriage or stillbirth for any of the comparisons based on use of placebo.

 

Further analyses by losses to follow up

Three trials reported less than three per cent losses to follow up (Chappell 1999; Czeizel 1994; Katz 2000), one trial reported three to less than 10 per cent losses to follow up (MRC 1991), two trials reported between ten and less than twenty per cent losses to follow up (Hemmi 2003; People's League 1942), two trials reported over twenty per cent losses to follow up (Fleming 1968; ICMR 2000) and two trials did not state any losses to follow up (Briscoe 1959; Steyn 2003). No difference was seen between women given any vitamins compared with controls for total fetal loss for any of the comparisons based on the percentage of losses to follow up reported. Similarly, no difference was seen between women supplemented with any vitamins compared with controls for early or late miscarriage or stillbirth for any of the comparisons based on losses to follow up.

 

Vitamin C supplementation

The trials involving vitamin C supplementation included the following interventions: vitamin C plus multivitamins versus placebo plus multivitamins (Briscoe 1959), vitamin C and vitamin E supplementation versus placebo (Chappell 1999) and vitamin C alone versus no supplement or placebo (Hemmi 2003; Steyn 2003). No significant difference was seen in the risk of total fetal loss between women receiving vitamin C with multivitamins compared with placebo plus multivitamins (RR 1.32, 95% CI 0.63 to 2.77, one trial, 406 women (Briscoe 1959)), vitamin C and vitamin E compared with placebo (RR 0.50, 95% CI 0.05 to 5.49, one trial, 283 women (Chappell 1999)) or vitamin C compared with no supplement or placebo (RR 1.28, 95% CI 0.58 to 2.83, two trials, 224 women (Hemmi 2003; Steyn 2003)). Similarly, there was no overall difference seen in early or late miscarriage between women receiving vitamin C with multivitamins compared with placebo plus multivitamins (RR 1.32, 95% CI 0.63 to 2.77, one trial, 406 women (Briscoe 1959)) or vitamin C compared with no supplement or placebo (RR 1.17, 95% CI 0.52 to 2.65, two trials, 224 women (Hemmi 2003; Steyn 2003)). No significant difference was seen in the risk of stillbirth between women receiving vitamin C and vitamin E compared with placebo (RR 0.50, 95% CI 0.05 to 5.49, one trial, 283 women (Chappell 1999)) or vitamin C compared with placebo (RR 3.00, 95% CI 0.12 to 72.77, one trial, 200 women (Steyn 2003)).

For the other primary and secondary outcomes reported, no significant difference was seen in the risk of placental abruption between women receiving vitamin C and vitamin E compared with placebo (RR 0.34, 95% CI 0.04 to 3.19, one trial, 283 women (Chappell 1999)), or the risk of antepartum haemorrhage including placental abruption between women receiving placebo compared with controls (RR 7.00, 95% CI 0.88 to 55.86, one trial, 200 women (Steyn 2003)). Women were at decreased risk of pre-eclampsia when they received vitamin C and vitamin E compared with placebo (RR 0.46, 95% CI 0.24 to 0.91, one trial, 283 women (Chappell 1999)), but not when they received vitamin C alone compared with placebo (RR 1.00, 95% CI 0.21 to 4.84, one trial, 200 women (Steyn 2003)). When women were given vitamin C compared with placebo, there was no significant difference seen in the risk of perinatal death (RR 0.51, 95% CI 0.05 to 5.54, one trial, 182 women (Steyn 2003)) or neonatal death (RR 0.69, 95% CI 0.12 to 4.03, one trial, 181 women (Steyn 2003)). Women supplemented with vitamin C compared with placebo were at increased risk of having a preterm birth (RR 1.43, 95% CI 1.03 to 1.99, one trial, 200 women (Steyn 2003)); however, no increased risk of preterm birth was seen when women were given vitamin C in addition to vitamin E compared with placebo (RR 1.21, 95% CI 0.38 to 3.87, one trial, 283 women (Chappell 1999)). No significant difference was seen in the risk of having a small-for-gestational-age infant when women were given vitamin C and vitamin E compared with controls (RR 0.74, 95% CI 0.50 to 1.08, one trial, 283 women (Chappell 1999)) or in the rate of very preterm birth between women receiving vitamin C compared with placebo (RR 1.30, 95% CI 0.78 to 2.17, one trial, 200 women (Steyn 2003)).

 

Vitamin A supplementation

The trials involving vitamin A supplementation included the following interventions: vitamin A and/or beta-carotene versus placebo (Katz 2000), vitamin A with or without multivitamins versus multivitamins (excluding vitamin A) or placebo (Fawzi 1998) and vitamin A plus iron and folate versus iron and folate (Kumwenda 2002; Schmidt 2001). No difference was seen in total fetal loss, between women given vitamin A compared with placebo (RR 1.04, 95% CI 0.92 to 1.17, one trial, 11,723 women (Katz 2000)), beta-carotene compared with placebo (RR 1.03, 95% CI 0.91 to 1.16, one trial, 11,303 women (Katz 2000)), vitamin A compared with beta-carotene (RR 1.01, 95% CI 0.90 to 1.14, one trial, 11,720 women (Katz 2000)), vitamin A or beta-carotene compared with placebo (RR 1.05, 95% CI 0.91 to 1.21, one trial, 17,373 women (Katz 2000)), vitamin A with or without multivitamins compared with multivitamins or placebo (RR 0.80, 95% CI 0.53 to 1.21, one trial, 1074 women (Fawzi 1998)) or vitamin A with iron and folate compared with iron and folate (RR 1.34, 95% CI 0.67 to 2.65, two trials, 940 women (Kumwenda 2002; Schmidt 2001)). Similarly, no differences were seen in the rate of early or late miscarriage, stillbirth, neonatal death or preterm birth between women given any type of vitamin A, alone or in combination with beta-carotene, multivitamin or iron and folate, compared with controls. Infants of women given vitamin A with iron and folate compared with iron and folate alone had higher birthweight (WMD 90.00 g, 95% CI 2.68 to 177.32, one trial, 594 women (Kumwenda 2002)). However, no difference was seen in the number of infants born small-for-gestational age between women given vitamin A with or without multivitamins compared with multivitamins or placebo (RR 0.84, 95% CI 0.58 to 1.21, one trial, 1075 women (Fawzi 1998)).

The rate of multiple pregnancy was higher in women given either vitamin A or beta-carotene compared with placebo (RR 1.39, 95% CI 1.05 to 1.84, one trial, 15,845 women (Katz 2000)). Increases in the rate of multiple pregnancy were also seen for women given vitamin A versus placebo (RR 1.35, 95% CI 0.99 to 1.85, one trial, 10,697 women (Katz 2000)) and beta-carotene versus placebo (RR 1.37, 95% CI 1.00 to 1.88, one trial, 10,294 women (Katz 2000)). No difference was seen for vitamin A versus beta-carotene (RR 1.03, 95% CI 0.77 to 1.37, one trial, 10,699 women (Katz 2000)). No difference was seen in very preterm birth between women given vitamin A with or without multivitamins compared with multivitamins or placebo (RR 1.11, 95% CI 0.71 to 1.74, one trial, 1075 women (Fawzi 1998)). Fewer infants of women given vitamin A and iron and folate compared with iron and folate alone had anaemia at six weeks (RR 0.58, 95% CI 0.45 to 0.75, one trial, 562 infants (Kumwenda 2002)); however, at 12 months, no difference was seen (RR 1.03, 95% CI 0.88 to 1.20, one trial, 478 infants (Kumwenda 2002)). At six weeks of age, infants of women given vitamin A and iron and folate compared with iron and folate alone had greater weight (WMD 169 g, 95% CI 16.55 to 321.45, one trial, 546 infants (Kumwenda 2002)) and length (WMD 0.70 cm, 95% CI 0.15 to 1.25, one trial, 546 infants (Kumwenda 2002)); however, at four months of age no significant difference was seen in weight (WMD -100.00 g, 95% CI -377.14 to 177.14, one trial, 148 infants (Schmidt 2001)) or length (WMD -0.50 cm, 95% CI -1.33 to 0.33, one trial, 148 infants (Schmidt 2001)).

 

Multivitamin supplementation

The trials involving multivitamin supplementation included the following interventions: multivitamins with or without folic acid versus no multivitamins or folic acid (Czeizel 1994; MRC 1991), multivitamins with or without folic acid versus folic acid (Kirke 1992; MRC 1991), multivitamins with or without vitamin A versus vitamin A or placebo (Fawzi 1998), multivitamins versus control (People's League 1942), multivitamins with vitamin E versus multivitamins without vitamin E or control (Rush 1980) and multivitamins with folic acid, iron, zinc and vitamin A versus no multivitamin and folic acid, iron, zinc, vitamin A (Christian 2003). Total fetal loss was significantly lower in women who were given multivitamins with or without vitamin A compared with those receiving vitamin A or placebo (RR 0.60, 95% CI 0.39 to 0.91, one trial, 1074 women (Fawzi 1998)). However, given that this finding has occurred during subgroup analyses, and the comparison group contains women receiving either vitamin A or placebo, caution should be taken in interpretation. No other differences were seen in total fetal loss for women receiving multivitamins with folic acid versus no multivitamins or folic acid (RR 1.09, 95% CI 0.95 to 1.25, three trials, 6883 women (Czeizel 1994; ICMR 2000; MRC 1991)), multivitamins without folic acid versus no multivitamins or folic acid (RR 0.83, 95% CI 0.56 to 1.25, one trial, 907 women (MRC 1991)), multivitamins with or without folic acid versus no multivitamins or folic acid (RR 0.91, 95% CI 0.65 to 1.27, one trial, 1368 women (MRC 1991)), multivitamins with folic acid versus folic acid (RR 1.03, 95% CI 0.72 to 1.48, two trials, 1096 women (Kirke 1992; MRC 1991)), multivitamins without folic acid versus folic acid (RR 0.90, 95% CI 0.62 to 1.30, two trials, 1090 women (Kirke 1992; MRC 1991)), multivitamins with or without folic acid versus folic acid (RR 0.95, 95% CI 0.69 to 1.30, two trials, 1644 women (Kirke 1992; MRC 1991)), multivitamins versus control (RR 0.83, 95% CI 0.58 to 1.17, one trial, 5021 women (People's League 1942)) and multivitamins with vitamin E versus multivitamins without vitamin E or control (RR 0.92, 95% CI 0.46 to 1.83, one trial, 823 women (Rush 1980)). No other differences were seen for early or late miscarriage or stillbirth for any of the multivitamin comparisons.

For the other primary outcomes, women receiving multivitamins compared with control were at lower risk of pre-eclampsia (RR 0.70, 95% CI 0.55 to 0.90, one trial, 5021 women (People's League 1942)). There were no differences demonstrated in the risk of perinatal death (RR 1.11, 95% CI 0.98 to 1.26, one trial, 4308 women (Christian 2003)) or neonatal death for any of the multivitamin comparisons. No difference was seen in preterm birth, birthweight, congenital malformations, maternal anaemia, the number of women breastfeeding or infant death, between women given multivitamins alone or with folic acid, vitamin A, vitamin E or iron and zinc compared with controls. A small reduction was demonstrated for the risk of having an infant with birthweight less than 2500 g for women receiving multivitamins with folic acid, iron, zinc and vitamin A versus folic acid, iron, zinc, vitamin A and no multivitamin (RR 0.95, 95% CI 0.90 to 1.00, one trial, 3325 women (Christian 2003); however, no difference was seen in small-for-gestational-age infants when defined as birthweight less than the 10th centile or birthweight less than 2500 g, between women receiving other combinations of multivitamins. Women given multivitamins with folic acid compared with no multivitamins or folic acid were more likely to have a multiple pregnancy (RR 1.36, 95% CI 1.00 to 1.85, two trials, 5141 women (Czeizel 1994b; ICMR 2000)).

 

Folic acid supplementation

The trials involving folic acid supplementation included the following interventions: folic acid with or without multivitamins compared with no folic acid or multivitamins (Czeizel 1994; ICMR 2000; MRC 1991), folic acid with or without multivitamins compared with multivitamins (Kirke 1992; MRC 1991), folic acid with iron, zinc, multivitamins and vitamin A compared with vitamin A alone (Christian 2003), folic acid and iron compared with iron (Fleming 1968) and folic acid compared with placebo (Correia 1982). No significant difference was seen in the risk of total fetal loss between women receiving folic acid with multivitamins compared with no folic acid or multivitamins (RR 1.09, 95% CI 0.95 to 1.25, three trials, 6883 women (Czeizel 1994; ICMR 2000; MRC 1991)); folic acid without multivitamins compared with no folic acid or multivitamins (RR 0.95, 95% CI 0.64 to 1.40, one trial, 903 women (MRC 1991)); folic acid with or without multivitamins compared with no folic acid or multivitamins (RR 0.97, 95% CI 0.69 to 1.35, one trial, 1364 women (MRC 1991)); folic acid with multivitamins compared with multivitamins (RR 1.15, 95% CI 0.80 to 1.67, two trials, 1102 women (Kirke 1992; MRC 1991)); folic acid without multivitamins compared with multivitamins (RR 1.12, 95% CI 0.77 to 1.62, two trials, 1090 women (Kirke 1992; MRC 1991)); folic acid with or without multivitamins compared with multivitamins (RR 1.14, 95% CI 0.82 to 1.57, two trials, 1644 women (Kirke 1992; MRC 1991)); and folic acid with iron compared with iron (RR 0.23, 95% CI 0.01 to 4.59, one trial, 75 women (Fleming 1968)). No differences were seen in the risk of early or late miscarriage, stillbirth, pre-eclampsia, perinatal death, neonatal death, preterm birth, small-for-gestational-age infants (birthweight less than 10th centile), congenital malformations or infant death between women given folic acid, alone or with multivitamins or iron, compared with controls.

Women given folic acid compared with placebo had a greater placental weight (WMD 96 g, 95% CI 30.73 to 161.27, one trial, 29 women (Correia 1982)), their infants had greater birthweight (WMD 312 g, 95% CI 108.52 to 515.48, one trial, 29 women (Correia 1982)); however, no difference was seen in birthweight between women given folic acid and multivitamins compared with no folic acid or multivitamins (WMD 3.00 g, 95% CI -24.15 to 30.15, one trial, 4862 women (Czeizel 1994)). Women receiving folic acid with iron, zinc, multivitamins and vitamin A compared with vitamin A alone were less likely to have an infant with a birthweight less than 2500 g (RR 0.94, 95% CI 0.90 to 0.99, one trial, 3325 women (Christian 2003)); however, no differences were seen in birthweight less than 2500 g for women any of the other folic acid comparisons. Women receiving folic acid and multivitamins compared with no folic acid or multivitamins were more likely to have a multiple pregnancy (RR 1.36, 95% CI 1.00 to 1.85, two trials, 5141 women (Czeizel 1994b; ICMR 2000)). Fewer women given folic acid with iron, zinc, multivitamins and vitamin A compared with vitamin A alone had anaemia in the third trimester (RR 0.83, 95% CI 0.77 to 0.91, one trial, 813 women (Christian 2003)); however, there no differences were seen for any of the folic acid comparisons for severe maternal anaemia.

 

Subgroup analyses by women's risk of spontaneous or recurrent miscarriage

Information enabling women to be classified at high or low risk of either spontaneous miscarriage or recurrent miscarriage was not clearly stated in any of the trials. One trial (Briscoe 1959) included women they termed 'habitual aborters' (i.e. experienced recurrent miscarriage) as well as women at high risk of miscarriage (more than two previous miscarriages and/or bleeding in the pregnancy) and low-risk women (two or less previous miscarriages and no bleeding in the pregnancy). After classifying women into these groups, the number of women in each group was too small to permit any meaningful comparisons and subanalyses were therefore not performed.

 

Subgroup analyses by dose of vitamins and duration of vitamin usage

Subgroup analyses by dose of vitamin(s) (below or above the recommended dietary intake) were complicated by the limited number of studies in each vitamin group, and by the use of multivitamin supplements. For many of the vitamin types and for those reporting pregnancy loss outcomes, all of the trials supplemented women with amounts that were above the recommended dietary intake. Similarly, the duration of vitamin usage was complicated by the fact that many of the trials had wide recruitment periods, and one trial (Katz 2000) supplemented women up until three years postpartum. Subgroup analyses were therefore not performed.

 

Subgroup analyses by dietary intake of vitamins

Five trials (Fleming 1968; Kumwenda 2002; People's League 1942; Schmidt 2001; Steyn 2003) reported information about women's nutritional status or the percentage of women that were dietary deficient at trial entry for the vitamin of interest. There were not enough trials within each vitamin group to assess the role of supplementation in women with dietary deficient intakes of the individual vitamins and results were not reported separately for women with a low dietary vitamin intake; therefore, no subgroup analyses could be performed.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

We did not find any evidence to support the use of any vitamins for preventing either early or late miscarriage or stillbirth. Women given multivitamins with or without vitamin A compared with those receiving vitamin A alone or placebo, were at lower risk of 'total fetal loss'. However, given this finding occurred in additional analyses by type of vitamin and the control group involved either vitamin A supplementation or placebo, there should be caution when interpreting these findings. Similarly, the Cochrane review 'Vitamin A supplementation during pregnancy' found no benefit for the risk of perinatal mortality with vitamin A supplementation (van den Broek 2002). For the other primary outcomes, supplementing women with any vitamins was associated with a significant reduction in the risk of pre-eclampsia, both when women were given vitamin C and E supplements, and when women were supplemented with multivitamins. The role of vitamins in the prevention of pre-eclampsia is explored in the Cochrane review 'Antioxidants for preventing pre-eclampsia' (Rumbold 2003). Significant heterogeneity was detected for birthweight in the comparisons of 'any vitamin versus no or minimal vitamins'. One explanation for finding heterogeneity may be in the combination of all trials regardless of vitamin type. When subgroup analyses were conducted by individual vitamin type, heterogeneity was no longer apparent for birthweight.

Women given any vitamins alone or in combination with other vitamins were more likely to have a multiple pregnancy. These differences persisted in the additional analyses by type of vitamin, whereby vitamin A, multivitamins and folic acid were found to be associated with an increase in multiple pregnancy. These findings are in agreement with the Cochrane review 'Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects' (Lumley 2001b), as well as a re-analysis of individual trial data (Czeizel 1994b) and several other large cohort studies on the rate of twinning amongst users of multivitamins and folic acid (Ericson 2001), and after food fortification with folic acid (Waller 2003). The potential mechanisms of action behind the vitamins and their impact on multiple pregnancy are not well understood, although there is some speculation that the vitamins may influence the rate of twinning rather than improving the survival of multiple fetuses (Katz 2001). An increase in multiple pregnancy along with increases in perinatal morbidity and mortality is of concern, however, as direct causality is yet to be established, further monitoring of pre and peri-conceptional vitamin supplementation is required.

For the individual vitamins, vitamin C supplementation was associated with a small increase in the risk of preterm birth. One trial, involving 200 women at high risk of giving birth preterm, contributed data for this outcome. The authors of this trial concluded that the increase in preterm birth in the vitamin group did not translate into poorer neonatal outcome (Steyn 2003). Further studies are required before any recommendations can be made regarding vitamin C supplementation. Vitamin A supplementation was associated with small increases in birthweight, infant weight and length at six weeks' of age, and decreases in infant anaemia at six weeks' of age. Similarly folic acid supplementation was associated with increases in placental weight and birthweight. However, the differences in birthweight and infant growth observed were small and may not be clinically relevant. Many of these findings include data contributed from small individual trials, hence readers should be cautioned from drawing any firm conclusions from results of single trials often with small sample sizes.

The review included trials that randomised women prior to conception, however, in some cases, not all women enrolled in these trials fell pregnant during the study period. Some of the trials reported outcomes only for women falling pregnant, whereas other trials did not distinguish between women that were never pregnant and women that may have been pregnant but were lost to follow up. The outcomes in this review relating to pregnancy complications are not relevant for the women that never became pregnant during the study period. In this review, where trials provided accurate information about the number of women who joined the study and became pregnant in the time period, we included this number in the totals, rather than the number of women that may have been randomised. Where it was not clear about the exact number of women with a confirmed pregnancy, we included all women that had been randomised. This may therefore mean that women in the denominator were never pregnant during the study period. By including these women who were never pregnant in the totals, the review assumes that if these women had become pregnant, they would not have had a miscarriage, which is unlikely to be entirely correct. Including these women creates the potential to underestimate any treatment effects observed.

Similarly, for one large trial (Katz 2000), some women were pregnant more than once during the study period. In this trial, 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. This has the potential to either underestimate or overestimate the results, depending on whether the women contributing data for more than one pregnancy may be more or less susceptible to experiencing miscarriage or stillbirth. One way to overcome this may be to summarise the data for each woman so that there is only one set of data points for each woman; however, we were unable to do this for this particular study.

Many of the trials included in the review were not of high quality, either due to poor allocation concealment or large losses to follow up, which increases the risk of bias in the results. The data were also complicated by differing definitions of miscarriage. For some trials, miscarriage was considered to occur up until 26 or 28 weeks' gestation, while other studies reported miscarriage as pregnancy loss prior to 20 weeks' gestation, and stillbirth as pregnancy loss greater or equal to 20 weeks' gestation. Other studies did not specify their definition of miscarriage or stillbirth. In addition to the problems with differing definitions, the timing of the onset of vitamin supplementation for some of the included trials occurred in mid pregnancy, which may limit the impact of supplementation on the risk of miscarriage. The review attempted to overcome these issues by using the outcome 'total fetal loss', which included either miscarriage or stillbirth.

Few studies recorded or reported any information about side-effects of vitamin supplementation, and the currently available evidence shows no maternal or infant adverse health effects of vitamin supplementation. No trials reported on any potential psychological effects such as anxiety and depression, for women experiencing miscarriage or stillbirth.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

Any vitamins, alone or in combination with other vitamins do not help prevent either early or late miscarriage or stillbirth. Supplementing women with multivitamins, with or without folic acid, may increase the risk of having a multiple birth, which may confer increases in perinatal morbidity and mortality. Supplementation with any vitamins was associated with a reduced risk of pre-eclampsia, and for vitamin A, multivitamins and folic acid, modest increases in birthweight and measures of infant growth were seen; however, further studies are required to confirm these findings.

 
Implications for research

The impact of vitamin supplementation on birthweight and measures of infant growth is unclear. Any future studies of vitamin supplementation should focus on women at high risk of miscarriage, assess the most appropriate vitamin type and dosage, show it is beneficial without causing any harms to the mother or fetus and include assessments of any psychological effects.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

We thank Simon Gates for statistical advice regarding inclusion of cluster randomised trials, Lelia Duley for helpful comments on the format of the review and Sonja Henderson for assisting with review administration.

As part of the pre-publication editorial process, this review has been commented on by two peers (an editor and referee who are external to the editorial team), one or more members of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. Any vitamins versus no vitamins (or minimal vitamins)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)1031167Relative risk (Fixed, 95% CI)1.05 [0.95, 1.15]

    1.1 Trial entry before pregnancy
525182Relative risk (Fixed, 95% CI)1.06 [0.96, 1.17]

    1.2 Trial entry < 12 weeks' gestation
1406Relative risk (Fixed, 95% CI)1.32 [0.63, 2.77]

   1.3 Trial entry >= 12 weeks' and < 20 weeks' gestation
00Relative risk (Fixed, 95% CI)Not estimable

    1.4 Trial entry 'mixed' both < 20 and >= 20 weeks' gestation
45579Relative risk (Fixed, 95% CI)0.87 [0.63, 1.20]

 2 Early or late miscarriage78490Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.95, 1.24]

    2.1 Trial entry before pregnancy
47809Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.93, 1.24]

    2.2 Trial entry < 12 weeks' gestation
1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]

   2.3 Trial entry >= 12 weeks but <20 weeks' gestation
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    2.4 Trial entry 'mixed' both < 20 and >= 20 week's gestation
2275Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.48, 2.60]

 3 Stillbirth713364Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.63, 1.14]

    3.1 Trial entry before pregnancy
37785Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.48, 1.85]

   3.2 Trial entry < 12 weeks' gestation
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   3.3 Trial entry >= 12 weeks' but < 20 weeks' gestation
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

    3.4 Trial entry 'mixed' both < 20 and >= 20 weeks' gestation
45579Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.59, 1.15]

 4 Placental abruption2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Placental abruption
1283Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.04, 3.19]

    4.2 Antepartum haemorrhage including placental abruption
1200Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.88, 55.86]

5 Psychological effects (anxiety and depression)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 6 Pre-eclampsia45580Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.54, 0.85]

 7 Perinatal death1182Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.54]

 8 Neonatal death425121Relative risk (Fixed, 95% CI)1.12 [0.95, 1.32]

 9 Preterm birth523433Relative risk (Fixed, 95% CI)1.06 [0.95, 1.18]

 10 Very preterm birth1200Risk Ratio (M-H, Fixed, 95% CI)1.3 [0.78, 2.17]

 11 Birthweight24891Mean Difference (IV, Random, 95% CI)140.37 [-160.58, 441.32]

 12 Small-for-gestational age45406Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.82, 1.27]

    12.1 Birthweight less than 10th centile or birthweight < 2500 g
45406Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.82, 1.27]

 13 Congenital malformations26679Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.73, 3.06]

 14 Multiple pregnancy320986Relative risk (Fixed, 95% CI)1.38 [1.12, 1.70]

15 Apgar score less than seven at five minutes00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

16 Use of blood transfusion for the mother00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

17 Anaemia (maternal)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

18 Anaemia (infant)00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

 19 Placental weight129Mean Difference (IV, Fixed, 95% CI)96.0 [30.73, 161.27]

 20 Method of feeding14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

    20.1 Breastfeeding
14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

   20.2 Formula
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

   20.3 Breastfeeding and formula
00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

21 Subsequent fertility00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

22 Poor growth at childhood follow up00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

23 Disability at childhood follow up00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

24 Any adverse effects of vitamin supplementation sufficient to stop supplementation00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

25 Maternal views of care00Mean Difference (IV, Fixed, 95% CI)Not estimable

26 Gynaecological hospital admission00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

27 Admission to neonatal intensive care unit00Risk Ratio (M-H, Fixed, 95% CI)Not estimable

28 Health care costs00Mean Difference (IV, Fixed, 95% CI)Not estimable

 29 Duration of admission to the neonatal intensive care unit1181Mean Difference (IV, Fixed, 95% CI)1.30 [-0.28, 2.88]

 
Comparison 2. Any vitamins (by allocation concealment)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths)1031167Relative risk (Fixed, 95% CI)1.02 [0.97, 1.07]

    1.1 Allocation concealment = A
32300Relative risk (Fixed, 95% CI)0.98 [0.84, 1.14]

    1.2 Allocation concealment = B
523771Relative risk (Fixed, 95% CI)1.03 [0.98, 1.09]

    1.3 Allocation concealment = C
25096Relative risk (Fixed, 95% CI)0.92 [0.77, 1.10]

 2 Early or late miscarriage78490Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.95, 1.24]

    2.1 Allocation concealment = A
22017Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.73, 1.34]

    2.2 Allocation concealment = B
46398Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.96, 1.30]

    2.3 Allocation concealment = C
175Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 9.03]

 3 Stillbirth713364Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.63, 1.14]

    3.1 Allocation concealment = A
32300Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.21, 1.96]

    3.2 Allocation concealment = B
25968Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.52, 2.43]

    3.3 Allocation concealment = C
25096Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.58, 1.15]

 
Comparison 3. Any vitamins (by use of placebo)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths)1031167Relative risk (Fixed, 95% CI)1.02 [0.97, 1.07]

    1.1 Placebo control
826122Relative risk (Fixed, 95% CI)1.03 [0.98, 1.08]

    1.2 No placebo control
25045Relative risk (Fixed, 95% CI)0.92 [0.77, 1.10]

 2 Early or late miscarriage78490Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.24]

    2.1 Placebo control
68466Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.24]

    2.2 No placebo control
124Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.10, 6.06]

 3 Stillbirth713364Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.63, 1.14]

    3.1 Placebo control
68343Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.49, 1.69]

    3.2 No placebo control
15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]

 
Comparison 4. Any vitamins (by losses to follow up)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths)1031167Relative risk (Fixed, 95% CI)1.02 [0.97, 1.07]

    1.1 Less than 3% losses to follow up
323158Relative risk (Fixed, 95% CI)1.04 [0.98, 1.09]

    1.2 3 to < 10% losses to follow up
11817Relative risk (Fixed, 95% CI)0.96 [0.82, 1.14]

    1.3 10 to < 20% losses to follow up
25045Relative risk (Fixed, 95% CI)0.92 [0.77, 1.10]

    1.4 >= 20% losses to follow up
2541Relative risk (Fixed, 95% CI)0.75 [0.50, 1.12]

    1.5 Not stated
2606Relative risk (Fixed, 95% CI)1.14 [0.85, 1.52]

 2 Early or late miscarriage78490Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.95, 1.24]

    2.1 Less than 3% losses to follow up
15502Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.97, 1.34]

    2.2 3 to < 10% losses to follow up
11817Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.69, 1.32]

    2.3 10 to < 20% losses to follow up
124Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.10, 6.06]

    2.4 >= 20 % losses to follow up
2541Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.18, 1.06]

    2.5 Not stated
2606Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.73, 2.28]

 3 Stillbirth713364Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.63, 1.14]

    3.1 Less than 3% losses to follow up
25785Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.46, 2.37]

    3.2 3 to < 10% losses to follow up
11817Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.10, 1.98]

    3.3 10 to < 20% losses to follow up
15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]

    3.4 >= 20% losses to follow up
2541Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.20, 3.28]

    3.5 Not stated
1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.77]

 
Comparison 5. Vitamin C

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Vitamin C + multivitamins versus placebo plus multivitamins
1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]

    1.2 Vitamin C and vitamin E versus placebo
1283Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.05, 5.49]

    1.3 Vitamin C versus no supplement/placebo
2224Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.58, 2.83]

 2 Early or late miscarriage3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Vitamin C + multivitamins versus placebo plus multivitamins
1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]

    2.2 Vitamin C versus no supplement/placebo
2224Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.52, 2.65]

 3 Stillbirth2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Vitamin C and vitamin E versus placebo
1283Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.05, 5.49]

    3.2 Vitamin C versus placebo
1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.77]

 4 Antepartum haemorrhage and placental abruption2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Vitamin C and vitamin E versus placebo - placental abruption only
1283Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.04, 3.19]

    4.2 Vitamin C versus placebo - antepartum haemorrhage including placental abruption
1200Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.88, 55.86]

 5 Pre-eclampsia2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Vitamin C and vitamin E versus placebo
1283Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.24, 0.91]

    5.2 Vitamin C versus placebo
1200Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.21, 4.84]

 6 Perinatal death1182Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.54]

    6.1 Vitamin C versus placebo
1182Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.54]

 7 Neonatal death1181Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.12, 4.03]

    7.1 Vitamin C versus placebo
1181Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.12, 4.03]

 8 Preterm birth2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Vitamin C and vitamin E versus placebo
1283Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.38, 3.87]

    8.2 Vitamin C versus placebo
1200Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.03, 1.99]

 9 Small-for-gestational age1283Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.50, 1.08]

    9.1 Vitamin C and vitamin E versus placebo
1283Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.50, 1.08]

 10 Very preterm birth1200Risk Ratio (M-H, Fixed, 95% CI)1.3 [0.78, 2.17]

    10.1 Vitamin C versus placebo
1200Risk Ratio (M-H, Fixed, 95% CI)1.3 [0.78, 2.17]

 
Comparison 6. Vitamin A

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)4Relative risk (Fixed, 95% CI)Subtotals only

    1.1 Vitamin A versus placebo
111723Relative risk (Fixed, 95% CI)1.04 [0.92, 1.17]

    1.2 B-carotene versus placebo
111303Relative risk (Fixed, 95% CI)1.03 [0.91, 1.16]

    1.3 Vitamin A versus B-Carotene
111720Relative risk (Fixed, 95% CI)1.01 [0.90, 1.14]

    1.4 Vitamin A or B-carotene versus placebo
117373Relative risk (Fixed, 95% CI)1.05 [0.91, 1.21]

    1.5 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11074Relative risk (Fixed, 95% CI)0.80 [0.53, 1.21]

    1.6 Vitamin A + iron + folate versus iron + folate
2940Relative risk (Fixed, 95% CI)1.34 [0.67, 2.65]

 2 Early or late miscarriage2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.37, 1.55]

    2.2 Vitamin A + iron + folate versus iron + folate
1697Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.47, 4.59]

 3 Stillbirth3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.60, 1.79]

    3.2 Vitamin A + iron + folate versus iron + folate
2940Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.53, 3.01]

 4 Neonatal death1Relative risk (Fixed, 95% CI)Subtotals only

    4.1 Vitamin A versus placebo
110214Relative risk (Fixed, 95% CI)1.09 [0.92, 1.30]

    4.2 B-carotene versus placebo
19788Relative risk (Fixed, 95% CI)1.09 [0.91, 1.30]

    4.3 Vitamin A versus B-Carotene
110228Relative risk (Fixed, 95% CI)1.0 [0.85, 1.18]

    4.4 Vitamin A or B-carotene versus placebo
115115Relative risk (Fixed, 95% CI)1.09 [0.91, 1.30]

 5 Preterm birth2Relative risk (Fixed, 95% CI)Subtotals only

    5.1 Vitamin A versus placebo
111723Relative risk (Fixed, 95% CI)1.04 [0.89, 1.21]

    5.2 B-carotene versus placebo
111303Relative risk (Fixed, 95% CI)1.01 [0.86, 1.18]

    5.3 Vitamin A versus B-Carotene
111720Relative risk (Fixed, 95% CI)1.03 [0.88, 1.20]

    5.4 Vitamin A or B-carotene versus placebo
117373Relative risk (Fixed, 95% CI)1.02 [0.89, 1.17]

    5.5 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Relative risk (Fixed, 95% CI)1.07 [0.84, 1.37]

 6 Birthweight1594Mean Difference (IV, Fixed, 95% CI)90.0 [2.68, 177.32]

    6.1 Vitamin A + iron + folate versus iron + folate
1594Mean Difference (IV, Fixed, 95% CI)90.0 [2.68, 177.32]

 7 Small-for-gestational age11075Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.58, 1.21]

    7.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.58, 1.21]

 8 Multiple pregnancy1Relative risk (Fixed, 95% CI)Subtotals only

    8.1 Vitamin A versus placebo
110697Relative risk (Fixed, 95% CI)1.35 [0.99, 1.85]

    8.2 B-carotene versus placebo
110294Relative risk (Fixed, 95% CI)1.37 [1.00, 1.88]

    8.3 Vitamin A versus B-Carotene
110699Relative risk (Fixed, 95% CI)1.03 [0.77, 1.37]

    8.4 Vitamin A or B-carotene versus placebo
115845Relative risk (Fixed, 95% CI)1.39 [1.05, 1.84]

 9 Very preterm birth11075Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.71, 1.74]

    9.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo
11075Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.71, 1.74]

 10 Infant anaemia1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Infant anaemia at 6 weeks' of age - vitamin A + iron + folate versus iron + folate
1562Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.45, 0.75]

    10.2 Infant anaemia at 12 months - vitamin A + iron + folate versus iron + folate
1478Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.88, 1.20]

 11 Poor growth at childhood follow up2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    11.1 Weight (g) at 6 weeks: vitamin A + iron + folate versus iron + folate
1546Mean Difference (IV, Fixed, 95% CI)169.0 [16.55, 321.45]

    11.2 Length (cm) at 6 weeks: vitamin A + iron + folate versus iron + folate
1546Mean Difference (IV, Fixed, 95% CI)0.70 [0.15, 1.25]

    11.3 Weight (g) at 4 months: vitamin A + iron + folate versus iron + folate
1148Mean Difference (IV, Fixed, 95% CI)-100.0 [-377.14, 177.14]

    11.5 Length (cm) at 4 months: vitamin A + iron + folate versus iron + folate
1148Mean Difference (IV, Fixed, 95% CI)-0.5 [-1.33, 0.33]

 
Comparison 7. Multivitamin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Multivitamin + folic acid versus no multivitamin/folic acid
36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]

    1.2 Multivitamin without folic acid versus no multivitamin/folic acid
1907Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.56, 1.25]

    1.3 Multivitamins with/without folic acid versus no multivitamins/folic acid
11368Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.65, 1.27]

    1.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.72, 1.48]

    1.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.62, 1.30]

    1.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.69, 1.30]

    1.7 Multivitamin with/without vitamin A versus vitamin A or placebo
11074Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.39, 0.91]

    1.8 Multivitamins versus control
15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]

    1.9 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1823Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.46, 1.83]

 2 Early or late miscarriage5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Multivitamin + folic acid versus no multivitamin/folic acid
36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.94, 1.26]

    2.2 Multivitamin without folic acid versus no multivitamin/folic acid
1907Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.59, 1.34]

    2.3 Multivitamin with/without folic acid versus no multivitamin/folic acid
11368Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.67, 1.34]

    2.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.72, 1.49]

    2.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.61, 1.31]

    2.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.70, 1.33]

    2.7 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1823Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.26, 4.13]

 3 Stillbirth6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Multivitamin + folic acid versus no multivitamin/folic acid
36883Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.51, 2.09]

    3.2 Multivitamin without folic acid versus no multivitamin/folic acid
1907Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.76]

    3.3 Multivitamin with/without folic acid versus no multivitamin/folic acid
11368Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.06, 1.97]

    3.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.14, 6.88]

    3.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.20, 4.88]

    3.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.19, 4.15]

    3.7 Multivitamin versus control
15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]

    3.8 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1823Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.39, 1.98]

 4 Pre-eclampsia15021Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.55, 0.90]

    4.1 Multivitamin versus control
15021Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.55, 0.90]

 5 Perinatal death14308Relative risk (Fixed, 95% CI)1.11 [0.98, 1.26]

    5.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
14308Relative risk (Fixed, 95% CI)1.11 [0.98, 1.26]

 6 Neonatal death4Relative risk (Fixed, 95% CI)Subtotals only

    6.1 Multivitamin + folic acid versus no multivitamin/folic acid
14930Relative risk (Fixed, 95% CI)1.59 [0.30, 8.30]

    6.2 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1787Relative risk (Fixed, 95% CI)1.44 [0.91, 2.27]

    6.3 Multivitamin versus control
14895Relative risk (Fixed, 95% CI)1.0 [0.75, 1.34]

    6.4 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
14122Relative risk (Fixed, 95% CI)1.15 [0.97, 1.36]

 7 Preterm birth3Relative risk (Fixed, 95% CI)Subtotals only

    7.1 Multivitamin + folic acid versus no multivitamin/folic acid
15502Relative risk (Fixed, 95% CI)1.01 [0.91, 1.12]

    7.2 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
13320Relative risk (Fixed, 95% CI)0.98 [0.90, 1.07]

    7.3 Multivitamin + vitamin E versus multivitamin without vitamin E or controls
1814Relative risk (Fixed, 95% CI)0.99 [0.85, 1.15]

 8 Birthweight14862Mean Difference (IV, Fixed, 95% CI)3.0 [-24.15, 30.15]

    8.1 Multivitamin + folic acid versus no multivitamin/folic acid
14862Mean Difference (IV, Fixed, 95% CI)3.0 [-24.15, 30.15]

 9 Small-for-gestational age3Relative risk (Fixed, 95% CI)Subtotals only

    9.1 Multivitamin + folic acid versus no multivitamin/folic acid
14862Relative risk (Fixed, 95% CI)1.09 [0.94, 1.26]

    9.2 Multivitamin + folic acid versus no multivitamin/folic acid (birthweight < 2500 g)
1186Relative risk (Fixed, 95% CI)0.91 [0.63, 1.32]

    9.3 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
13320Relative risk (Fixed, 95% CI)0.98 [0.95, 1.02]

    9.4 Multivitamin+folic acid+iron+zinc+vitamin A versus folic acid+iron+zinc+vitamin A (birthweight < 2500 g)
13325Relative risk (Fixed, 95% CI)0.95 [0.90, 1.00]

 10 Congenital malformations3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Multivitamin + folic acid versus no multivitamin/folic acid
25777Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.81, 3.53]

    10.2 Multivitamin without folic acid without versus no multivitamin/folic acid
1907Risk Ratio (M-H, Fixed, 95% CI)1.60 [0.53, 4.86]

    10.3 Multivitamin with/without folic acid versus no multivitamin/folic acid
11368Risk Ratio (M-H, Fixed, 95% CI)1.99 [0.75, 5.26]

    10.4 Multivitamin + folic acid versus folic acid
21096Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.72, 4.04]

    10.5 Multivitamin without folic acid versus folic acid
21090Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.67, 3.85]

    10.6 Multivitamin with/without folic acid versus folic acid
21644Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.76, 3.63]

 11 Multiple pregnancy25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]

    11.1 Multivitamin + folic acid versus no multivitamin/folic acid
25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]

 12 Maternal anaemia1Relative risk (Fixed, 95% CI)Subtotals only

    12.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A (any anaemia)
1813Relative risk (Fixed, 95% CI)0.92 [0.83, 1.03]

    12.2 Multivitamin + folic acid + iron + zinc+vitamin A versus folic acid + iron + zinc + vitamin A (severe anaemia)
1813Relative risk (Fixed, 95% CI)0.82 [0.53, 1.27]

 13 Breastfeeding14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

    13.1 Mulitivitamin versus control
14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]

 14 Additional outcomes - infant death14122Relative risk (Fixed, 95% CI)1.10 [0.94, 1.29]

    14.1 Multivitamin + folic acid + iron + zinc + vitamin A versus folic acid + iron + zinc + vitamin A
14122Relative risk (Fixed, 95% CI)1.10 [0.94, 1.29]

 
Comparison 8. Folic acid

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Folic acid + multivitamin versus no folic acid/multivitamin
36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]

    1.2 Folic acid without multivitamin versus no folic acid/multivitamin
1903Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.64, 1.40]

    1.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.69, 1.35]

    1.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.80, 1.67]

    1.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.62]

    1.6 Folic acid with or without multivitamin versus multivitamin
21644Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.82, 1.57]

    1.7 Folic acid + iron versus iron
175Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 4.59]

 2 Early or late miscarriage5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Folic acid + multivitamin versus no folic acid/multivitamin
36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.94, 1.26]

    2.2 Folic acid without multivitamins versus no folic acid/multivitamin
1903Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.65, 1.44]

    2.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.70, 1.39]

    2.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.80, 1.69]

    2.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.64]

    2.6 Folic acid with/without multivitamin versus multivitamin
21642Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.79, 1.51]

    2.7 Folic acid + iron versus iron
175Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 9.03]

 3 Stillbirth5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Folic acid + multivitamin versus no folic acid/multivitamin
36883Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.51, 2.09]

    3.2 Folic acid without multivitamin versus no folic acid/multivitamin
1903Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.11, 4.02]

    3.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.15, 2.96]

    3.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.20, 4.99]

    3.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Fixed, 95% CI)4.97 [0.58, 42.29]

    3.6 Folic acid with/without multivitamin versus multivitamin
21644Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.20, 3.53]

    3.7 Folic acid + iron versus iron
175Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 9.03]

 4 Pre-eclampsia175Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.17, 7.69]

    4.1 Folic acid + iron versus iron
175Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.17, 7.69]

 5 Perinatal death14308Relative risk (Fixed, 95% CI)0.97 [0.85, 1.11]

    5.1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
14308Relative risk (Fixed, 95% CI)0.97 [0.85, 1.11]

 6 Neonatal death2Relative risk (Fixed, 95% CI)Subtotals only

    6.1 Folic acid + multivitamin versus no folic acid/multivitamin
14930Relative risk (Fixed, 95% CI)1.59 [0.30, 8.28]

    6.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
14122Relative risk (Fixed, 95% CI)0.96 [0.80, 1.14]

 7 Preterm birth3Relative risk (Fixed, 95% CI)Subtotals only

    7.1 Folic acid + multivitamin versus no folic acid/multivitamin
15502Relative risk (Fixed, 95% CI)1.01 [0.91, 1.12]

    7.2 Folic acid + multivitamin versus no folic acid/multivitamin
175Relative risk (Fixed, 95% CI)1.01 [0.65, 1.56]

    7.3 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
13320Relative risk (Fixed, 95% CI)1.02 [0.94, 1.11]

 8 Birthweight2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    8.1 Folic acid + multivitamin versus no folic acid/multivitamin
14862Mean Difference (IV, Fixed, 95% CI)3.0 [-24.15, 30.15]

    8.2 Folic acid versus placebo
129Mean Difference (IV, Fixed, 95% CI)312.0 [108.52, 515.48]

 9 Small-for-gestational age4Relative risk (Fixed, 95% CI)Subtotals only

    9.1 Folic acid + multivitamin versus no folic acid/multivitamin
14862Relative risk (Fixed, 95% CI)1.09 [0.94, 1.26]

    9.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
13320Relative risk (Fixed, 95% CI)0.97 [0.92, 1.03]

    9.3 Folic acid + iron versus iron (birthweight < 2500 g)
175Relative risk (Fixed, 95% CI)1.06 [0.48, 2.33]

    9.4 Folic acid + multivitamin versus no folic acid/multivitamin (birthweight < 2500 g)
1186Relative risk (Fixed, 95% CI)0.91 [0.63, 1.32]

    9.5 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (birthweight < 2500 g)
13325Relative risk (Fixed, 95% CI)0.94 [0.90, 0.99]

 10 Congenital malformations3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Folic acid + multivitamin versus no folic acid/multivitamin
25777Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.81, 3.53]

    10.2 Folic acid without multivitamin versus no folic acid/multivitamin
1903Risk Ratio (M-H, Fixed, 95% CI)1.42 [0.45, 4.43]

    10.3 Folic acid with/without multivitamin versus no folic acid/multivitamin
11364Risk Ratio (M-H, Fixed, 95% CI)1.90 [0.71, 5.04]

    10.4 Folic acid + multivitamin versus multivitamin
21102Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.51, 2.26]

    10.5 Folic acid without multivitamin versus multivitamin
21090Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.26, 1.49]

    10.6 Folic acid with or without multvitamin versus multivitamin
21644Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.43, 1.67]

 11 Multiple pregnancy2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    11.1 Folic acid + multivitamin versus no folic acid/multivitamin
25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]

 12 Maternal anaemia2Relative risk (Fixed, 95% CI)Subtotals only

    12.1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (any anaemia)
1813Relative risk (Fixed, 95% CI)0.83 [0.77, 0.91]

    12.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A (severe anaemia)
1813Relative risk (Fixed, 95% CI)0.82 [0.59, 1.16]

    12.3 Folic acid + iron versus iron (severe anaemia)
185Relative risk (Fixed, 95% CI)1.06 [0.25, 4.42]

 13 Placental weight129Mean Difference (IV, Fixed, 95% CI)96.0 [30.73, 161.27]

    13.1 Folic acid versus placebo
129Mean Difference (IV, Fixed, 95% CI)96.0 [30.73, 161.27]

 14 Additional outcomes - infant death14122Relative risk (Fixed, 95% CI)0.95 [0.81, 1.11]

    14.1 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A
14122Relative risk (Fixed, 95% CI)0.95 [0.81, 1.11]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. Search strategy

  1. miscarriage*
  2. spontaneous abortion
  3. recurrent abortion
  4. habitual abortion
  5. spontaneous pregnancy loss
  6. recurrent pregnancy loss
  7. early pregnancy loss
  8. early pregnancy bleeding
  9. fetal death
  10. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9
  11. vitamin*
  12. retinol*
  13. carotenoid*
  14. thiamin*
  15. riboflavin
  16. niacin or nicotinamide or nicotinic acid
  17. pantothenic acid or pantothenate
  18. pyridox*
  19. cyanocobalamin or cobalamin
  20. ascorb*
  21. calciferol
  22. tocopherol* or alpha-tocopherol
  23. folate*
  24. folic acid
  25. phylloquinone
  26. menaquinone
  27. #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #11 or #12
  28. #10 and #27
  29. random*
  30. controlled-clinical-trial
  31. #29 or #30
  32. #28 and #31

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 1 February 2005.


DateEventDescription

20 September 2008AmendedConverted to new review format.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 1, 2003
Review first published: Issue 2, 2005

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Alice Rumbold developed and wrote the protocol, extracted data and prepared the review. Philippa Middleton extracted data and was involved in the analysis and writing of the review. Caroline Crowther commented on and revised the various drafts of the protocol and review during its development.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Caroline Crowther is a chief investigator for the Australian Collaborative Trial of Supplements with vitamin C and vitamin E for the prevention of pre-eclampsia. Alice Rumbold is the PhD student involved with this trial.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • Department of Obstetrics and Gynaecology, The University of Adelaide, Australia.

 

External sources

  • Department of Health and Ageing, Australia.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Briscoe 1959 {published data only}
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.
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, 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;133:3492-98.
  • Christian P, West Jr 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;78:1194-202.
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.
Czeizel 1994 {published data only}
Fawzi 1998 {published data only}
  • 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, 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.
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.
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.
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 Jr, 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 Jr, 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 Jr, 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 Jnr 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 Jr, 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.
  • West KP Jr, 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}
Kumwenda 2002 {published data only}
  • Kumwenda D, Miotti PG, Taha TE, Broadhead R, Biggar RJ, Brookes Jackson J, 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;35:618-74.
MRC 1991 {published data only}
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.
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.
Steyn 2003 {published data only}
  • 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):150-55.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Baumslag 1970 {published data only}
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}
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.
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}
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}
Fletcher 1971 {published data only}
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.
Hibbard 1968 {published data only}
Hunt 1984 {published data only}
  • Hunt IF, Murphy NJ, Cleaver AE, Faraji B, Swendseid ME, et al. Zinc supplementation during pregnancy: effects on selected blood constitutents and on progress and outcome of pregnancy in low-income women of Mexican descent. American Journal of Clinical Nutrition 1984;40:508-21.
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. BMJ (Clinical Research Edition) 1981;282:1509-11.
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}
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}
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;39(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.
Ross 1985 {published data only}
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}
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}
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.
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;6:228-30.
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.

References to studies awaiting assessment

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Fleming 1985 {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;80:211-33.
  • 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.
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.
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.
Taylor 1982 {published data only}
Van den Broek 1998 {published data only}
  • Van den Broek N. Vitamin A supplementation for anaemia in pregnancy. Personal communication 1998.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
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 2002
  • Beazley D, Livingston J, Kao L, Sibai B. Vitamin c and e supplementation in women at high risk for preeclampsia: a double-blind placebo controlled trial [abstract]. American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S76.
Bendich 1993
  • Bendich A, Machlin LJ. The safety of oral intake of vitamin E: data from clinical studies from 1986-1991. In: Packer L, Fuchs J editor(s). Vitamin E in health and disease. New York: Marcel Dekker, 1993.
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.
Coulam 1991
Czeizel 1994b
  • Czeizel AE, Metneki J, Dudas 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.
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.
Ericson 2001
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Everett 1997
Godfrey 1996
Goyaux 2001
  • Goyaux N, Alihonou E, Diadhiou F, Leke R, Thonneau PF. Complications of induced abortion and miscarriage in three African countries: a hospital-based study among WHO collaborating centres. Acta Obstetricia et Gynecologica Scandinavica 2001;80:568-73.
Jauniaux 2000
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Katz 2001
Lee 1996
Lumley 2001a
Lumley 2001b
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Morris 2001
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NHMRC 2001
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NRC 1989
  • National Research Council Committee on Diet and Health. Diet and health: implications for reducing chronic disease risk. Washington DC: National Academy Press, 1989.
Oates-Whitehead 2003
Olsen 1999
  • Olsen RE. Vitamin deficiency, dependency, and toxicity. In: Beers MH, Berkow R editor(s). The Merck manual of diagnosis and therapy [electronic resource]. 17th Edition. Whitehouse Station, NJ: Merck & Co, Inc, 1999.
Preston 1996
Ray 1999
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Regan 1989
RevMan 2004
  • The Cochrane Collaboration. Review Manager (Revman). 4.2.7 for Windows. Oxford, England: The Cochrane Collaboration, 2004.
Rivas 2000
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Rumbold 2003
  • Rumbold A, Duley L, Crowther C, Haslam R. Antioxidants for preventing pre-eclampsia. The Cochrane Database of Systematic Reviews 2003, Issue 2. [Art. No.: CD004227. DOI: 10.1002/14651858.CD004227.pub3]
Scott 2003
Simsek 1998
Stern 1996
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van den Broek 2002
Waller 2003
WHO 1998
  • WHO. Safe Vitamin A dosage during pregnancy and lactation. Recommendations and report of a consultation (WHO/NUT/98). Geneva: World Health Organisation, 1998.