Vitamin supplementation for preventing miscarriage

  • Review
  • Intervention

Authors


Abstract

Background

Miscarriage is a common complication of pregnancy that can be caused by a wide range of factors. Poor dietary intake of vitamins has been associated with an increased risk of miscarriage, therefore supplementing women with vitamins either prior to or in early pregnancy may help prevent miscarriage.

Objectives

The objectives of this review are to determine the effectiveness and safety of any vitamin supplementation, on the risk of spontaneous miscarriage, maternal adverse outcomes and fetal and infant adverse outcomes.

Search strategy

We searched the Cochrane Pregnancy and Childbirth Group Trials Register (8 September 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003) and MEDLINE (1966 to May 2003), Current Contents (1998 to May 2003) and EMBASE (1980 to May 2003).

Selection criteria

All randomised 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 pregnancy (less than 20 weeks' gestation).

Data collection and analysis

Two review authors independently assessed trials for inclusion, extracted data and assessed trial quality.

Main results

We identified seventeen trials assessing supplementation with any vitamin(s) starting prior to 20 weeks' gestation and reporting at least one primary outcome that were eligible for the review. Overall, the included trials involved 35,812 women and 37,353 pregnancies. Two trials were cluster randomised and contributed data for 20,758 women and 22,299 pregnancies in total. No difference was seen between women taking any vitamins 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) and most of the other primary outcomes, using fixed-effect models. 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) and more likely to have a multiple pregnancy (RR 1.38, 95% CI 1.12 to 1.70, three trials, 20,986 women).

Authors' conclusions

Taking vitamin supplements, alone or in combination with other vitamins, prior to pregnancy or in early pregnancy, does not prevent women experiencing miscarriage or stillbirth. However, women taking vitamin supplements may be less likely to develop pre-eclampsia and more likely to have a multiple pregnancy.

Plain language summary

Vitamin supplementation for preventing miscarriage

Supplementing women with any vitamins, alone or in combination with other vitamins, does not reduce the number of women who miscarry or have a stillbirth.

Poor diet, without enough vitamins, has been associated with an increased risk of women losing their baby in early pregnancy. Taking vitamin supplements prior to pregnancy or in early pregnancy may reduce the risk of miscarriage, but this review did not find this to be the case. However, women taking vitamin supplements may be less likely to develop pre-eclampsia and more likely to have a multiple pregnancy. More research is needed.

Background

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

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

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

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 .

Table 1. Additional outcomes
Study IDOutcomeVitamin - NVitamin - MedianVitamin - RangePlacebo - NPlacebo - MedianPlacebo - Range
Steyn 2003Median birthweight1002491240-38341002664334-4680

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

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

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

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

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 pregnancy525182Relative risk (Fixed, 95% CI)1.06 [0.96, 1.17]
1.2 Trial entry < 12 weeks' gestation1406Relative risk (Fixed, 95% CI)1.32 [0.63, 2.77]
1.3 Trial entry >= 12 weeks' and < 20 weeks' gestation00Relative risk (Fixed, 95% CI)Not estimable
1.4 Trial entry 'mixed' both < 20 and >= 20 weeks' gestation45579Relative 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 pregnancy47809Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.93, 1.24]
2.2 Trial entry < 12 weeks' gestation1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]
2.3 Trial entry >= 12 weeks but <20 weeks' gestation00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
2.4 Trial entry 'mixed' both < 20 and >= 20 week's gestation2275Risk 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 pregnancy37785Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.48, 1.85]
3.2 Trial entry < 12 weeks' gestation00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
3.3 Trial entry >= 12 weeks' but < 20 weeks' gestation00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
3.4 Trial entry 'mixed' both < 20 and >= 20 weeks' gestation45579Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.59, 1.15]
4 Placental abruption2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Placental abruption1283Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.04, 3.19]
4.2 Antepartum haemorrhage including placental abruption1200Risk 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 g45406Risk 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 Breastfeeding14878Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.96, 1.01]
20.2 Formula00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
20.3 Breastfeeding and formula00Risk 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]
Analysis 1.1.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths).

Analysis 1.2.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 2 Early or late miscarriage.

Analysis 1.3.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 3 Stillbirth.

Analysis 1.4.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 4 Placental abruption.

Analysis 1.6.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 6 Pre-eclampsia.

Analysis 1.7.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 7 Perinatal death.

Analysis 1.8.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 8 Neonatal death.

Analysis 1.9.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 9 Preterm birth.

Analysis 1.10.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 10 Very preterm birth.

Analysis 1.11.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 11 Birthweight.

Analysis 1.12.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 12 Small-for-gestational age.

Analysis 1.13.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 13 Congenital malformations.

Analysis 1.14.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 14 Multiple pregnancy.

Analysis 1.19.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 19 Placental weight.

Analysis 1.20.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 20 Method of feeding.

Analysis 1.29.

Comparison 1 Any vitamins versus no vitamins (or minimal vitamins), Outcome 29 Duration of admission to the neonatal intensive care unit.

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 = A32300Relative risk (Fixed, 95% CI)0.98 [0.84, 1.14]
1.2 Allocation concealment = B523771Relative risk (Fixed, 95% CI)1.03 [0.98, 1.09]
1.3 Allocation concealment = C25096Relative 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 = A22017Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.73, 1.34]
2.2 Allocation concealment = B46398Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.96, 1.30]
2.3 Allocation concealment = C175Risk 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 = A32300Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.21, 1.96]
3.2 Allocation concealment = B25968Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.52, 2.43]
3.3 Allocation concealment = C25096Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.58, 1.15]
Analysis 2.1.

Comparison 2 Any vitamins (by allocation concealment), Outcome 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths).

Analysis 2.2.

Comparison 2 Any vitamins (by allocation concealment), Outcome 2 Early or late miscarriage.

Analysis 2.3.

Comparison 2 Any vitamins (by allocation concealment), Outcome 3 Stillbirth.

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 control826122Relative risk (Fixed, 95% CI)1.03 [0.98, 1.08]
1.2 No placebo control25045Relative 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 control68466Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.24]
2.2 No placebo control124Risk 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 control68343Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.49, 1.69]
3.2 No placebo control15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]
Analysis 3.1.

Comparison 3 Any vitamins (by use of placebo), Outcome 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths).

Analysis 3.2.

Comparison 3 Any vitamins (by use of placebo), Outcome 2 Early or late miscarriage.

Analysis 3.3.

Comparison 3 Any vitamins (by use of placebo), Outcome 3 Stillbirth.

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 up323158Relative risk (Fixed, 95% CI)1.04 [0.98, 1.09]
1.2 3 to < 10% losses to follow up11817Relative risk (Fixed, 95% CI)0.96 [0.82, 1.14]
1.3 10 to < 20% losses to follow up25045Relative risk (Fixed, 95% CI)0.92 [0.77, 1.10]
1.4 >= 20% losses to follow up2541Relative risk (Fixed, 95% CI)0.75 [0.50, 1.12]
1.5 Not stated2606Relative 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 up15502Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.97, 1.34]
2.2 3 to < 10% losses to follow up11817Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.69, 1.32]
2.3 10 to < 20% losses to follow up124Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.10, 6.06]
2.4 >= 20 % losses to follow up2541Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.18, 1.06]
2.5 Not stated2606Risk 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 up25785Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.46, 2.37]
3.2 3 to < 10% losses to follow up11817Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.10, 1.98]
3.3 10 to < 20% losses to follow up15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]
3.4 >= 20% losses to follow up2541Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.20, 3.28]
3.5 Not stated1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.77]
Analysis 4.1.

Comparison 4 Any vitamins (by losses to follow up), Outcome 1 Total fetal loss (including miscarriage or combined miscarriages and stillbirths).

Analysis 4.2.

Comparison 4 Any vitamins (by losses to follow up), Outcome 2 Early or late miscarriage.

Analysis 4.3.

Comparison 4 Any vitamins (by losses to follow up), Outcome 3 Stillbirth.

Comparison 5. Vitamin C
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total fetal loss4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Vitamin C + multivitamins versus placebo plus multivitamins1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]
1.2 Vitamin C and vitamin E versus placebo1283Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.05, 5.49]
1.3 Vitamin C versus no supplement/placebo2224Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.58, 2.83]
2 Early or late miscarriage3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Vitamin C + multivitamins versus placebo plus multivitamins1406Risk Ratio (M-H, Fixed, 95% CI)1.32 [0.63, 2.77]
2.2 Vitamin C versus no supplement/placebo2224Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.52, 2.65]
3 Stillbirth2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Vitamin C and vitamin E versus placebo1283Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.05, 5.49]
3.2 Vitamin C versus placebo1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.77]
4 Antepartum haemorrhage and placental abruption2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Vitamin C and vitamin E versus placebo - placental abruption only1283Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.04, 3.19]
4.2 Vitamin C versus placebo - antepartum haemorrhage including placental abruption1200Risk Ratio (M-H, Fixed, 95% CI)7.0 [0.88, 55.86]
5 Pre-eclampsia2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Vitamin C and vitamin E versus placebo1283Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.24, 0.91]
5.2 Vitamin C versus placebo1200Risk 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 placebo1182Risk 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 placebo1181Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.12, 4.03]
8 Preterm birth2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Vitamin C and vitamin E versus placebo1283Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.38, 3.87]
8.2 Vitamin C versus placebo1200Risk 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 placebo1283Risk 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 placebo1200Risk Ratio (M-H, Fixed, 95% CI)1.3 [0.78, 2.17]
Analysis 5.1.

Comparison 5 Vitamin C, Outcome 1 Total fetal loss.

Analysis 5.2.

Comparison 5 Vitamin C, Outcome 2 Early or late miscarriage.

Analysis 5.3.

Comparison 5 Vitamin C, Outcome 3 Stillbirth.

Analysis 5.4.

Comparison 5 Vitamin C, Outcome 4 Antepartum haemorrhage and placental abruption.

Analysis 5.5.

Comparison 5 Vitamin C, Outcome 5 Pre-eclampsia.

Analysis 5.6.

Comparison 5 Vitamin C, Outcome 6 Perinatal death.

Analysis 5.7.

Comparison 5 Vitamin C, Outcome 7 Neonatal death.

Analysis 5.8.

Comparison 5 Vitamin C, Outcome 8 Preterm birth.

Analysis 5.9.

Comparison 5 Vitamin C, Outcome 9 Small-for-gestational age.

Analysis 5.10.

Comparison 5 Vitamin C, Outcome 10 Very preterm birth.

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)4 Relative risk (Fixed, 95% CI)Subtotals only
1.1 Vitamin A versus placebo111723Relative risk (Fixed, 95% CI)1.04 [0.92, 1.17]
1.2 B-carotene versus placebo111303Relative risk (Fixed, 95% CI)1.03 [0.91, 1.16]
1.3 Vitamin A versus B-Carotene111720Relative risk (Fixed, 95% CI)1.01 [0.90, 1.14]
1.4 Vitamin A or B-carotene versus placebo117373Relative risk (Fixed, 95% CI)1.05 [0.91, 1.21]
1.5 Vitamin A (with/without multivitamins) versus multivitamins or placebo11074Relative risk (Fixed, 95% CI)0.80 [0.53, 1.21]
1.6 Vitamin A + iron + folate versus iron + folate2940Relative risk (Fixed, 95% CI)1.34 [0.67, 2.65]
2 Early or late miscarriage2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo11075Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.37, 1.55]
2.2 Vitamin A + iron + folate versus iron + folate1697Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.47, 4.59]
3 Stillbirth3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Vitamin A (with/without multivitamins) versus multivitamins or placebo11075Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.60, 1.79]
3.2 Vitamin A + iron + folate versus iron + folate2940Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.53, 3.01]
4 Neonatal death1 Relative risk (Fixed, 95% CI)Subtotals only
4.1 Vitamin A versus placebo110214Relative risk (Fixed, 95% CI)1.09 [0.92, 1.30]
4.2 B-carotene versus placebo19788Relative risk (Fixed, 95% CI)1.09 [0.91, 1.30]
4.3 Vitamin A versus B-Carotene110228Relative risk (Fixed, 95% CI)1.0 [0.85, 1.18]
4.4 Vitamin A or B-carotene versus placebo115115Relative risk (Fixed, 95% CI)1.09 [0.91, 1.30]
5 Preterm birth2 Relative risk (Fixed, 95% CI)Subtotals only
5.1 Vitamin A versus placebo111723Relative risk (Fixed, 95% CI)1.04 [0.89, 1.21]
5.2 B-carotene versus placebo111303Relative risk (Fixed, 95% CI)1.01 [0.86, 1.18]
5.3 Vitamin A versus B-Carotene111720Relative risk (Fixed, 95% CI)1.03 [0.88, 1.20]
5.4 Vitamin A or B-carotene versus placebo117373Relative risk (Fixed, 95% CI)1.02 [0.89, 1.17]
5.5 Vitamin A (with/without multivitamins) versus multivitamins or placebo11075Relative 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 + folate1594Mean 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 placebo11075Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.58, 1.21]
8 Multiple pregnancy1 Relative risk (Fixed, 95% CI)Subtotals only
8.1 Vitamin A versus placebo110697Relative risk (Fixed, 95% CI)1.35 [0.99, 1.85]
8.2 B-carotene versus placebo110294Relative risk (Fixed, 95% CI)1.37 [1.00, 1.88]
8.3 Vitamin A versus B-Carotene110699Relative risk (Fixed, 95% CI)1.03 [0.77, 1.37]
8.4 Vitamin A or B-carotene versus placebo115845Relative 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 placebo11075Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.71, 1.74]
10 Infant anaemia1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Infant anaemia at 6 weeks' of age - vitamin A + iron + folate versus iron + folate1562Risk 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 + folate1478Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.88, 1.20]
11 Poor growth at childhood follow up2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
11.1 Weight (g) at 6 weeks: vitamin A + iron + folate versus iron + folate1546Mean Difference (IV, Fixed, 95% CI)169.0 [16.55, 321.45]
11.2 Length (cm) at 6 weeks: vitamin A + iron + folate versus iron + folate1546Mean Difference (IV, Fixed, 95% CI)0.70 [0.15, 1.25]
11.3 Weight (g) at 4 months: vitamin A + iron + folate versus iron + folate1148Mean Difference (IV, Fixed, 95% CI)-100.0 [-377.14, 177.14]
11.5 Length (cm) at 4 months: vitamin A + iron + folate versus iron + folate1148Mean Difference (IV, Fixed, 95% CI)-0.5 [-1.33, 0.33]
Analysis 6.1.

Comparison 6 Vitamin A, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths).

Analysis 6.2.

Comparison 6 Vitamin A, Outcome 2 Early or late miscarriage.

Analysis 6.3.

Comparison 6 Vitamin A, Outcome 3 Stillbirth.

Analysis 6.4.

Comparison 6 Vitamin A, Outcome 4 Neonatal death.

Analysis 6.5.

Comparison 6 Vitamin A, Outcome 5 Preterm birth.

Analysis 6.6.

Comparison 6 Vitamin A, Outcome 6 Birthweight.

Analysis 6.7.

Comparison 6 Vitamin A, Outcome 7 Small-for-gestational age.

Analysis 6.8.

Comparison 6 Vitamin A, Outcome 8 Multiple pregnancy.

Analysis 6.9.

Comparison 6 Vitamin A, Outcome 9 Very preterm birth.

Analysis 6.10.

Comparison 6 Vitamin A, Outcome 10 Infant anaemia.

Analysis 6.11.

Comparison 6 Vitamin A, Outcome 11 Poor growth at childhood follow up.

Comparison 7. Multivitamin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths)7 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Multivitamin + folic acid versus no multivitamin/folic acid36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]
1.2 Multivitamin without folic acid versus no multivitamin/folic acid1907Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.56, 1.25]
1.3 Multivitamins with/without folic acid versus no multivitamins/folic acid11368Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.65, 1.27]
1.4 Multivitamin + folic acid versus folic acid21096Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.72, 1.48]
1.5 Multivitamin without folic acid versus folic acid21090Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.62, 1.30]
1.6 Multivitamin with/without folic acid versus folic acid21644Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.69, 1.30]
1.7 Multivitamin with/without vitamin A versus vitamin A or placebo11074Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.39, 0.91]
1.8 Multivitamins versus control15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]
1.9 Multivitamin + vitamin E versus multivitamin without vitamin E or controls1823Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.46, 1.83]
2 Early or late miscarriage5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Multivitamin + folic acid versus no multivitamin/folic acid36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.94, 1.26]
2.2 Multivitamin without folic acid versus no multivitamin/folic acid1907Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.59, 1.34]
2.3 Multivitamin with/without folic acid versus no multivitamin/folic acid11368Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.67, 1.34]
2.4 Multivitamin + folic acid versus folic acid21096Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.72, 1.49]
2.5 Multivitamin without folic acid versus folic acid21090Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.61, 1.31]
2.6 Multivitamin with/without folic acid versus folic acid21644Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.70, 1.33]
2.7 Multivitamin + vitamin E versus multivitamin without vitamin E or controls1823Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.26, 4.13]
3 Stillbirth6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Multivitamin + folic acid versus no multivitamin/folic acid36883Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.51, 2.09]
3.2 Multivitamin without folic acid versus no multivitamin/folic acid1907Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.76]
3.3 Multivitamin with/without folic acid versus no multivitamin/folic acid11368Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.06, 1.97]
3.4 Multivitamin + folic acid versus folic acid21096Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.14, 6.88]
3.5 Multivitamin without folic acid versus folic acid21090Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.20, 4.88]
3.6 Multivitamin with/without folic acid versus folic acid21644Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.19, 4.15]
3.7 Multivitamin versus control15021Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.58, 1.17]
3.8 Multivitamin + vitamin E versus multivitamin without vitamin E or controls1823Risk 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 control15021Risk 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 A14308Relative risk (Fixed, 95% CI)1.11 [0.98, 1.26]
6 Neonatal death4 Relative risk (Fixed, 95% CI)Subtotals only
6.1 Multivitamin + folic acid versus no multivitamin/folic acid14930Relative risk (Fixed, 95% CI)1.59 [0.30, 8.30]
6.2 Multivitamin + vitamin E versus multivitamin without vitamin E or controls1787Relative risk (Fixed, 95% CI)1.44 [0.91, 2.27]
6.3 Multivitamin versus control14895Relative 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 A14122Relative risk (Fixed, 95% CI)1.15 [0.97, 1.36]
7 Preterm birth3 Relative risk (Fixed, 95% CI)Subtotals only
7.1 Multivitamin + folic acid versus no multivitamin/folic acid15502Relative 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 A13320Relative risk (Fixed, 95% CI)0.98 [0.90, 1.07]
7.3 Multivitamin + vitamin E versus multivitamin without vitamin E or controls1814Relative 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 acid14862Mean Difference (IV, Fixed, 95% CI)3.0 [-24.15, 30.15]
9 Small-for-gestational age3 Relative risk (Fixed, 95% CI)Subtotals only
9.1 Multivitamin + folic acid versus no multivitamin/folic acid14862Relative 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 A13320Relative 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 malformations3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Multivitamin + folic acid versus no multivitamin/folic acid25777Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.81, 3.53]
10.2 Multivitamin without folic acid without versus no multivitamin/folic acid1907Risk Ratio (M-H, Fixed, 95% CI)1.60 [0.53, 4.86]
10.3 Multivitamin with/without folic acid versus no multivitamin/folic acid11368Risk Ratio (M-H, Fixed, 95% CI)1.99 [0.75, 5.26]
10.4 Multivitamin + folic acid versus folic acid21096Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.72, 4.04]
10.5 Multivitamin without folic acid versus folic acid21090Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.67, 3.85]
10.6 Multivitamin with/without folic acid versus folic acid21644Risk 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 acid25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]
12 Maternal anaemia1 Relative 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 control14878Risk 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 A14122Relative risk (Fixed, 95% CI)1.10 [0.94, 1.29]
Analysis 7.1.

Comparison 7 Multivitamin, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths).

Analysis 7.2.

Comparison 7 Multivitamin, Outcome 2 Early or late miscarriage.

Analysis 7.3.

Comparison 7 Multivitamin, Outcome 3 Stillbirth.

Analysis 7.4.

Comparison 7 Multivitamin, Outcome 4 Pre-eclampsia.

Analysis 7.5.

Comparison 7 Multivitamin, Outcome 5 Perinatal death.

Analysis 7.6.

Comparison 7 Multivitamin, Outcome 6 Neonatal death.

Analysis 7.7.

Comparison 7 Multivitamin, Outcome 7 Preterm birth.

Analysis 7.8.

Comparison 7 Multivitamin, Outcome 8 Birthweight.

Analysis 7.9.

Comparison 7 Multivitamin, Outcome 9 Small-for-gestational age.

Analysis 7.10.

Comparison 7 Multivitamin, Outcome 10 Congenital malformations.

Analysis 7.11.

Comparison 7 Multivitamin, Outcome 11 Multiple pregnancy.

Analysis 7.12.

Comparison 7 Multivitamin, Outcome 12 Maternal anaemia.

Analysis 7.13.

Comparison 7 Multivitamin, Outcome 13 Breastfeeding.

Analysis 7.14.

Comparison 7 Multivitamin, Outcome 14 Additional outcomes - infant death.

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)5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Folic acid + multivitamin versus no folic acid/multivitamin36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.25]
1.2 Folic acid without multivitamin versus no folic acid/multivitamin1903Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.64, 1.40]
1.3 Folic acid with/without multivitamin versus no folic acid/multivitamin11364Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.69, 1.35]
1.4 Folic acid + multivitamin versus multivitamin21102Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.80, 1.67]
1.5 Folic acid without multivitamin versus multivitamin21090Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.62]
1.6 Folic acid with or without multivitamin versus multivitamin21644Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.82, 1.57]
1.7 Folic acid + iron versus iron175Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 4.59]
2 Early or late miscarriage5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Folic acid + multivitamin versus no folic acid/multivitamin36883Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.94, 1.26]
2.2 Folic acid without multivitamins versus no folic acid/multivitamin1903Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.65, 1.44]
2.3 Folic acid with/without multivitamin versus no folic acid/multivitamin11364Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.70, 1.39]
2.4 Folic acid + multivitamin versus multivitamin21102Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.80, 1.69]
2.5 Folic acid without multivitamin versus multivitamin21090Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.64]
2.6 Folic acid with/without multivitamin versus multivitamin21642Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.79, 1.51]
2.7 Folic acid + iron versus iron175Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.02, 9.03]
3 Stillbirth5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Folic acid + multivitamin versus no folic acid/multivitamin36883Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.51, 2.09]
3.2 Folic acid without multivitamin versus no folic acid/multivitamin1903Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.11, 4.02]
3.3 Folic acid with/without multivitamin versus no folic acid/multivitamin11364Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.15, 2.96]
3.4 Folic acid + multivitamin versus multivitamin21102Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.20, 4.99]
3.5 Folic acid without multivitamin versus multivitamin21090Risk Ratio (M-H, Fixed, 95% CI)4.97 [0.58, 42.29]
3.6 Folic acid with/without multivitamin versus multivitamin21644Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.20, 3.53]
3.7 Folic acid + iron versus iron175Risk 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 iron175Risk 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 A14308Relative risk (Fixed, 95% CI)0.97 [0.85, 1.11]
6 Neonatal death2 Relative risk (Fixed, 95% CI)Subtotals only
6.1 Folic acid + multivitamin versus no folic acid/multivitamin14930Relative risk (Fixed, 95% CI)1.59 [0.30, 8.28]
6.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A14122Relative risk (Fixed, 95% CI)0.96 [0.80, 1.14]
7 Preterm birth3 Relative risk (Fixed, 95% CI)Subtotals only
7.1 Folic acid + multivitamin versus no folic acid/multivitamin15502Relative risk (Fixed, 95% CI)1.01 [0.91, 1.12]
7.2 Folic acid + multivitamin versus no folic acid/multivitamin175Relative risk (Fixed, 95% CI)1.01 [0.65, 1.56]
7.3 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A13320Relative risk (Fixed, 95% CI)1.02 [0.94, 1.11]
8 Birthweight2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
8.1 Folic acid + multivitamin versus no folic acid/multivitamin14862Mean Difference (IV, Fixed, 95% CI)3.0 [-24.15, 30.15]
8.2 Folic acid versus placebo129Mean Difference (IV, Fixed, 95% CI)312.0 [108.52, 515.48]
9 Small-for-gestational age4 Relative risk (Fixed, 95% CI)Subtotals only
9.1 Folic acid + multivitamin versus no folic acid/multivitamin14862Relative risk (Fixed, 95% CI)1.09 [0.94, 1.26]
9.2 Folic acid + iron + zinc + multivitamin + vitamin A versus vitamin A13320Relative 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 malformations3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Folic acid + multivitamin versus no folic acid/multivitamin25777Risk Ratio (M-H, Fixed, 95% CI)1.69 [0.81, 3.53]
10.2 Folic acid without multivitamin versus no folic acid/multivitamin1903Risk Ratio (M-H, Fixed, 95% CI)1.42 [0.45, 4.43]
10.3 Folic acid with/without multivitamin versus no folic acid/multivitamin11364Risk Ratio (M-H, Fixed, 95% CI)1.90 [0.71, 5.04]
10.4 Folic acid + multivitamin versus multivitamin21102Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.51, 2.26]
10.5 Folic acid without multivitamin versus multivitamin21090Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.26, 1.49]
10.6 Folic acid with or without multvitamin versus multivitamin21644Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.43, 1.67]
11 Multiple pregnancy2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
11.1 Folic acid + multivitamin versus no folic acid/multivitamin25141Risk Ratio (M-H, Fixed, 95% CI)1.36 [1.00, 1.85]
12 Maternal anaemia2 Relative 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 placebo129Mean 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 A14122Relative risk (Fixed, 95% CI)0.95 [0.81, 1.11]
Analysis 8.1.

Comparison 8 Folic acid, Outcome 1 Total fetal loss (including miscarriages or combined miscarriages and stillbirths).

Analysis 8.2.

Comparison 8 Folic acid, Outcome 2 Early or late miscarriage.

Analysis 8.3.

Comparison 8 Folic acid, Outcome 3 Stillbirth.

Analysis 8.4.

Comparison 8 Folic acid, Outcome 4 Pre-eclampsia.

Analysis 8.5.

Comparison 8 Folic acid, Outcome 5 Perinatal death.

Analysis 8.6.

Comparison 8 Folic acid, Outcome 6 Neonatal death.

Analysis 8.7.

Comparison 8 Folic acid, Outcome 7 Preterm birth.

Analysis 8.8.

Comparison 8 Folic acid, Outcome 8 Birthweight.

Analysis 8.9.

Comparison 8 Folic acid, Outcome 9 Small-for-gestational age.

Analysis 8.10.

Comparison 8 Folic acid, Outcome 10 Congenital malformations.

Analysis 8.11.

Comparison 8 Folic acid, Outcome 11 Multiple pregnancy.

Analysis 8.12.

Comparison 8 Folic acid, Outcome 12 Maternal anaemia.

Analysis 8.13.

Comparison 8 Folic acid, Outcome 13 Placental weight.

Analysis 8.14.

Comparison 8 Folic acid, Outcome 14 Additional outcomes - infant death.

Appendices

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

DateEventDescription
20 September 2008AmendedConverted to new review format.

History

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

Contributions of authors

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

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

Internal sources

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

External sources

  • Department of Health and Ageing, Australia.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Briscoe 1959

Methods

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

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

Documentation of exclusion: none reported.

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

Participants406 women were recruited in the study. Eligible women were "unselected patients" in private obstetrics care, that were less than or equal to 10 weeks' pregnant, and were eligible regardless of whether they were currently bleeding or the number of previous pregnancies. Women greater than 10 weeks' gestation were excluded. 406 women were randomised to either vitamin C (n = 303) or placebo (n = 103) no losses to follow up were reported. 77 women in the study had more than 2 previous miscarriages and/or bleeding in the pregnancy, and 329 had 2 or less miscarriages and no bleeding in the pregnancy.
InterventionsAll women were given 200 tablets, containing either 100 mg each of ascorbic acid and hesperidin or placebo (an inert powder).
The study lasted for 7 weeks. For the first two weeks, women were asked to take 8 tablets daily (i.e. daily 800 mg each of vitamin C and hesperidin or placebo). For the following 5 weeks, women took 4 tablets daily (i.e. daily 400 mg each of vitamin C and hesperidin or placebo). All women received a multiple vitamin supplement containing 50 mg vitamin C.
Outcomes1. Spontaneous miscarriage.
2. Spontaneous miscarriage in women with 2 or fewer previous miscarriages and no bleeding in the current pregnancy.
3. Spontaneous miscarriage in women with more than 2 previous miscarriages and/or bleeding in the current pregnancy.
4. Spontaneous miscarriage in women who experienced recurrent miscarriage.
NotesWomen's risk of spontaneous and recurrent miscarriage is unclear, as there is no information about concurrent medical conditions or other risk factors for miscarriage. 9 of the 406 women were classified as experiencing recurrent miscarriage.
No information is available about women's nutritional status.
No sample-size calculation reported.
Intention-to-treat analyses performed (no losses to follow up reported).
Compliance: no compliance information reported.
Location: Philadelphia, USA.
Timeframe: unclear.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Chappell 1999

Methods

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

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

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

Use of placebo control: placebo control.

Participants283 women were recruited into the study. Inclusion criteria: abnormal Doppler waveform in either uterine artery at 18-22 weeks' gestation or a history in the preceding pregnancy of pre-eclampsia necessitating delivery before 37 weeks' gestation, eclampsia or the syndrome of HELLP.
Exclusion criteria: heparin or warfarin treatment, abnormal fetal-anomaly scan or multiple pregnancy.
Women were randomised at 18-22 weeks' gestation; however, women with a previous history who were identified at an earlier stage were randomised at 16 weeks' gestation. Women with abnormal Doppler waveform analysis returned for a second scan at 24 weeks' gestation, those with a normal waveform at this time stopped treatment and were withdrawn from the study. The remaining women who had persistently abnormal waveforms, and those with a previous history or pre-eclampsia remained in the study and were seen every 4 weeks through the rest of pregnancy. 1512 women underwent Doppler screening, 273 women had abnormal waveforms and of these, 242 women consented to the study. An additional 41 women who had a history of pre-eclampsia consented. 283 women were randomised to either the vitamin C and E group (n = 141) or the placebo group (n = 142), 72 women had normal Doppler scans at 24 weeks' gestation and 24 women did not return for a second scan and were withdrawn. A further 27 women withdrew from the trial after 24 weeks' gestation for various reasons. In total, 160 women completed the trial protocol until delivery, 79 in the vitamin C and E group and 81 in the placebo group. Pregnancy outcome data were presented for all women randomised (n = 283) as well as only for those women completing the trial protocol (n = 160).
InterventionsWomen randomised to the vitamin C and E group received tablets containing 1000 mg vitamin C daily and capsules containing 400 IU vitamin E daily.
Women randomised to the placebo group received tablets containing microcrystalline cellulose and soya bean oil, that were identical in appearance to the vitamin C tablets and vitamin E capsules. After 24 weeks' gestation women were seen every 4 weeks, and blood samples were taken at each visit.
Outcomes1. Ratio of PAI-1 to PAI-2.
2. Incidence of pre-eclampsia.
3. Placental abruption.
4. Spontaneous preterm delivery (< 37 weeks).
5. Intrauterine death.
6. Small-for-gestational-age infants (on or below the 10th centile).
7. Mean systolic and diastolic blood pressure before delivery.
8. Gestational age at delivery (median, IQR).
9. Birthweight (median, IQR).
10. Birthweight centile (median, IQR).
NotesWomen's risk of spontaneous and recurrent miscarriage is unclear, women were at high risk of pre-eclampsia.
No information is available about women's nutritional status.
Sample-size calculation reported, based on a 30% reduction in PAI-1.
Intention-to-treat analyses performed.
Compliance: "within the treated group, plasma ascorbic acid concentration increased by 32% from baseline values and plasma alpha-tocopherol increased by 54%".
Location: London, UK.
Timeframe: unclear.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Christian 2003

Methods

Randomisation and allocation concealment: cluster randomisation of 30 "village development communities" using blocks of 5 within each community, randomisation occurred by "drawing numbered identical chits from a hat".

Blinding of outcome assessment: women, field staff, investigators and statisticians did not know the treatment codes until the end of the study.

Documentation of exclusion: 534 (10.7%) women or infants were excluded and 343 (6.7%) infants were lost to follow up.

Use of placebo control: no placebo given, women in the control group were given vitamin A only.

ParticipantsAll women of reproductive age in the 30 village development communities were considered eligible. Women who were currently pregnant, breastfeeding a baby < 9 months' old, menopausal, sterilised or widowed were excluded.
Within the timeframe, 14,185 women were identified as likely to become pregnant. Of these, 4998 pregnancies were confirmed with urine testing; however, 4926 women remained in the trial with 72 women excluded either due to false positive pregnancy testing, unknown outcomes or induced abortions. Women were allocated to either vitamin A control (n = 1037), folic acid (n = 929), folic acid-iron (n = 940), folic acid-iron-zinc (n = 982) or multiple micronutrients (n = 1038). 830 pregnancies (16.8%) ended in either miscarriage, stillbirth or maternal death. The remaining pregnancies resulted in 4130 livebirths. Of these, 805 (19.5%) were excluded as they were either lost to follow up or birthweight was measured after 72 hours after birth. The final analysis involved 3325 infants allocated to control (n = 685), folic acid (n = 628), folic acid-iron (n = 635), folic acid-iron-zinc (n = 672) or multiple micronutrients (n = 705).
InterventionsWomen were allocated to one of five groups:
1. control (1000 mcg vitamin A);
2. folic acid (400 mcg, 1000 mcg vitamin A);
3. folic acid-iron (60 mg ferrous fumarate, 400 mcg folic acid, 1000 mcg vitamin A);
4. folic acid-iron-zinc (30 mg zinc sulphate, 60 mg ferrous fumarate, 400 mcg folic acid, 1000 mcg vitamin A);
5. multiple micronutrients-folic acid-iron-zinc (60 mg ferrous fumarate, 400 mcg folic acid, 30 mg zinc sulphate,1000 mcg vitamin A, 10 mcg vitamin D,10 mg vitamin E, 1.6 mg vitamin B-1, 1.8 mg vitamin B-2, 20 mg niacin, 2.2 mg vitamin B-6, 2.6 mcg vitamin B12, 100 mg vitamin C, 65 mcg vitamin K, 2.0 mg copper, 100 mg magnesium).
At enrolment women received 15 caplets and were instructed to take one caplet every night. Women were then visited by field staff twice a week to monitor compliance and replenish supplies of the caplets.
Outcomes1. Perinatal death, defined as stillbirths (gestational age >= 28 wk) and deaths among liveborn infants in the first 7 days of life.
2. Neonatal deaths, defined as deaths from 0 to 28 days of life.
3. Infant death, defined as deaths from 0 to 90 days of life.
4. Birthweight.
5. Length.
6. Chest circumference.
7. Head circumference.
8. Low birthweight (< 2500 g).
9. Small-for-gestational age (below 10th centile for USA national reference for fetal growth).
10. Preterm birth (< 37 weeks).
"The rate if miscarriage did not differ by treatment group and ranged between 12% and 15% (data not show)". "Miscarriage was defined as a pregnancy that ended in a fetal loss before 28 wk of gestation."
NotesThe following information was given about multiple births: "the numbers of twin pregnancies (34 pairs of liveborn twins and 8 pairs with one stillborn) was comparable across treatment groups".
Women's risk of spontaneous and recurrent miscarriage is unclear, as there is no information about concurrent medical conditions or other risk factors for miscarriage.
Information on women's diet was recorded; however, no information was reported about micronutrient intake, including vitamin A.
Sample-size calculation reported, 1000 pregnancies per group allowed for a minimum detectable difference of 75 g in birthweight, and >= 34% reduction in fetal loss and >= 45% reduction in infant mortality, with 80% power.
Intention-to-treat analyses performed and the relative risks and confidence intervals were adjusted to account for any cluster design effect.
Compliance: median compliance during pregnancy was 88%.
Location: Salarhi, Nepal.
Timeframe: December 1998-April 2001.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Correia 1982

Methods

Randomisation and allocation concealment: unclear, "randomised" stated in text but no details given.

Blinding of outcome assessment: "double blind clinical test" stated in the text.

Documentation of exclusion: 16 women (35%) excluded.

Use of placebo control: placebo control.

Participants45 women were initially recruited into the study; however, results are presented for 29 women (folic acid group n = 16, placebo group n = 13). Women were excluded if they had any "pathological data" or if there was "evidence of neglect". No other details given.
InterventionsWomen were randomised to either daily ingestion of 10 mg folic acid or placebo. Women were asked to take the tablets from between 12 and 16 weeks until the end of pregnancy.
Outcomes1. Fetal weight (birthweight).
2. Placental weight.
NotesWomen risk of spontaneous and recurrent miscarriage is unclear. Women's nutritional status is also unclear.
No sample-size calculation reported.
Compliance: unclear, no details given.
Country: Portugal.
Timeframe: unknown.
Published in Portuguese.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Czeizel 1994

Methods

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

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

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

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

Participants7765 women were recruited into the study. Women participating in the HOFPP who volunteered to take part, were not currently pregnant, and who conceived within 12 months of ceasing contraception. In the first two years of the HOFPP, women were also required to be aged < 35 years, and not to have had a previous pregnancy except a prior induced abortion. 7905 women were approached, of which 140 refused participation, 7765 were randomised and 5502 women had a confirmed pregnancy and were allocated to either multivitamins (n = 2819) or control (n = 2683). 49 women of the 5502 confirmed pregnancies were lost to follow up.
InterventionsWomen were provided with multivitamin or trace element 'control' from at least 28 days before conception continuing until at least the second missed menstrual period.
The multivitamin with folate contained 6000 IU vitamin A, 1.6 mg vitamin B1, 1.8 mg vitamin B2, 2.6 mg vitamin B6, 4.0 mcg vitamin B12, 100 mg vitamin C, 500 IU vitamin D, 15 mg vitamin E, 19 mg nicotinamide, 10 mg calcium pantothenate, 0.2 mg biotin, 0.8 mg folic acid, 125 mg calcium, 125 mg phosphorus, 100 mg magnesium, 60 mg iron, 1 mg copper, 1 mg manganese, 7.5 mg zinc.
The trace element control contained 7.5 mg vitamin C, 1 mg copper, 1 mg manganese and 7.5 mg zinc.
Outcomes1. Neural tube defects and other birth defects.
2. Miscarriage.
3. Ectopic pregnancy.
4. Termination of pregnancy.
5. Live births.
6. Stillbirths.
7. Multiple gestation.
Subgroup data is available on menstrual cycle, first trimester symptoms and sexual activity.
NotesWomen's risk of spontaneous and recurrent miscarriage is unclear.
Information on their dietary status is unknown.
No sample-size calculation reported.
Partial intention-to-treat analyses performed.
Compliance: compliance was assessed by questioning, checking the tick-off on the basal temperature chart and counting of unused tablets. 70% of women in the multivitamin group and 71% in the control group took the full course of the supplements, with an additional 20% and 21% in the multivitamin and control groups respectively receiving a partial course of supplementation.
Location: Hungary.
Time frame: 1 February 1984-30 April 1992.
The denominators used for this trial are the number of women randomised and with a confirmed pregnancy (i.e. 2819 for the multivitamin group and 2683 for the control group).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Fawzi 1998

Methods

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

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

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

Use of placebo control: placebo given.

Participants1085 women were recruited into the study. Pregnant women between 12 and 27 weeks' gestation who were HIV-1 infected, living in Dar es Salaam and intended to stay there for at least one year were eligible for the study. Women not HIV-1 positive or moving out of Dar es Salaam were excluded. 13,879 pregnant women consented to be HIV-1 tested, of which 1806 were positive, and 1085 were randomised. Of these, 3 women were not pregnant and 7 women died before delivery and were excluded from the trial. Of the remaining 1075 women, 54 women (5%) were lost to follow up by the time of delivery, leaving birth outcomes reported for 1021 women. Women were randomised to 1 of 4 groups: vitamin A (n = 269), multivitamins excluding vitamin A (n = 269); multivitamins including vitamin A (n = 270) or placebo (n = 267).
InterventionsWomen were randomised to 1 of 4 groups:
1. vitamin A (30 mg beta-carotene plus 5000 IU preformed vitamin A);
2. multivitamins excluding vitamin A (20 mg vitamin B1, 20 mg vitamin B2, 25 mg vitamin B6, 100 mg niacin, 50 mcg vitamin B12, 500 mg vitamin C, 30 mg vitamin E, 0.8 mg folic acid);
3. multivitamins including vitamin A, all formulated in 2 tablets; or
4. placebo.
All women received 400 mg ferrous sulphate and 5 mg folate daily, as well as 500 mg chloroquine phosphate weekly. At delivery, all women taking vitamin A were to receive an additional oral dose of 200,000 IU vitamin A and the others an extra dose of a placebo. Pill counts were conducted at each visit and new tablets were given out at each visit.
Outcomes1. Miscarriage, defined as delivery before 28 weeks' gestation.
2. Stillbirth, defined as delivery of a dead baby at or after 28 weeks' gestation.
3. Fetal death, defined as either miscarriage or stillbirth.
4. Low birthweight, defined as birthweight less than 2500 g.
5. Very low birthweight, defined as birthweight less than 2000 g.
6. Preterm delivery, defined as delivery before 37 weeks.
7. Severe preterm birth, defined as delivery before 34 weeks.
8. Small-for-gestational age, defined as birth weight less than the 10th percentile for gestational age.
NotesWomen's risk of spontaneous and recurrent miscarriage was unclear, although may be increased due to their HIV-1 positive status.
Women's nutritional status is also unclear.
Figures change with serial publications, particularly for secondary outcomes, and results are not reported separately for the individual 4 groups. Results are reported as: any multivitamins, multivitamin, any vitamin A or no vitamin A.
Sample-size calculation performed allowing for 20% loss to follow up.
Intention-to-treat analyses performed.
Compliance: compliance assessed by the percentage of prescribed tablets absent from the returned bottles, and in plasma vitamin A concentrations in a subset of 100 women. Median compliance assessed using pill counts was 90% by the time of delivery.
Location: Tanzania.
Timeframe: April 1995-July 1997.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Fleming 1968

Methods

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

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

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

Use of placebo control: control tablet containing iron given.

Participants75 women were recruited into the trial. Women were eligible if they were primigravida, less than 26 weeks' pregnant (range of gestation 10-26 weeks'), with haematocrit value (PCV) 27 per cent or more, and who had not received treatment so far as was known. Women with Haemoglobin (Hb) SC, Hb.SS, Hb.CC were excluded. Alternate patients were allocated to group A (placebo) or B (folic acid). 75 women were included (40 in group A and 35 in group B) initially; however, only 26 in group A and 28 in group B completed the trial. 16 women (10 in group A and 8 in group B) defaulted from the trial, 3 (2 in group A and 1 in group B) were anaemic on the second visit warranting folic acid treatment, 1 in group A self medicated with folic acid and 1 in group A 'aborted'.
InterventionsAll women received antimalarials and iron supplements as per the standard antenatal care at the hospital.
Women in group B received 5 mg folic acid tablets on each attendance, which was fortnightly initially and weekly in the last trimester.
Group A received "one tablet of lactose base and colouring matter in the same manner."
Outcomes1. PCV and reticulocyte index.
2. Serum folic acid concentration and 'megaloblastic score'.
3. Malarial infection.
4. Maternal morbidity (pyelonephritis, pre-eclamptic toxaemia, septicaemia, puerperal psychosis).
5. Prematurity.
6. Birthweight (mean birthweight but no standard deviation).
7. Fetal mortality.
NotesResults not reported as intention to treat; however, where possible, the review authors included data in the review as intention to treat.
Unclear of women's risk of spontaneous and recurrent miscarriage.
16 women in the trial showed evidence of folate deficiency at trial entry.
Sample-size calculation: none reported.
No intention-to-treat analyses performed.
Compliance: no compliance information reported specifically; however, women were "seen to swallow" the tablets at their fortnightly and weekly visits.
Location: Nigeria.
Time frame: unclear.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?NoC - Inadequate

Hemmi 2003

Methods

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

Blinding of outcome assessment: unclear, no details given.

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

Use of placebo control: no placebo control.

Participants150 women were recruited into the study. Women with a luteal phase defect, as described by a peak serum P level < 120 mg/mL in the mid-luteal phase measured at 3 time points, were eligible and invited to participate. Luteal phase defects were ascertained in two consecutive menstrual cycles, and the third cycle was the intervention cycle. Women receiving IVF-ET treatment were excluded. 313 women were considered for enrolment in the study, 150 (48%) were randomised. 28 women were withdrawn from the control group, leaving 122 women in the study, who were allocated to vitamin C (n = 76) or control (n = 46). 5 women in the control group and 19 women in the vitamin C group became pregnant during the study period.
InterventionsWomen in the intervention group took 750 mg vitamin C per day from the first day of the third menstrual cycle until a urinary pregnancy test was positive. Pregnancy rate was checked up until 6 months after the study cycle was started. Women in the control group received no supplementation and no treatment was given in the third cycle.
Outcomes1. Serum P concentrations.
2. Serum E2 (oestrogen) concentrations.
3. Pregnancy rate.
4. Miscarriage.
NotesWomen's risk of spontaneous or recurrent miscarriage was unclear according to criteria specified in the review.
Their dietary intake of vitamin C is unknown.
No sample-size calculation was reported.
Analyses were not based on intention to treat.
Compliance: no details of any compliance assessments were given.
Country: Japan.
Time frame: January 1997-December 2000.
The denominators used for this trials are the number of women randomised and with a confirmed pregnancy (i.e. 19 for the vitamin group and 5 for the control group).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

ICMR 2000

Methods

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

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

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

Use of placebo control: placebo control.

Participants466 women were recruited into the study. Women who had previously given birth to a child with an open NTD, and planned to have another child were eligible and invited to participate. This was regardless of their parity, number of previous births with an NTD, age, consanguinity, and socio-economic status. Women who had previously given birth to a child with closed spina bifida, or with a history of diabetes or abnormal fasting and post-prandial blood sugar, history of epilepsy, congenital anomalies indicative of a genetic syndrome in the previous NTD, history of vitamin intake in the 3 months prior to enrolment, and pregnancy were excluded. 466 women were enrolled and randomised to either vitamin (n = 231) or placebo (n = 235), of these women, 90 were lost to follow up immediately and 71 did not conceive until the final follow up. Of the remaining 305 women who were known to become pregnant (vitamin n = 152, placebo n = 153), pregnancy outcomes were unknown for 26 women. In the paper, 279 of the initial 466 women were included in the analysis; however, in this review results are presented for main outcomes on an intention-to-treat basis (i.e. n = 466).
InterventionsThe folic acid containing multivitamin included 120 mg ferrous sulphate, 240 mg calcium phosphate, 4000 IU vitamin A, 400 IU vitamin D, 2.5 mg vitamin B1, 2.5 mg vitamin B2, 2 mg vitamin B6, 15 mg nicotinamide, 40 mg vitamin C, 4 mg folic acid, 10 mg zinc.
The placebo tablets contained the following trace elements: 120 mg ferrous sulphate and 240 mg calcium phosphate. Both capsules were identical in appearance and women were provided with the tablets from at least 28 days before conception and continuing until at least the second missed menstrual period.
Outcomes1. Recurrence of neural tube defects.
2. Livebirths.
3. Stillbirths.
4. Spontaneous and induced abortion.
5. Multiple birth.
NotesThe risk profile of women in the trial for spontaneous and recurrent miscarriage is unclear, as is the dietary intake of participants.
Sample-size calculation performed, assuming a 20 per cent drop out rate. The trial was terminated after publication of the MRC trial in 1991.
Compliance: compliance was assessed at 3 monthly visits, by checking a diary card maintained by the woman and the number of capsules returned. If the total number of missed days in 3 months did not exceed 10 days, and the total number of missed days at a stretch did not exceed three, compliance was taken as satisfactory. Women not meeting the above criteria were excluded if they became pregnant in that particular quarter. No compliance data are specifically reported.
Analyses not based on intention to treat.
Country: India.
Time frame: 1988-1991.
The denominators used for this trial are based on the number of women randomised (i.e. 231 for the vitamin group and 235 for the placebo group). There was not enough information to accurately confirm the number of women that did or did not become pregnant due to the large number of losses to follow up.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Katz 2000

Methods

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

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

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

Use of placebo: placebo control.

Participants15,832 women were recruited into the study. All married women of child bearing age in the Salarhi district, Nepal, were eligible and invited to participate in the study. Women migrating into the study area, or women that were never pregnant or refused participation, or women who migrated before being pregnant, were excluded from the analysis. Eligible women were identified from census data and marriage registers. 44,646 women were recruited, of which 1136 (2.5%) were excluded as they either emigrated before becoming pregnant, died or refused consent. During the study period 15,832 women identified themselves as being pregnant, and 157 women were lost to follow up in the postpartum period. Results are reported for 17,373 pregnancies, allocated to the following groups: vitamin A (n = 6070), beta-carotene (n = 5650) or placebo (n = 5653). Denominators for the treatment groups vary for the measures of early infant mortality, due to losses to follow up after birth.
InterventionsThe three treatment groups consisted of a weekly single oral supplement of either:
1. 23,300 IU preformed vitamin A as retinyl palmitate;
2. 42 mg of all trans beta-carotene;
3. placebo.
All capsules contained mg dl-alpha-tocopherol as an antioxidant. Women took the tablets prior to conception, during pregnancy and postpartum, for a total of 3.5 years.
Outcomes1. Fetal loss, defined as any reported miscarriage, stillbirth or maternal death during pregnancy. The outcomes were based on self reports, and women who reported to be pregnant for >= 6 weeks but then no longer reported being pregnant were considered to have had a miscarriage.
Serial publications also reported neonatal death.
NotesWomen's risk profile for spontaneous or recurrent miscarriage was unclear, as was their dietary intake of vitamin A.
Compliance: women were distributed the capsules in their home on a weekly basis, receipt of capsules was noted only if the distributor observed the woman swallowing the capsule. Over half of the women who became pregnant during the study received over 80% of their intended supplements, and 75% of pregnant women received at least half of their eligible doses.
There were serial publications of this study causing the study numerators and denominators to vary between published versions, and multiple pregnancy figures reported did not include higher order pregnancies.
Sample-size calculation performed.
Partial intention-to-treat analyses, and the relative risks and confidence intervals were adjusted to account for any cluster design effect.
Country: Nepal.
Timeframe: April 1994-September 1997.
The denominators used for this trial are the number of women randomised who identified themselves as pregnant (i.e. 6070 for the vitamin A group, 5650 for the beta-carotene group and 5653 for the placebo group).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Kirke 1992

Methods

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

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

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

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

Participants354 women were recruited into the study. Women with a previous neural tube defect defined as anencephalus, iniencephalus, encephalocoele, and spina bifida aperta, who were not pregnant when contacted but were planning a future pregnancy, were eligible and invited to participate. Women were identified from case registers at the participating hospitals. Women with conditions likely to result in impaired absorption from the gastrointestinal tract were excluded.
435 women were approached, of which 354 (84%) consented and were randomised to either F (n = 115 ), MV (n = 119) or MF (n = 120). 16 women did not become pregnant, and 75 women withdrew; however, their pregnancy outcome status was known, and 18 of these women subsequently became pregnant after withdrawing. 3 women were lost to follow up. 281 women (93 in the F group, 93 in the MF group and 95 in the MV group) became pregnant in the study period and their pregnancy outcome was known.
InterventionsIndistinguishable trial tablets were initially made by Beecham and Glaxo, however Beecham withdrew their support after 55 women had been randomised. After this time a commercially available pregnavite Forte F was used (MF tablet) and Antigen Pharmaceuticals produced a white multivitamin tablet without folic acid. This was associated with a loss of blinding. Women were randomised to one of three treatments:
1. folic acid alone (F);
2. multivitamin with folic acid (MF);
3. multivitamin with no folic acid (MV).
The F and MF resulted in a daily dose of 0.3 mg folic acid. The MF and MV resulted in a daily dose of 4000 IU vitamin A, 400 IU calciferol, 1.5 mg thiamine hydrochloride, 1.5 mg riboflavine, 1 mg pyridoxine hydrochloride, 15 mg nicotinamide, 40 mg ascorbic acid, 480 mg calcium phosphate, and 252 mg ferrous sulphate. Women took the tablets for at least 2 months prior to conception and until the date of the 3rd missed period.
Outcomes1. Recurrence risk of neural tube defects.
2. Spontaneous abortion.
3. Ectopic pregnancy.
4. Livebirth.
5. Stillbirth.
6. Congenital malformations excluding neural tube defects.
NotesThe trial was stopped after there were poor recruitment rates and birth rates. A sample-size calculation required 462 women to show a reduction in neural tube defects from 5% to 1%. Data from 106 women who were already pregnant at time of recruitment are also included.
The risk profile of women in the trial for spontaneous and recurrent miscarriage is unclear, as is their dietary intake.
Compliance: compliance was assessed on tablet counts and blood tests; however, the results are not presented.
Intention-to-treat analyses were performed.
Country: Republic of Ireland.
Timeframe: December 1981-January 1988.
The denominators used for this trial are the number of women randomised who became pregnant in the study period and their pregnancy outcome was known (i.e. 93 in the F group, 93 in the MF group and 95 in the MV group).
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Kumwenda 2002

Methods

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

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

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

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

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

ParticipantsPregnant women between 18 and 29 weeks' gestation and infected with HIV. The average gestation of participants was 23 weeks. 693 women were enrolled and allocated to either vitamin A (n = 340) or control (n = 357), of which pregnancy outcomes were known for 623 women. 63 women were lost to follow up and 14 sets of twins were excluded due to their higher risk of low birthweight and infant mortality.
InterventionsAll women received orally administered daily doses of 30 mg iron and 400 mcg folate during the study. Women in the intervention group received 10,000 IU vitamin A (3 mg retinol equivalent) orally, in addition to the iron and folate supplements. Women were asked to take the tablets from enrolments until delivery. Tablet counts were conducted every 4 weeks. All women received 30 mg retinol equivalents at 6 weeks postpartum, according to standard postpartum care in Malawi.
Outcomes1. Infant haemoglobin level at 6 weeks and 12 months of age.
2. Percentage of infants with anaemia at 6 weeks of age and at 12 months, defined as a haemoglobin level of < 110 g/L.
3. Birthweight.
4. Percentage of infants < 2500 g at birth.
5. Weight and length at 6 weeks, 14 weeks and 6 months of age.
6. Transmission of HIV to the infant, infant mortality at < 6 weeks of age, at 12 months and at 24 months.
7. Stillbirth and spontaneous abortion (undefined).
NotesWomen's risk of spontaneous and recurrent miscarriage is unclear, although may be increased due to their HIV status.
50% of women in the vitamin A group and 51% of women in the control group had deficient levels of vitamin A (defined as plasma vitamin A < 0.70 umol/L) at trial entry.
Sample-size calculation performed.
No intention-to-treat analyses were performed.
Compliance: more than 95% of women in both groups took > 90% of study supplements, as ascertained by tablet counts.
Location: Malawi.
Timeframe: November 1995-December 1996.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

MRC 1991

Methods

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

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

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

Use of placebo control: placebo control.

Participants1817 women were recruited into the study. Women who had a previous pregnancy affected by a neural tube defect, and were planning another pregnancy and not already taking supplements were eligible for the study. Women whose affected child had Meckel's syndrome and those women with epilepsy were excluded. 1817 women were randomised to either F (n = 449), MV (n = 453), MF (n = 461) or P (n = 454), of which, 1195 were informative pregnancies that is, where the outcome of NTD or not was definitely known (F n = 298, MV n = 302, MF n = 295, P n = 300). Results for pregnancy loss are reported for both informative and not informative pregnancies. 164 women were excluded as they may have been pregnant at the time of randomisation.
InterventionsWomen were randomised into 1 of 4 groups:
1. 4 mg, 240 mg di-calcium phosphate and 120 mg ferrous sulphate (F);
2. 4000 IU vitamin A, 400 IU calciferol, 1.5 mg thiamine hydrochloride, 1.5 mg riboflavine, 1 mg pyridoxine hydrochloride, 15 mg nicotinamide, 40 mg ascorbic acid, 240 mg di-calcium phosphate and 120 mg ferrous sulphate (MV);
3. folic acid combined with the multivitamins specified above (MF);
4. placebo containing 240 mg di-calcium phosphate and 120 mg ferrous sulphate only (P).
Women took the tablets prior to conception and attended the site every 3 months to collect additional supplies and again during the 12th week of pregnancy. No special dietary advice was given to women.
Outcomes1. Neural tube defect and other birth defects.
2. Spontaneous abortions.
3. Ectopic pregnancy.
4. Termination or pregnancy.
5. Livebirth.
6. Stillbirth.
7. Multiple pregnancy.
Subsequent publications report on blood folate and zinc concentrations.
NotesThe trial was stopped early after there were 1195 informative pregnancies, according to prespecified stopping rules. The aim of the study was to obtain information on at least 2000 informative pregnancies unless a sufficiently clear result emerged sooner.
Women's risk profile for spontaneous and recurrent miscarriage was unclear, as was their nutritional status.
Compliance: compliance based on self reports, and data were available for women with an informative pregnancy only, where 79 (6%) women reported they stopped taking their capsules before their last scheduled visit.
Intention-to-treat analyses are reported in this review including not informative pregnancies (i.e. n = 1817).
Location: multi-national study coordinated from the United Kingdom.
Timeframe: July 1983-April 1991.
The denominators used for this trial are the number of women randomised i.e. (449 for the F group, 453 for the MV group, 461 for the MF and 454 for the P group). There was no information provided about any women randomised that did not become pregnant in the study period.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

People's League 1942

Methods

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

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

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

Use of placebo control: no placebo given.

Participants5644 women were recruited into the study. All women attending the antenatal clinics and who were less than or equal to 24 weeks' gestation and who were in 'good health' were eligible for the study. Women who were more than 24 weeks' gestation and women who suffered from any disease or physical abnormality were excluded from the study. After enrolment, women who had twin births and who miscarriage at an early stage were also excluded.
5644 women were initially enrolled in the study of which 5022 (89%) remained in the study. Of the 622 (11%) women withdrawn from the trial, 494 were evacuated from the London area (due to World War 2), 39 women had twin births and 89 women miscarried at an early stage. 5022 women remained in the study and were allocated to wither multivitamins (n = 2510) or control (n = 2512). Women were further divided into primiparae and multiparae, and various age groups.
InterventionsWomen allocated to the treatment group were given daily vitamin C 100 mg, ferrous iron 0.26 g, calcium 0.26 g, minute quantities of iodine, manganese and copper, adsorbate of vitamin B1 containing all factors of the B complex and halibut liver oil 0.36 g containing vitamin A (52,000 IU per g) and vitamin D (2500 IU per g).
Women allocated to the control group received no placebo.
Outcomes1. Toxaemia classified into subgroups based on: hypertension only, albuminuria with or without hypertension, or hypertension with albuminuria (pre-eclampsia).
2. Maternal sepsis.
3. Length of gestation (categorised as less than 40 weeks, 40 weeks, and greater than 40 weeks).
4. Percentage of women breastfeeding.
5. Stillbirth.
6. Neonatal mortality (defined as death before 8 days).
7. Birthweight (pounds) (only reported for primiparae and multiparae separately).
NotesWomen risk status for spontaneous and recurrent miscarriage is unclear.
Dietary intake at trial entry: "vitamin C shortage affected about half the women".
Intention-to-treat analyses: not performed.
Compliance: unclear, no information provided.
Sample-size calculation: unclear. "It was decided that the investigation should include a minimum of 5000 pregnant women". No other details given.
Location: England.
Timeframe: 1938-1939.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?NoC - Inadequate

Rush 1980

Methods

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

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

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

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

Participants1051 women were recruited into the study. Women eligible were Black, English speaking, and not greater than 30 weeks' gestation. They also had one of the following criteria: low pre-pregnant weight (under 110 pounds at conception); low weight gain at the time of recruitment; at least 1 previous low birthweight infant; a history of protein intake of less than 50 g in the 24 hours preceding recruitment. Women were not eligible if they were known to be seeking a termination, had specific chronic health disorders, if they admitted to recent use of narcotics or heavy use of alcohol, or weighed >= 140 pounds at conception.
The mean gestation at enrolment ranged from 16-18 weeks for the treatment groups.
1225 women were invited to join the study, of which 1051 (84%) consented. Of these, 237 (22%) were excluded and 814 women (77%) remained active in the study until delivery and were allocated to one of three groups: supplement (n = 263), complement (n = 272) or control (n = 279).
InterventionsWomen were randomised to 1 of 3 groups:
1. high protein supplement (daily 40 g animal protein, 470 calories, 1000 mg calcium, 100 mg magnesium, 60 mg iron, 4 mg zinc, 2 mg copper, 150 mcg iodine, 6000 IU vitamin A, 400 IU vitamin D, 30 USPU vitamin E, 60 mg vitamin C, 3 mg vitamin B1, 15 mg vitamin B2, 15 mg niacin, 2.5 mg vitamin B6, 1 mg pantothenic acid, 200 mcg biotin, 350 mcg folic acid, 8 mcg vitamin B12);
2. balanced protein-energy complement (6 g animal protein, 250 mg calcium, 12 mg magnesium, 40 mg iron, 0.084 mg zinc, 0.15 mg copper, 100 mcg iodine, 4000 IU vitamin A, 400 IU vitamin D, 60 mg vitamin C, 3 mg vitamin B1, 15 mg vitamin B2, 10 mg niacin, 3 mg vitamin B6, 1 mg pantothenic acid, 350 mcg folic acid, 3 mcg vitamin B12);
3. control (250 mg calcium, 0.15 mg magnesium, 117 mg iron, 0.85 mg zinc, 0.15 mg copper, 100 mcg iodine, 4000 IU vitamin A, 400 IU vitamin D, 60 mg vitamin C, 3 mg vitamin B1, 2 mg vitamin B2, 10 mg niacin, 3 mg vitamin B6, 1 mg pantothenic acid, 350 mcg folic acid, 3 mcg vitamin B12).
Women received the high protein or balanced protein-energy supplements in the format of a drink. Women in the control group received a standard oral prenatal multivitamin supplement.
Outcomes1. Total weight gain, average weight gain and early weight gain during pregnancy.
2. Duration of gestation (presented as cumulative rates of delivery from life tables for each treatment group).
3. Preterm birth < 37 weeks.
4. Fetal death (before < 20 weeks' gestation and >= 20 weeks' gestation).
5. Neonatal death ( according to gestation at delivery).
6. Birthweight (mean).
7. Somatic measures of infant growth at 1 year of age.
8. Psychological measures at 1 year of age.
NotesWomen's risk of spontaneous and recurrent miscarriage is unclear, as there is no information about concurrent medical conditions or other risk factors for miscarriage. Women in the trial had a low caloric intake at trial entry, and unexpectedly, an adequate protein intake. No other specific nutritional information is reported.
Sample-size calculation reported: 250 women were required in each treatment group to show a 125 g difference in birthweight. A 25% loss to follow up was incorporated into the sample size.
Intention-to-treat analyses not performed.
There were 9 sets of twins amongst the three treatment groups.
Compliance: "on average, about three quarters of the prescribed amount of beverage was probably ingested".
Location: New York City, USA.
Timeframe: 1969-1976.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Schmidt 2001

Methods

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

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

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

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

Participants243 women were recruited into this study. Pregnant women between 16 and 20 weeks' gestation, aged between 17 and 35 years old, with a parity < 6 and haemoglobin level between 80-140 g/l, were eligible for this study. Women were randomised to receive either vitamin A plus iron and folate (n = 122) or iron and folate only (n = 121). Of these 22 (18%) and 20 (17%) women in vitamin A plus iron and folate and the iron and folate groups respectively, dropped out between enrolment and the follow up at 4 months.
InterventionsWomen were randomised to a weekly supplementation with 120 mg ferrous sulfate and 500 mcg folic acid, with or without vitamin A (2400 retinol equivalents). Women were asked to take the trial tablets from between 16 and 20 weeks' gestation until birth.
Outcomes1. Stillbirth.
2. Concentrations of haemoglobin, serum ferritin and serum transferrin receptors, at or near term.
3. Concentrations of iron and vitamin A in breastmilk.
4. Haemoglobin and serum vitamin A concentrations in the mother and infant at 4 months postpartum.
5. General health, growth and development measures in the first year of life.
NotesWomen risk status for spontaneous and recurrent miscarriage is unclear.
At baseline, between 13% and 17% of women had marginal vitamin A deficiency 44% to 50% of women were anaemic.
Sample-size calculation performed allowing for a 50% drop out during the study period.
Intention-to-treat analyses were not performed.
Compliance: adherence to the tablet intake was assessed through interview during a postnatal home visit, which revealed that the median tablet intake was 50 tablets (i.e. 25 weeks), while only 17% of the subjects took more than ninety tablets.
Location: Indonesia.
Serial publications of this data report different denominators.
Time frame: November 1997-May 1998.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Steyn 2003

  1. a

    F: folic acid
    HELLP syndrome: haemolysis, elevated liver enzymes, low platelet count syndrome
    HIV-1: Human Immunodeficiency Virus-1
    HOFPP: Hungarian Optimal Family Planning Programme
    IQR: interquartile range
    IU: international units
    IVF-ET: in vitro fertilization and embryo transfer
    mcg: micrograms
    MF: multivitamins with folic acid
    mg: milligrams
    MV: multivitamins without folic acid
    NTD: neural tube defect
    P: progesterone
    PAI-1: plasminogen activator inhibitor-1
    PAI-2: plasminogen activator inhibitor-2
    PCV: packed cell volume
    UK: United Kingdom
    USA: United States of America
    wk: week

Methods

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

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

Documentation of exclusion: none reported.

Use of placebo control: placebo control.

Participants200 women were recruited into the study. Women with a history of a previous mid trimester abortion (defined as spontaneous expulsion of the uterine contents between 13 and 26 weeks' gestational age), or previous preterm labour, and less than 26 weeks' gestation were eligible and invited to participate. Women with iatrogenic causes of their previous preterm labour such as previous induction of labour before term for severe pre-eclampsia, were excluded. 203 consecutive women were approached, of which 200 (98.5%) consented and were randomised to either vitamin C (n = 100) or placebo (n = 100). No losses to follow up were reported.
InterventionsTwice daily tablet of either 250 mg vitamin C or placebo, from trial entry until 34 weeks' gestation. All women were tested for bacterial vaginosis and all women with positive cultures for Mycoplasma hominis (and between 22 and 32 weeks' gestation) were treated with erythromycin for 7 days.
Outcomes1. Preterm labour, defined as spontaneous onset of labour and delivery before 37 completed weeks.
2. The secondary outcome was perinatal outcome, a composite endpoint including birthweight, gestational age at delivery, perinatal mortality, duration of admission in the neonatal intensive care unit and neonatal complications.
The age of fetal viability was considered to be 28 weeks' gestation.
NotesResults are from an interim analysis performed when 100 participants were recruited into each arm. Recruitment was stopped after the interim analysis revealed few differences between the two groups. Unclear if there was a sample-size calculation performed. Women's risk profile spontaneous and recurrent miscarriage is unclear, although they are clearly at high risk of preterm birth. It is also unclear if multiple births were included.
6 % of women had an inadequate dietary intake of vitamin C, defined as an intake < 67% of the recommended dietary allowance (70 mg per day).
Compliance: women were requested to bring the containers to each visit and the remaining tablets were counted to improve and control compliance; however, no compliance data were reported.
Country: South Africa.
Timeframe: unclear.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Baumslag 1970Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with either iron, iron and folic acid or iron, folic acid and vitamin B12 from "after the 24th week of pregnancy".
Biswas 1984Unclear of the gestational age at which women entered the trial.
Blot 1981Onset of supplementation was > 20 weeks' gestation.
Supplementation with either iron and folic acid or iron alone occurred "at the end of the 6th month of pregnancy". Unclear if women were randomised to the treatment groups.
Chanarin 1968Onset of supplementation was > 20 weeks' gestation.
Women were given a folate supplement after the 20th week of pregnancy. Abortion was reported according to folate status at 15 weeks, prior to supplementation.
Colman 1974Onset of supplementation was > 20 weeks' gestation.
Women were supplemented "during the final month of pregnancy". Outcomes reported included folate red cell and serum folate concentration and haemoglobin concentration.
Coutsoudis 1999Onset of supplementation was > 20 weeks' gestation.
Women were given vitamin A and beta-carotene "during the third trimester of pregnancy".
Dawson 1962Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with folic acid "on or after the 28th week". Group allocation was not done randomly. Reported outcomes include incidence of folic acid deficiency and megaloblastic anaemia, and haemoglobin concentration.
Edelstein 1968Onset of supplementation was > 20 weeks' gestation.
Supplementation was started at the 28th week of pregnancy. Outcomes reported included serum folate activity and serum folic acid, urinary formiminoglutamic acid, serum vitamin B12, mean haemoglobin and haematocrit values.
Ferguson 1955Only 24 (9%) of the 269 women in the trial began to participate before 15 weeks of gestation and outcomes not reported separately according to gestation at enrolment.
Fletcher 1971No inclusion/exclusion criteria reported, unclear of gestational age at enrolment to the study, reports combined outcomes for "antepartum and threatened or complete abortion" and "stillbirth or neonatal death or congenital malformation" (not reported separately).
Giles 1971Onset of supplementation was > 20 weeks' gestation for a large proportion of the participants.
4 groups in the study, two of which involved supplementation after 20 weeks' gestation. Results were not reported separately between groups.
Hampel 1974Unclear of the gestational age at which women entered the trial.
Hankin 1966No main outcomes reported.
Supplementation was from "approximately 20 weeks", no clinically relevant outcomes, outcomes relating to vitamin C status in plasma and breast milk reported.
Hibbard 1968No main outcomes reported.
Biochemical measures of blood folate status reported.
Hunt 1984All women received a multivitamin in addition to the zinc supplement or placebo.
Laurence 1981No main outcomes or pregnancy loss outcomes reported. Miscarriage reported in those women where there was a neural tube defect, but not in all women according to treatment group.
Lira 1989No main outcomes reported.
Biochemical measures of iron and folate status reported.
Lumeng 1976Unclear gestational age at enrolment, 5 women were excluded due to abortion, premature labour, inadequate dietary records or missing more than 3 prenatal visits. Exclusions were not reported by group allocation. Outcomes related to maternal and fetal plasma levels of pyridoxal 5'-phosphate and coenzyme saturation of aspartate aminotransferase and alanine aminotransferase in maternal erthrocytes were reported.
Marya 1981Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with vitamin D "throughout the 3rd trimester".
Meirinho 1987No clinical outcomes reported.
Maternal plasma concentrations of trophoblastic protein SP1 were reported.
Metz 1965Onset of supplementation was > 20 weeks' gestation.
Women were supplemented with either iron or iron and folic acid, or iron, folic acid and vitamin B12. Supplementation was started after the 24th week of pregnancy.
Mock 2002No main outcome reported.
Women were enrolled in either early or late pregnancy. Biochemical measures of biotin status reported.
Moldenhauer 2002No main outcomes reported.
Unclear if this is a cohort study or randomised trial. Women in this study were participating in a randomised placebo controlled trial of calcium supplementation, and completed a dietary assessment at 12-21 weeks' gestation and 29-31 weeks' gestation. Unclear whether all women took a standard prenatal multivitamin or just women in the placebo group. Results are presented according to "teens", "twins" and "singleton" pregnancies, not according to whether women took the supplement or not. Outcomes reported included dietary intakes of vitamin C and E (with and without the contribution of the prenatal vitamin supplement).
Owen 1966Onset of supplementation was > 20 weeks' gestation.
Women supplemented with oral vitamin K1 "several days before delivery".
Ross 1985Unclear about content of vitamin supplements.
Women were supplemented with high or low 'bulk' dietary supplements with vitamins added; however, the vitamin supplements added were not specified.
Schuster 1984Unclear of gestation at enrolment to the trial.
No pregnancy loss outcomes reported.
Semba 2001No main outcomes reported.
Women enrolled between 18 and 28 weeks' gestation, no clinical outcomes reported, only haemoglobin and plasma erythropoietin concentrations.
Smithells 1981Non-randomised study of periconceptional multivitamin supplementation for the prevention of neural tube defects.
Suharno 1993No main outcomes reported.
Anaemic pregnant women were enrolled between 16 and 24 weeks' gestation. The only clinical outcome reported was the percentage of women with anaemia following treatment with a combination of vitamin A and iron or placebo.
Tanumihardjo 2002No main outcomes reported.
Mean gestation at enrolment was 17.6 weeks, no clinical outcomes reported, markers of vitamin A and iron status reported.
Thauvin 1992No main outcomes reported.
Women were supplemented from 3 months gestation, data on pregnancy outcomes including spontaneous abortion were collected but not reported.
Trigg 1976Unclear of gestation at enrolment to the trial.
Ulrich 1999Non-randomised study.
Observational cohort study of folic acid users, randomised to different doses of folic acid, but no controls.
Villamor 2002No main outcomes reported.
Women enrolled between 12 and 27 weeks' gestation, no pregnancy loss or main outcomes reported, only reports measures of weight gain during pregnancy.
Vutyavanich 1995No main outcomes reported.
Women were enrolled in the study if they were less than 17 weeks' gestation; however, no pregnancy loss or main outcomes were reported, only measures of nausea and vomiting.

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