Vitamin supplementation for preventing miscarriage

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

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.


Miscarriage or pregnancy loss within the first 20 weeks of gestation is a frequent complication of pregnancy, with 12 to 16 per cent of all clinically recognised pregnancies ending in miscarriage (Regan 1989; Everett 1997). 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. A large proportion of early pregnancy losses (miscarriage before 12 weeks' gestation), up to two thirds, 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 2002; Scott 2002).

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 (Simsek 1998; Jauniaux 2000). 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.

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 2002). Periconceptional folate and multivitamin supplementation for the prevention of neural tube defects has been covered in another Cochrane review (Lumley 2002). Concerns have been raised about the impact of folate and multivitamin supplementation on the rate of multiple births (Lumley 2001; Lumley 2002), 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, 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.


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.

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 pregnancy.

Types of participants

Pregnant women 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.

Women will be 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. Pre-conceptional, peri-conceptional or post-conceptional vitamin use.
4. The type of vitamin(s) used (e.g. single vitamins, multivitamins, antioxidants).
5. The dose of vitamin(s) (below or above the recommended dietary intake).
6. The duration of vitamin usage.
7. 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).

Types of intervention

Comparisons of any vitamin(s) 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. 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.
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. Health care costs.

Search strategy for identification of studies

See: Unavailable search strategy

This review will draw on the search strategy developed for the Pregnancy and Childbirth Group as a whole. The full list of journals and conference proceedings as well as the search strategies for the electronic databases, which are searched by the Group on behalf of its reviewers, are described in detail in the 'Search strategies for the identification of studies section' within the editorial information about the Cochrane Pregnancy and Childbirth Group. Briefly, the Group searches on a regular basis MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and reviews the Contents tables of a further 38 relevant journals received via ZETOC, an electronic current awareness service.

Relevant trials, which are identified through the Group's search strategy, are entered into the Group's specialised register of controlled trials. Please see Review Group's details for more detailed information.

In addition, CENTRAL will be searched for the following terms: miscarriage*, spontaneous abortion, recurrent abortion, spontaneous pregnancy loss, recurrent pregnancy loss, fetal death, vitamin*, folate, folic acid.

MEDLINE, CURRENT CONTENTS and EMBASE will also be searched for potentially eligible studies, using the following 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

Methods of the review

Two reviewers will assess potentially eligible trials found after the literature search for their suitability for inclusion in the review. Decisions regarding inclusion will be made separately and results compared. Any disagreement will be resolved through discussion. Data will be extracted by two reviewers using an agreed format, and again discrepancies resolved through discussion. If agreement cannot be reached that item will be excluded until further information is available from the trialists. Data will be entered and double checked.

Validity of each included trial will be assessed according to the criteria outlined in the Cochrane Handbook (Clarke 2000). Trials will be assessed with a grade allocated to each trial on the basis of allocation concealment: A (adequate), B (unclear), C (inadequate) or D (not used). Where the method of allocation concealment is unclear, attempts will be made to contact authors to provide further details.

Blinding, completeness of follow-up and placebo control will be assessed 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. Excluded: if 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.

Statistical analyses will be carried out using the RevMan software (RevMan 2000), with results presented as summary relative risk (RR), risk difference (RD) and number needed to treat (1/RD). Tests of heterogeneity between trials will be applied to assess the significance of any differences between trials (p < 0.1) and possible causes of any heterogeneity will be explored. Summary relative risks will be calculated using a fixed effects model. If heterogeneity is detected, subgroup analyses for the main outcomes will be performed by risk of miscarriage, time of trial entry, type of vitamin used, vitamin dosage, use of placebo, adequacy of prior dietary intake of vitamins. Heterogeneity that is not explained by subgroup analyses will be modelled using random effects analysis.

All included trials will be included in the initial analyses and sensitivity analyses carried out to the explore the effect of trial quality. This will involve analysis based on an A, B, C or D rating of allocation concealment, blinding of assessment of outcome and placebo control. The results of high quality studies will be compared with those of poorer quality studies, where studies rated A will be compared with those rated B or C. Further analyses will assess the other measures of quality such as quasi-randomisation.

Potential conflict of interest

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



Sources of support

External sources of support

  • No sources of support supplied

Internal sources of support

  • Department of Obstetrics and Gynaecology, University of Adelaide AUSTRALIA