Administración de suplementos de vitamina E durante el embarazo
Resumen
Antecedentes
La administración de suplementos de vitamina E puede ayudar a reducir el riesgo de complicaciones del embarazo relacionadas con el estrés oxidativo, como la preeclampsia. Es necesario evaluar la eficacia y la seguridad de la administración de suplementos de vitamina E en el embarazo.
Objetivos
Evaluar los efectos de la administración de suplementos de vitamina E, solos o en combinación con otros suplementos separados, sobre los desenlaces del embarazo, los eventos adversos, los efectos secundarios y el uso de los servicios sanitarios.
Métodos de búsqueda
Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Embarazo y parto (Cochrane Pregnancy and Childbirth Group) (31 de marzo de 2015) y en las listas de referencias de los estudios identificados.
Criterios de selección
Todos los ensayos controlados aleatorizados o cuasialeatorizados que evaluaron la administración de suplementos de vitamina E en embarazadas. Se excluyeron las intervenciones que utilizaron un suplemento multivitamínico con vitamina E.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, evaluaron los ensayos para inclusión y el riesgo de sesgo, extrajeron los datos y verificaron su exactitud.
Resultados principales
Fueron elegibles para esta revisión 21 ensayos con 22 129 mujeres. Cuatro ensayos no aportan datos. Los 17 ensayos restantes evaluaron la vitamina E en combinación con la vitamina C y otros agentes. En general, el riesgo de sesgo varió de bajo a incierto a alto; diez ensayos se consideraron con bajo riesgo de sesgo, seis ensayos con riesgo incierto de sesgo y cinco ensayos con alto riesgo de sesgo. No se encontraron diferencias claras entre las mujeres que recibieron suplementos de vitamina E en combinación con otros suplementos durante el embarazo en comparación con placebo en el riesgo de mortinato (razón de riesgos [RR] 1,17; intervalo de confianza [IC] del 95%: 0,88 a 1,56; nueve estudios, 19 023 participantes; I² = 0%; evidencia de calidad moderada), muerte neonatal (RR 0,81; IC del 95%: 0,58 a 1,13, nueve ensayos, 18 617 participantes, I² = 0%), preeclampsia (RR media 0,91; IC del 95%: 0,79 a 1,06; 14 ensayos, 20 878 participantes; I² = 48%; evidencia de calidad moderada), parto prematuro (RR media 0,98; IC del 95%: 0,88 a 1,09, 11 ensayos, 20 565 participantes, I² = 52%; evidencia de calidadalta) o restricción del crecimiento intrauterino (RR 0,98; IC del 95%: 0,91 a 1,06, 11 ensayos, 20 202 participantes, I² = 17%; evidencia de calidadalta). Las mujeres que recibieron suplementos de vitamina E en combinación con otros suplementos, en comparación con placebo, tuvieron un menor riesgo de presentar desprendimiento placentario (RR 0,64; IC del 95%: 0,44 a 0,93; siete ensayos, 14 922 participantes; I² = 0%; evidencia de calidadalta). Por el contrario, la administración de suplementos de vitamina E se asoció con un aumento en el riesgo de dolor abdominal comunicado por la participante (RR 1,66; IC del 95%: 1,16 a 2,37; un ensayo, 1877 participantes) y de rotura prematura de membranas (RPM) a término (RR media 1,77; IC del 95%: 1,37 a 2,28, dos ensayos, 2504 participantes, I² = 0%); sin embargo, no hubo un correspondiente aumento en el riesgo de RPM (RR promedio 1,27; IC del 95%: 0,93 a 1,75, cinco ensayos, 1999 participantes, I² = 66%; evidencia de calidad baja). No hubo diferencias claras entre los grupos de vitamina E y placebo o control en ningún otro desenlace materno o infantil. No hubo patrones claramente diferentes en subgrupos de mujeres sobre la base del momento de comienzo de la administración de suplementos o en el riesgo inicial de desenlaces adversos del embarazo. La calidad GRADE de la evidencia fue alta para el parto prematuro, el retraso del crecimiento intrauterino y el desprendimiento placentario, moderada para los mortinatos y la preeclampsia clínica, y baja para la RPM antes del término.
Conclusiones de los autores
Los datos no apoyan la administración sistemática de suplementos de vitamina E en combinación con otros suplementos para la prevención de los mortinatos, la muerte neonatal, el parto prematuro, la preeclampsia, la RPM antes del término o a término o el crecimiento fetal deficiente. Se necesitan más estudios de investigación para dilucidar la posible función de la vitamina E en la prevención del desprendimiento placentario. No hubo evidencia convincente de que la administración de suplementos de vitamina E en combinación con otros suplementos produzca otros efectos beneficiosos o perjudiciales importantes.
PICO
Resumen en términos sencillos
Administración de suplementos de vitamina E durante el embarazo
¿Cuál es el problema?
¿Administrar suplementos de vitamina E, solos o en combinación con otras vitaminas, a las mujeres durante el embarazo mejora los desenlaces de los recién nacidos al reducir la incidencia de preeclampsia y el número de recién nacidos que nacen demasiado temprano? ¿O causa efectos perjudiciales?
¿Por qué es esto importante?
Aunque la carencia de vitamina E es poco frecuente en los adultos sanos, en el caso de las embarazadas, la insuficiencia de vitamina E en la dieta (que se encuentra en los aceites vegetales, los frutos secos, los cereales y algunas verduras de hojas verdes) puede provocar complicaciones como la preeclampsia y el parto de un recién nacido pequeño. Además, la deficiencia de vitamina E puede empeorar por el exceso de hierro, por lo que es importante investigar las cantidades óptimas para el embarazo.
¿Qué evidencia se encontró?
Esta revisión incluyó 21 ensayos con más de 21 000 mujeres. Cuatro ensayos no aportaron datos a los análisis. En general, los ensayos fueron de calidad variable. Sólo hubo tres estudios sobre la administración de suplementos de vitamina E solos, pero ninguno de ellos aportó datos. Todos los demás estudios incluyeron vitamina C y suplementos o medicamentos adicionales.
Los resultados indican que la administración habitual de suplementos de vitamina E en combinación con otros suplementos durante el embarazo no mejora los desenlaces de los recién nacidos o las mujeres. Hubo una reducción en el número de placentas que se desprendían temprano (desprendimiento placentario) en las mujeres que recibieron suplementos de vitamina E en combinación con otros agentes, lo que se consideró evidencia de calidad alta. Sin embargo, no está claro si este hallazgos se debió a la vitamina E o a los otros agentes utilizados en el suplemento. Lo anterior se debe explorar en estudios de investigación adicionales que examinen los mecanismos que provocan el desprendimiento placentario.
La revisión encontró que podría haber efectos perjudiciales asociados con los suplementos de vitamina E en el embarazo, ya que hubo un aumento en el riesgo de dolor abdominal y rotura prematura de las membranas fetales a término en las mujeres que recibieron suplementos de vitamina E en combinación con otros suplementos. No hubo un aumento de la rotura prematura de membranas antes del término en las mujeres que recibieron suplementos de vitamina E y otros agentes.
¿Qué significa esto?
El gran conjunto de evidencia no apoya tomar suplementos de vitamina E, solos o en combinación, durante el embarazo. Esta recomendación se debe a que tomar vitamina E en combinación con otros suplementos durante el embarazo no ayuda a prevenir los problemas del embarazo incluido el mortinato, la muerte del recién nacido, el parto prematuro, la preeclampsia ni los recién nacidos con bajo peso al nacer. En realidad, podría aumentar el dolor abdominal en las mujeres y también aumentar el número de mujeres que presentan rotura prematura de las membranas a término.
Authors' conclusions
Summary of findings
| Any vitamin E supplementation versus placebo, no placebo or other supplements | ||||||
| Population: pregnant women receiving vitamin E supplementation or control, living in areas where there is either inadequate dietary intake of vitamin E or where there is presumed adequate intake. | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Any vitamin E supplementation | |||||
| Stillbirth | Study population | RR 1.17 | 19023 | ⊕⊕⊕⊝ | ||
| 9 per 1000 | 11 per 1000 | |||||
| Moderate | ||||||
| 14 per 1000 | 16 per 1000 | |||||
| Preterm birth (less than 37 weeks' gestation) | Study population | RR 0.98 | 20565 | ⊕⊕⊕⊕ | ||
| 159 per 1000 | 156 per 1000 | |||||
| Moderate | ||||||
| 235 per 1000 | 230 per 1000 | |||||
| Clinical pre‐eclampsia (random‐effects model) | Study population | RR 0.91 | 20878 | ⊕⊕⊕⊝ | ||
| 95 per 1000 | 87 per 1000 | |||||
| Moderate | ||||||
| 146 per 1000 | 133 per 1000 | |||||
| Intrauterine growth restriction (various definitions) | Study population | RR 0.98 | 20202 | ⊕⊕⊕⊕ | ||
| 106 per 1000 | 104 per 1000 | |||||
| Moderate | ||||||
| 119 per 1000 | 117 per 1000 | |||||
| Prelabour rupture of fetal membranes ‐ preterm | Study population | RR 1.27 | 1999 | ⊕⊕⊝⊝ | ||
| 29 per 1000 | 37 per 1000 | |||||
| Moderate | ||||||
| 26 per 1000 | 33 per 1000 | |||||
| Bleeding episodes (placental abruption) | Study population | RR 0.64 | 14922 | ⊕⊕⊕⊕ | ||
| 9 per 1000 | 6 per 1000 | |||||
| Moderate | ||||||
| 19 per 1000 | 12 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Wide confidence interval crossing the line of no effect. 3 Publication bias detected. | ||||||
Background
Description of the condition
Vitamin E is the generic name given to eight lipid‐soluble and plant‐derived compounds; four are referred to as tocopherols (alpha, beta, gamma, delta) and four are known as tocotrienols (alpha, beta, gamma, delta) (Roberts 1990). Natural source alpha‐tocopherol is the most biologically active form of vitamin E, and consequently vitamin E activity is expressed in terms of alpha‐tocopherol equivalents (mg alpha‐TE). In foods, the main source of tocopherol is wheatgerm oil and other vegetable oils, nuts, in the fat of meat, some cereals and some leafy green vegetables (NHMRC 2006). Synthetic forms of vitamin E are also available and commonly used in vitamin preparations; however, these forms have less biological activity than their naturally occurring counterparts (IOM 2000).
Vitamin E deficiency is rarely seen in healthy adults and has primarily been characterised in preterm infants, low birthweight infants and those with fat malabsorption disorders. Reported symptoms of deficiency include haemolytic anaemia, reticulocytosis, hyperbilirubinaemia, low haemoglobin levels (Gross 1982) and peripheral neuropathy (Roberts 1990). Vitamin E deficiency is exacerbated in the presence of iron overload and a high dietary intake of polyunsaturated fatty acids (PUFAs), which is of particular relevance for preterm infants fed formula containing high levels of iron and PUFAs (Roberts 1990). Establishing a recommended dietary intake (RDI) of vitamin E has been impeded by the low observance of overt vitamin E deficiency; however, current RDI range from 7 mg to 10 mg alpha‐TE (Roberts 1990). During pregnancy, losses of vitamin E to the fetus are thought to be minimal and thus the RDI during pregnancy is often unchanged (NHMRC 2006).
Description of the intervention
Vitamin E functions as an antioxidant in the lipid phase, protecting phospholipid fatty acids from oxidation by harmful free radicals (reactive oxygen molecules) and thus stabilising cell membranes. As an antioxidant, vitamin E helps to prevent oxidative stress, which is characterised by an excess of free radicals coupled with decreased antioxidants available to quench these free radicals. Vitamin E interacts synergistically with vitamin C, a water soluble antioxidant, where vitamin C helps to convert oxidised vitamin E back into a useful form (Packer 1979). This relationship may account for the limited observation of overt vitamin E deficiency in humans, as vitamin C may aid in recycling vitamin E stores. Vitamin E and vitamin C supplements are often given concurrently to utilise this relationship and to promote antioxidant defences in both the aqueous and lipid phase. Little is known about other potential functions of vitamin E as research to date has focused on its antioxidant properties. Doses of vitamin E required to have an antioxidant effect have been reported at least to 400 international units (approximately 268 mg alpha‐TE) (Devaraj 1997).
How the intervention might work
Oxidative stress has been linked to the development of adult diseases including cardiovascular disease, cancer, chronic inflammation and neurologic disorders, resulting in many large multicentre clinical trials of vitamin E supplementation. However, the results of these large trials of vitamin E supplementation have been disappointing and in fact provide evidence of harm, including an increased risk of mortality (Bjelakovic 2012; Bjelakovic 2013). During pregnancy, oxidative stress has been implicated in the development of pre‐eclampsia (Roberts 1990), and proposed in the disease processes of intrauterine growth restriction (Kingdom 2000) and prelabour rupture of membranes(PROM) both preterm and at term (Woods 2001). Oxidative stress has also been implicated in many of the disorders common to preterm infants including chronic lung disease, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotising enterocolitis and bronchopulmonary dysplasia (Saugstad 1988; Saugstad 2001). Preventing complications in pregnancy like pre‐eclampsia, growth restriction, preterm PROM and serious neonatal morbidities would represent significant cost savings in hospital and intensive care unit admissions and the use of other healthcare resources. Other Cochrane reviews are assessing 'Antioxidants for preventing pre‐eclampsia' (Rumbold 2005a) and 'Vitamin C supplementation in pregnancy' (Rumbold 2005b).
Why it is important to do this review
Vitamin E appears to have low toxicity in humans. However there is limited evidence on the safety of using vitamin E in pregnancy. Despite the lack of evidence on safety, the United States Institute of Medicine Food and Nutrition Board has set an upper tolerable limit of vitamin E ingestion in pregnancy at 1000 mg per day (IOM 2000), indicating the highest level of intake that is likely to pose no risk of adverse health effects to almost all women. In non‐pregnant adults controlled clinical trials of vitamin E supplementation in a variety of doses have failed to demonstrate any consistent side effects (Bendich 1993). Observational studies, however, have reported adverse effects including fatigue, weakness, creatinuria, dermatitis, reduced thyroid function, increased urinary androgen excretion, reduced leukocyte action and altered coagulation factors resulting in increased bleeding in vitamin K deficient individuals (Bendich 1993; Roberts 1990). The mechanisms leading to altered coagulation factors are unclear; however, vitamin E has been reported to potentiate the effect of anticoagulant therapy, such as warfarin. Newborn infants have a relative vitamin K deficiency at birth, hence vitamin E supplementation during pregnancy may influence the risk of vitamin K deficiency bleeding or haemorrhagic disease of the newborn unfavourably if vitamin K is not given at birth. In controlled trials of vitamin E supplementation in preterm infants for the treatment of retinopathy of prematurity, vitamin E supplementation has been associated with an increased risk of bacterial sepsis and necrotising enterocolitis (Johnson 1985). Given the lipid soluble nature of vitamin E, supplementation may result in increased storage of the vitamin in organs such as the liver, muscle and adipose tissue when used in high doses. The need to demonstrate the efficacy and safety of using vitamin E in pregnancy is particularly important when vitamin E is given in high doses.
The aims of this review are (i) to identify all published, unpublished randomised and quasi‐randomised controlled trials investigating vitamin E supplementation in pregnancy and (ii) to investigate the benefits and hazards of vitamin E supplementation in pregnancy.
Objectives
To assess, using the best available evidence, the effects of vitamin E supplementation, alone or in combination with other separate supplements, on pregnancy outcomes, adverse events, side effects and use of health services.
Methods
Criteria for considering studies for this review
Types of studies
All randomised or quasi‐randomised controlled trials evaluating the effect of vitamin E supplementation in pregnant women.
Types of participants
Pregnant women receiving vitamin E supplementation or control, living in areas where there is either inadequate dietary intake of vitamin E or where there is presumed adequate intake.
Women were classified into subgroups where possible, based on:
(a) the dosage of the vitamin E supplement (above or equal to/below the recommended dietary intake of 7 mg alpha‐TE);
(b) the gestation at trial entry (trial entry less than 20 weeks or greater than or equal to 20 weeks);
(c) whether women have low or adequate dietary vitamin E intake prior to trial entry (low intake defined as intake less than the recommended dietary intake in that setting as measured by dietary questionnaire);
(d) the use of vitamin E in combination with other dietary supplements;
(e) women's risk status for adverse pregnancy outcomes (as defined by the trial authors).
Types of interventions
Vitamin E supplementation, alone or in combination with other separate supplements compared with placebo, no placebo or other supplements. Interventions using a multivitamin supplement (more than two vitamins or minerals combined in the one tablet preparation) that contained vitamin E were excluded.
Types of outcome measures
Primary outcomes
Maternal
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Development of clinical pre‐eclampsia
-
Maternal haematological measures: haemolytic anaemia, reticulocytosis, hyperbilirubinaemia and haemoglobin concentrations
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Preterm birth (defined as less than 37 weeks' gestation)
Neonatal
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Stillbirth, neonatal death, perinatal death
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Infant haematological measures: haemolytic anaemia, reticulocytosis, hyperbilirubinaemia and haemoglobin concentrations
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Intrauterine growth restriction (defined as birthweight less than third centile or the most extreme centile reported)
Secondary outcomes
Maternal
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Prelabour rupture of membranes (PROM), preterm and at term
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Death up to six weeks postpartum
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Elective delivery (induction of labour or elective caesarean section)
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Caesarean section (emergency plus elective)
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Bleeding episodes (such as placental abruption, antepartum hemorrhage, postpartum hemorrhage, complications of epidural anaesthesia, need for transfusion)
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Measures of serious maternal morbidity (such as eclampsia, liver failure, renal failure, disseminated intravascular coagulation, pulmonary oedema), peripheral neuropathy
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Adverse events related to vitamin E supplementation sufficient to stop supplementation
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Side effects of vitamin E supplementation such as fatigue, weakness, altered coagulation times, immunosuppression, creatinuria, dermatitis, altered thyroid function and increased urinary androgen excretion
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Maternal satisfaction with care
Neonatal
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Birthweight
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Infant death
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Gestational age at birth
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Congenital malformations
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Apgar score less than seven at five minutes
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Vitamin K deficiency bleeding or haemorrhagic disease of the newborn
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Respiratory distress syndrome
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Chronic lung disease or bronchopulmonary dysplasia
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Periventricular hemorrhage
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Periventricular leukomalacia
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Bacterial sepsis
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Necrotising enterocolitis
-
Retinopathy of prematurity
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Peripheral neuropathy
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Disability at childhood follow‐up (such as cerebral palsy, intellectual disability, hearing disability and visual impairment)
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Poor childhood growth
Use of health service resources
Woman
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Antenatal hospital admission
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Visits to day care units
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Use of intensive care
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Ventilation
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Dialysis
Infant
-
Admission to special care/intensive care nursery
-
Duration of mechanical ventilation
-
Length of stay in hospital
-
Development
-
Special needs after discharge
Search methods for identification of studies
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (31 March 2015).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
-
monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
-
weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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monthly searches of CINAHL (EBSCO);
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE, Embase and CINAHL, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
[See Appendix 1 for details of additional searches carried out in the previous version of the review (Rumbold 2005).]
Searching other resources
We searched the reference lists of retrieved studies.
We did not apply any language or date restrictions.
Data collection and analysis
For methods used in the previous version of this review, seeRumbold 2005.
For this update, the following methods were used for assessing the 62 reports that were identified as a result of the updated search.
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Selection of studies
Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted the third review author.
Data extraction and management
We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted the third review author. Data were entered into Review Manager software (RevMan 2014) and checked for accuracy.
When information regarding any of the above was unclear, we planned to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion or by involving a third assessor.
(1) Random sequence generation (checking for possible selection bias)
We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the method as:
-
low risk of bias (any truly random process, e.g. random number table; computer random number generator);
-
high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
-
unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:
-
low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
-
high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
-
unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
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low, high or unclear risk of bias for participants;
-
low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed methods used to blind outcome assessment as:
-
low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we planned to re‐include missing data in the analyses which we undertook.
We assessed methods as:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
-
high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
-
unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
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high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We described for each included study any important concerns we had about other possible sources of bias.
(7) Overall risk of bias
We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we planned to assess the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. We also explored the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.
Assessment of quality of the evidence
For this update, we assessed the quality of the evidence using the GRADE approach (Schunemann 2009) in order to assess the quality of the body of evidence relating to the following outcomes for the main comparisons:
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stillbirth;
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preterm birth (defined as less than 37 weeks' gestation);
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development of clinical pre‐eclampsia;
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intrauterine growth restriction (defined as birthweight less than third centile or the most extreme centile reported);
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preterm prelabour rupture of membranes (PROM) ;
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bleeding episodes (placental abruption).
We used the GRADE profiler (GRADE 2014) to import data from Review Manager 5.3 (RevMan 2014) in order to create a 'Summary of findings’ table. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.
Measures of treatment effect
Dichotomous data
For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals.
Continuous data
We used the mean difference if outcomes were measured in the same way between trials. We planned to use the standardised mean difference to combine trials that measured the same outcome, but used different methods.
Unit of analysis issues
Cluster‐randomised trials
We did not identify any cluster‐randomised trials in this update. In future updates, we will include cluster‐randomised trials in the analyses along with individually‐randomised trials,we will adjust their sample sizes using the methods described in the Handbook using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.
Cross‐over trial
This is not a valid study design for this review.
Other unit of analysis issues
In future updates, if we include multi‐arm studies (more than one treatment group), we will combine treatment groups if appropriate, and create a single pair‐wise comparison. We will not double count participants according to methods described in the Handbook (Higgins 2011).
Dealing with missing data
For included studies, we noted levels of attrition. In future updates, if more eligible studies are included, we will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we carried out analyses, as far as possible, on an intention‐to‐treat basis i.e. we attempted to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either a Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. If we identified substantial heterogeneity (above 30%), we planned to explore it by pre‐specified subgroup analysis.
Assessment of reporting biases
If there were 10 or more studies in the meta‐analysis we investigated reporting biases (such as publication bias) using funnel plots for primary outcomes. We assessed funnel plot asymmetry visually. If asymmetry was suggested by a visual assessment, we explored possible reasons.
Data synthesis
We carried out statistical analysis using the Review Manager software (RevMan 2014). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar.
If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials. Where we used random‐effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I².
Subgroup analysis and investigation of heterogeneity
If we identified substantial heterogeneity, we investigated it using subgroup analyses and sensitivity analyses. We considered whether an overall summary was meaningful, and if it was, we used random‐effects analysis to produce it.
We carried out the following subgroup analyses for primary outcomes:
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the dosage of the vitamin E supplement (above or equal to versus below the recommended dietary intake of 7 mg alpha‐TE);
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the gestation at trial entry (trial entry less than 20 weeks versus greater than or equal to 20 weeks);
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whether women had low versus adequate dietary vitamin E intake prior to trial entry (low intake defined as intake less than the recommended dietary intake in that setting as measured by dietary questionnaire);
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the use of vitamin E in combination with other dietary supplements versus vitamin E alone;
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women's risk status for adverse pregnancy outcomes (as defined by the trial authors) versus all women.
We assessed subgroup differences by interaction tests available within RevMan (RevMan 2014). We reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.
Sensitivity analysis
We carried out sensitivity analyses to explore the effect of trial quality assessed by determining the overall risk of bias taking into consideration the method of random sequence generation and allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other potential bias. Studies with an overall high or unclear risk of bias were excluded from the analyses in order to assess whether this makes any difference to the overall result.
Results
Description of studies
Results of the search
We examined 62 reports of 27 trials. In this update, we included 21 trials (Anthony 1996; Beazley 2005; Borna 2005; Chappell 1999; Gulmezoglu 1997; Gungorduk 2014; Huria 2010; Kalpdev 2011; Mahdy 2004; McCance 2010; Nasrolahi 2006; Poston 2006; Pressman 2003; Rivas 2000; Roberts 2010; Rumbold 2006; Sawhney 2000; Shahraki 2006; Spinnato 2007; Villar 2009; Xu 2010), excluded five trials (Bolisetty 2002; Clark 2012; Lietz 2001; Moldenhauer 2002; Wibowo 2012) and one study (Tan 1997) is still awaiting classification because the full paper cannot be traced.
Included studies
We identified 21 trials involving 22,129 women as eligible for inclusion in the review. Of these, 14 trials assessed vitamin E supplementation for the prevention of pre‐eclampsia (Beazley 2005; Chappell 1999; Huria 2010; Kalpdev 2011; Mahdy 2004; McCance 2010; Nasrolahi 2006; Poston 2006; Rivas 2000; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009; Xu 2010). Three trials assessed vitamin E supplementation for the prevention of perinatal complications in women with established pre‐eclampsia (Anthony 1996; Gulmezoglu 1997; Sawhney 2000). Two trials assessed whether vitamin E supplementation prolonged the time to birth for women with preterm prelabour rupture of membranes (PROM) (Borna 2005; Gungorduk 2014). One trial assessed vitamin E for the treatment of leg cramps (Shahraki 2006), and one trial assessed the effect of vitamin E supplementation on concentrations of vitamin E in maternal plasma and amniotic fluid (Pressman 2003). Four studies did not report any clinically meaningful outcomes (Anthony 1996; Pressman 2003; Sawhney 2000; Shahraki 2006), therefore in the meta‐analyses data were analysed for 17 studies involving 21,856 women.
Participants
Nine trials recruited women who were at "high" or "increased" risk of pre‐eclampsia (Beazley 2005; Chappell 1999; Kalpdev 2011; McCance 2010; Poston 2006; Rivas 2000; Spinnato 2007; Villar 2009; Xu 2010). The criteria for women being at high risk varied between trials, and included: essential hypertension (Kalpdev 2011); type 1 diabetes (McCance 2010); chronic hypertension or a prior history of pre‐eclampsia in the most recent pregnancy (Spinnato 2007); previous pre‐eclampsia, chronic hypertension, insulin‐requiring diabetes mellitus or multiple gestation (Beazley 2005; Xu 2010); abnormal doppler waveform in either uterine artery at 18 to 22 weeks' gestation or a history in the preceding pregnancy of pre‐eclampsia necessitating delivery before 37 weeks' gestation, eclampsia or the syndrome of haemolysis, elevated liver enzymes, low platelets (HELLP) (Chappell 1999); chronic hypertension, renal disease, pre‐eclampsia‐eclampsia in the pregnancy preceding the index pregnancy requiring delivery before 37 weeks’ gestation, HELLP syndrome in any previous pregnancy, pregestational diabetes, primiparous with a body mass index (BMI) of ≥ 30 kg/m2, history of medically indicated preterm delivery, abnormal uterine artery Doppler waveforms and women with antiphospholipid syndrome (Villar 2009); pre‐eclampsia in the pregnancy preceding the index pregnancy, requiring delivery before 37 weeks’ gestation, diagnosis of HELLP in any previous pregnancy, eclampsia in any previous pregnancy, essential hypertension requiring medication, maternal diastolic blood pressure of 90 mm Hg or more before 20 weeks’ gestation in the current pregnancy, type 1 or type 2 diabetes, requiring insulin or oral hypoglycaemic therapy, antiphospholipid syndrome, chronic renal disease, multiple pregnancy, abnormal uterine artery doppler waveforms, and primiparity with BMI at first antenatal appointment of ≥ 30 kg/m² (Poston 2006); or nulliparity, previous pre‐eclampsia, obesity, hypertension, less than 20 years old, diabetes, nephropathy, mean arterial pressure above of 85 mmHg, positive roll‐over test, black race, family history of hypertension or pre‐eclampsia, twin pregnancy and poor socioeconomic conditions (Rivas 2000). The trial by Xu 2010 had an additional low‐risk arm which included nulliparous women, a further five trials involved women who were either primigravid or nulliparous (Huria 2010; Mahdy 2004; Nasrolahi 2006; Roberts 2010; Rumbold 2006). Three trials included women with established pre‐eclampsia (Anthony 1996; Gulmezoglu 1997; Sawhney 2000). Two trials involved women with established preterm PROM(Borna 2005; Gungorduk 2014), and one trial enrolled with pregnant women experiencing leg cramps (Shahraki 2006). The remaining trial involved women with planned caesarean section over 35 weeks of gestation (Pressman 2003).
The timing of commencement of supplementation differed widely, however, most started supplementation in the second trimester. The range in gestational ages at commencement included: eight to 22 weeks' (McCance 2010), nine to 16 weeks' (Roberts 2010), 12 weeks' (Huria 2010), 12 to 18 weeks' (Xu 2010), 12 to 19 weeks' (Spinnato 2007), 13 to 19 weeks' (Kalpdev 2011), 14 to 20 weeks' (Beazley 2005), 14 to 21 weeks' (Poston 2006), 14 to 22 weeks' (Rumbold 2006; Villar 2009),16 to 22 weeks' (Chappell 1999), 24 to 32 weeks' (Gulmezoglu 1997), 24 to 34 weeks' (Gungorduk 2014), 24 to 34 weeks' (Borna 2005), 25 to 28 weeks' (Shahraki 2006), less than 29 weeks' (Rivas 2000) and 35 weeks' or more (Pressman 2003). For four trials, the commencement of supplementation was unknown (Anthony 1996; Mahdy 2004; Nasrolahi 2006; Sawhney 2000).
Interventions
Three trials supplemented women with vitamin E alone (Anthony 1996; Sawhney 2000; Shahraki 2006). Seventeen trials gave women supplements with vitamin E in addition to vitamin C (Beazley 2005; Borna 2005; Chappell 1999; Gulmezoglu 1997; Gungorduk 2014; Huria 2010; Kalpdev 2011; McCance 2010; Nasrolahi 2006; Poston 2006; Pressman 2003; Rivas 2000; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009; Xu 2010). Of these, two trials supplemented women with additional supplements to vitamin E and vitamin C, either allopurinol (Gulmezoglu 1997) or aspirin and fish oil (Rivas 2000). A further trial supplemented women with a vitamin E rich fraction of palm oil, however no further information was provided (Mahdy 2004). Fifteen trials used the same dose of daily 400 international units (IU) vitamin E (Beazley 2005; Borna 2005; Chappell 1999; Gungorduk 2014; Kalpdev 2011; McCance 2010; Nasrolahi 2006; Poston 2006; Pressman 2003; Rivas 2000; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009; Xu 2010). Three trials gave women either daily 100 mg (Shahraki 2006), 200 IU (Huria 2010) or 800 IU vitamin E (Gulmezoglu 1997). The dose of vitamin E was unknown for three trials (Anthony 1996; Mahdy 2004; Sawhney 2000).
Outcomes
For maternal primary outcomes, development of clinical pre‐eclampsia was reported in 14 trials, preterm births was reported in 11 trials, bleeding episodes was reported in seven trials. For neonatal primary outcomes, stillbirth was reported in nine trials, neonatal deaths for nine trials, perinatal deaths for six trials and intrauterine growth restriction for 11 trials. For secondary outcomes, birthweight was reported in 10 trials, PROM was reported in five trials and maternal death was reported in seven trials.
Settings
The 21 trials were from 15 countries including low‐ to high‐income countries such as Australia, Brazil, Canada, Holland, India, Iran, Malaysia, Mexico, Peru, South Africa, Turkey, UK, USA, Vietnam, and Venezuela. One trial was undertaken in populations with 'evidence of overall low nutritional status' (Villar 2009).
Excluded studies
Five studies were excluded (see Characteristics of excluded studies). Three studies were excluded because they were non‐randomised (Bolisetty 2002; Lietz 2001; Moldenhauer 2002). One study was excluded due to intervention was not supplementation but dietary advice to optimise vitamin E intake (Clark 2012). The other study was excluded because the intervention included more than 14 different vitamins (Wibowo 2012).
Risk of bias in included studies
Overall, we judged 10 trials to be at low risk of bias, six trials to be at unclear risk of bias and five trials to be at high risk of bias (Figure 1; Figure 2).
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Eleven trials were judged to have used adequate methods to generate their random sequence and to conceal allocation (Chappell 1999; Gulmezoglu 1997; Gungorduk 2014; McCance 2010; Poston 2006; Pressman 2003; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009; Xu 2010), and therefore judged to be at low risk of selection bias. One trial (Kalpdev 2011) used adequate methods for sequence generation but provided insufficient detail about allocation concealment and was judged to be at unclear risk of selection bias. Two trials (Nasrolahi 2006; Shahraki 2006) had inadequate methods of both sequence generation and allocation concealment, and were judged to be at high risk of selection bias. The remaining seven trials (Anthony 1996; Beazley 2005; Borna 2005; Huria 2010; Mahdy 2004; Rivas 2000; Sawhney 2000) were judged to be at unclear risk of selection bias as there was insufficient information reported about their methods to permit a judgement.
Blinding
Ten trials undertook adequate blinding of participants, caregivers and outcome assessors and were therefore judged to be at low risk of both performance bias and detection bias (Chappell 1999; Gulmezoglu 1997; McCance 2010; Poston 2006; Pressman 2003; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009; Xu 2010). One study (Borna 2005) had adequate blinding of participants but provided no detail on blinding of outcome assessors, and was therefore judged as having an unclear risk of detection bias. Three trials used no placebo control and were judged to be at high risk of performance bias (Kalpdev 2011; Nasrolahi 2006; Shahraki 2006). Another trial (Gungorduk 2014) used a placebo control, however the tablet was not identical to the vitamin supplement which led to a lack of blinding; this trial was judged to be at high risk of performance and detection bias. Six trials were judged as having an unclear risk of both performance and detection bias due to insufficient information about any methods of blinding (Anthony 1996; Beazley 2005; Huria 2010; Mahdy 2004; Rivas 2000; Sawhney 2000). Four trials were judged as having an unclear risk of detection bias due to lack of information about blinding of outcome assessment (Borna 2005; Kalpdev 2011; Nasrolahi 2006; Shahraki 2006).
Incomplete outcome data
Sixteen trials reported information on attrition and exclusion of participants. Fifteen were judged to have a low risk of attrition bias (Beazley 2005; Chappell 1999; Gulmezoglu 1997; Gungorduk 2014; Kalpdev 2011; McCance 2010; Nasrolahi 2006; Poston 2006; Pressman 2003; Roberts 2010; Rumbold 2006; Shahraki 2006; Spinnato 2007; Villar 2009; Xu 2010), and one was judged to be at high risk (Huria 2010). Five trials provided insufficient information to assess the risk of attrition bias (Anthony 1996; Borna 2005; Mahdy 2004; Rivas 2000; Sawhney 2000).
Selective reporting
Eight trials were judged to be at low risk of reporting bias as they reported data for all expected outcomes (Gungorduk 2014; McCance 2010; Poston 2006; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009; Xu 2010). Thirteen trials were judged to be at unclear risk as there was insufficient information to assess selective reporting (Anthony 1996; Beazley 2005; Borna 2005; Chappell 1999; Gulmezoglu 1997; Huria 2010; Kalpdev 2011; Mahdy 2004; Nasrolahi 2006; Pressman 2003; Rivas 2000; Sawhney 2000; Shahraki 2006).
Other potential sources of bias
Twelve trials were judged to be at low risk of other potential sources of bias (Borna 2005; Chappell 1999; Gulmezoglu 1997; Gungorduk 2014; Kalpdev 2011; McCance 2010; Poston 2006; Pressman 2003; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009). For the other nine trials, there was insufficient information to confidently assess the risk of other sources of bias (Anthony 1996; Beazley 2005; Huria 2010; Mahdy 2004; Nasrolahi 2006; Rivas 2000; Sawhney 2000; Shahraki 2006; Xu 2010). For further details see the Characteristics of included studies tables.
Effects of interventions
Twenty‐one trials involving 22,129 women were identified and of these, 17 trials involving 21,856 women reported data available for analysis. Of the 17 trials included in the analyses, all supplemented women with vitamin E in combination with other supplements (vitamins or other agents).
Vitamin E in combination with other supplements compared with placebo or no control
Primary outcomes
No clear difference was found between women supplemented with vitamin E in combination with other supplements compared with placebo for the risk of stillbirth (risk ratio (RR) 1.17, 95% confidence intervals (CI) 0.88 to 1.56, nine trials, 19,023 participants, Analysis 1.1), neonatal death (RR 0.81, 95% CI 0.58 to 1.13, nine trials, 18,617 participants, Analysis 1.2), infant death (RR 3.02, 95% CI 0.12 to 74.12, one trial, 2694 participants, Analysis 1.4) or infant hyperbilirubinaemia (RR 0.78, 95% CI 0.59 to 1.04, one trial, 725 participants, Analysis 1.7), using fixed‐effect models. Substantial heterogeneity was detected for perinatal death (I² = 43%). When using a random‐effects model, there was no clear difference in the risk of perinatal death between treatment groups (average RR 1.09, 95% CI 0.77 to 1.54,six trials, 16,923 participants, Analysis 1.3). No trials reported the outcomes haemolytic anaemia, reticulocytosis or maternal or infant haemoglobin concentrations.
Substantial heterogeneity was identified for the outcomes preterm birth (I² = 52%) and clinical pre‐eclampsia (I² = 48%). When using a random‐effects model, no clear difference was found between women supplemented with vitamin E in combination with other supplements compared with placebo or no control for the risk of preterm birth (average RR 0.98, 95% CI 0.88 to 1.09, 11 trials, 20,565 participants, Analysis 1.9) or clinical pre‐eclampsia (average RR 0.91, 95% CI 0.79 to 1.06, 14 trials, 20,878 participants, Analysis 1.10). The funnel plot of preterm birth did not show any publication bias, however, the plot for clinical pre‐eclampsia was visually asymmetric (Figure 3, Figure 4, respectively).
Funnel plot of comparison: 1 Any vitamin E supplementation, outcome: 1.9 Preterm birth (less than 37 weeks' gestation).
Funnel plot of comparison: 1 Any vitamin E supplementation, outcome: 1.10 Clinical pre‐eclampsia (random‐effects model).
No clear difference was found for the risk of intrauterine growth restriction (RR 0.98, 95% CI 0.91 to 1.06, 11 trials, 20,202 participants, Analysis 1.11) between women supplemented with vitamin E in combination with other supplements compared with placebo or no control. Substantial heterogeneity was detected for birthweight (I² = 68%). When using a random‐effects model, there was no clear difference between women supplemented with vitamin E in combination with other supplements compared with placebo or no control for birthweight (mean difference (MD) 22.17, 95% CI ‐23.01 to 67.36, 10 trials, 16,888 participants, Analysis 1.12). The funnel plots for intrauterine growth restriction did not show any publication bias (Figure 5).
Funnel plot of comparison: 1 Any vitamin E supplementation, outcome: 1.11 Intrauterine growth restriction (various definitions).
Secondary outcomes
Women supplemented with vitamin E in combination with other supplements compared with placebo had a reduced risk of placental abruption (RR 0.64, 95% CI 0.44 to 0.93, seven trials, 14,922 participants, Analysis 1.16), however there was no difference in the risk of antepartum hemorrhage (RR 1.25, 95% CI 0.85 to 1.82, two trials, 12,256 participants, Analysis 1.16).
Substantial heterogeneity was detected for preterm PROM (I² = 66%). When using a random‐effects model, there was no clear difference between women supplemented with vitamin E in combination with other supplements compared with placebo for preterm PROM (average RR 1.27, 95% CI 0.93 to 1.75, five trials, 1999 participants). Conversely, women supplemented with vitamin E alone or in combination with other supplements had an increased risk of term PROM when compared with women given a placebo control (average RR 1.77, 95% CI 1.37 to 2.28, two trials, 2504 participants, Analysis 1.13).
There were no other differences in any maternal secondary outcomes between women supplemented with vitamin E in combination with other supplements compared with placebo or no control including maternal death (RR 0.60, 95% CI 0.14 to 2.51, seven trials, 17,120 participants, Analysis 1.14), any caesarean section (RR 1.02, 95% CI 0.97 to 1.07, six trials, 15,297 participants, Analysis 1.15), prelabour caesarean section (RR 1.15, 95% CI 0.85 to 1.56, two trials, 1932 participants, Analysis 1.15), induction of labour (RR 1.11, 95% CI 0.97 to 1.26, one trial, 1877 participants, Analysis 1.15), eclampsia (RR 1.67, 95% CI 0.82 to 3.41, eight trials, 19,471 participants, Analysis 1.17), renal failure or renal insufficiency (RR 1.49, 95% CI 0.55 to 4.02, two trials, 1933 participants, Analysis 1.17), disseminated intravascular coagulation (RR 0.36, 95% CI 0.02 to 8.41, one trial, 56 participants, Analysis 1.17), or pulmonary oedema (RR 0.40, 95% CI 0.16 to 1.03. four trials, 12,569 participants, Analysis 1.17).
For the infant, substantial heterogeneity was detected for gestational age at birth, bacterial sepsis, necrotising enterocolitis and chronic lung disease or bronchopulmonary dysplasia. When using a random‐effects models, there were no clear differences between treatment groups in gestational age at birth (MD 0.15, 95% CI ‐0.12 to 0.43, seven trials, 13,783 participants, I² = 81%; Analysis 1.20), or the risk of bacterial sepsis (average RR 1.10, 95% CI 0.73 to 1.67, five trials, 13,324 participants; I² = 40%), necrotising enterocolitis (average RR 0.74, 95% CI 0.36 to 1.55, seven trials, 18,514 participants; I² = 45%, Analysis 1.28), or chronic lung disease/bronchopulmonary dysplasia (average RR 0.69, 95% CI 0.10 to 4.69, three trials, 3262 participants; I² = 57%, Analysis 1.25). There were no clear differences between treatment groups for any other infant outcomes including: congenital malformations (RR 1.16, 95% CI 0.83 to 1.63, four trials, 5511 participants, Analysis 1.21), or Apgar score less than seven at five minutes (RR 0.73, 95% CI 0.42 to 1.27, three trials, 3531 participants, Analysis 1.22), respiratory distress syndrome (RR 0.98, 95% CI 0.89 to 1.08, eight trials, 18,574 participants, Analysis 1.24), periventricular hemorrhage and periventricular leukomalacia (RR 0.91, 95% CI 0.58 to 1.42, six trials, 17,787 participants, Analysis 1.26) or retinopathy of prematurity (RR 1.18, 95% CI 0.72 to 1.93, six trials, 18,270 participants, Analysis 1.29).
No trials reported maternal or infant peripheral neuropathy, maternal satisfaction with care, vitamin K deficiency bleeding or haemorrhagic disease of the newborn, disability at childhood follow‐up, poor childhood growth or any adverse events related to vitamin E supplementation.
None of the studies reported on adverse events that were sufficient to stop supplementation. Possible side effects of supplementation were poorly reported (Analysis 1.33). Three trials (Roberts 2010; Rumbold 2006; Xu 2010) reported on the presence of elevated liver enzymes, and there was overall no clear difference in the risk of this outcome between treatment groups (RR 1.00, 95% CI 0.71 to 1.41, three studies, 14,209 participants). An additional study (Poston 2006), reported that there was no clear difference in liver enzymes between treatment groups, however the data could not be included in the meta‐analysis. One trial reported an increased risk of abdominal pain in women supplemented with vitamin E in combination with other supplements (RR 1.66, 95% CI 1.16 to 2.37, 1877 participants). However, there were no clear differences in the risk of developing other side effects including acne (RR 3.21, 95% CI 0.14 to 75.68, one trial, 56 participants), transient weakness (RR 5.36, 95% CI 0.27 to 106.78, one trial, 56 participants), or skin rash (RR 3.21, 95% CI 0.14 to 75.68, one trial, 56 participants), or any side effect (symptoms combined) (RR 1.16, 95% CI 0.39 to 3.41, one trial, 707 participants) between treatment groups.
Furthemore, one study (McCance 2010), stated in the text that there were "no adverse events or side effects attributable to supplementation."
Substantial heterogeneity for found for outcomes related to use of health service resources for the mother (Analysis 1.34).There was no clear difference between women supplemented with vitamin E in combination with other supplements compared with placebo in the risk of admission to the adult intensive care unit (average RR 0.60, 95% CI 0.16 to 2.30; two trials, 3718, participants; I² = 45%), or hospitalisations in pregnancy (average RR 0.74, 95% CI 0.30 to 1.80, two trials, 2407 participants; I² = 61%), when using a random‐effects model. There were no clear differences between treatment groups for any of the outcomes related to use of health service resources for the infant (Analysis 1.35), including: admission to the intensive care unit (RR 1.01, 95% CI 0.95 to 1.08, eight trials, 17,594 participants) and use of mechanical ventilation (RR 1.02, 95% CI 0.84 to 1.25, six trials, 8531 participants).
Sensitivity analyses by trial quality
Assessments of the treatment effects were made for the primary outcomes based on trial quality. Ten trials were judged to have a low overall risk of bias (Chappell 1999; Gulmezoglu 1997; McCance 2010; Poston 2006; Pressman 2003; Roberts 2010; Rumbold 2006; Spinnato 2007; Villar 2009; Xu 2010), for six trials the overall risk was unclear (Anthony 1996; Beazley 2005; Borna 2005; Mahdy 2004; Rivas 2000; Sawhney 2000), and five trials had a high overall risk of bias (Gungorduk 2014; Huria 2010; Kalpdev 2011; Nasrolahi 2006; Shahraki 2006). When the analyses were restricted to studies at low overall risk of bias, the risks of stillbirth, neonatal death, perinatal death, preterm birth, pre‐eclampsia and intrauterine growth restriction did not change substantively to the analyses which included all trials (Analysis 2.1; Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5; Analysis 2.6). However, for the outcomes preterm birth and clinical pre‐eclampsia (Analysis 2.4; Analysis 2.5), restricting the analyses to studies at low risk of bias reduced the heterogeneity, from 52% to 32% and 48% to 25%, respectively, and there was a small reduction in the effect sizes (although both remained not statistically significant), suggesting that variation in trial quality explains some of the heterogeneity detected for these outcomes.
Subgroup analyses
Dosage of the vitamin E supplement (above or equal to/below the recommended dietary intake of 7 mg alpha‐TE)
All of the included studies supplemented women with vitamin E in a dosage above the recommended dietary intake (RDI). Therefore, subgroup analyses based on dosage were not performed. Furthermore, there was limited variation in the dosages used above the RDI. For example, 15 trials used the same dose of daily 400 international units (IU) vitamin E, a further three trials gave women either daily 100 mg, 200 IU or 800 IU vitamin E, and the dose was unknown for a further three trials.
Gestation at trial entry (less than 20 weeks or greater than or equal to 20 weeks)
Five trials ( Huria 2010; Kalpdev 2011; Roberts 2010; Spinnato 2007; Xu 2010) enrolled women from less than 20 weeks' gestation; five trials (Borna 2005; Gulmezoglu 1997; Gungorduk 2014; Pressman 2003; Shahraki 2006) enrolled women after 20 weeks' gestation; and the other seven trials (Beazley 2005:Chappell 1999; McCance 2010; Poston 2006; Rivas 2000; Rumbold 2006; Villar 2009) enrolled women both before and after 20 weeks' gestation. For a further four trials (Anthony 1996; Mahdy 2004; Nasrolahi 2006; Sawhney 2000), the gestation at trial entry was unknown.
When the analyses were stratified across these groups, the test for subgroup differences was not significant for stillbirth, preterm birth, neonatal death, perinatal death, preterm birth and intrauterine growth restriction (Analysis 3.1; Analysis 3.2; Analysis 3.3; Analysis 3.4; Analysis 3.5; Analysis 3.6), and the findings in the subgroups were not substantively different to the main analyses. Subgroup differences were apparent for the outcome pre‐eclampsia (Chi² = 7.11, P = 0.03, I² = 71.9%), indeed the risk of pre‐eclampsia was reduced in the two trials that reported pre‐eclampsia and where gestation at trial entry was unknown (RR 0.32, 95% CI 0.13 to 0.79, two trials, 693 participants, I² = 0%). However, there was no significant difference in risk of pre‐eclampsia in the trials that enrolled women prior to 20 weeks' (RR 1.03, 95% CI 0.91 to 1.16,five trials, 13,299 participants; I² = 0%), or those that enrolled both women before and after 20 weeks' (RR 0.90, 95% CI 0.73 to 1.12, seven trials, 6886 participants; I² = 57%). As the only significant difference was detected in trials with an unknown gestation at trial entry, the subgroup findings for pre‐eclampsia are likely to reflect characteristics related to the quality of the trial, not the timing of commencement of supplementation. Collectively, these findings suggest that the treatment effect does not vary substantively by the gestation at trial entry and that differences in this characteristic do not contribute significantly to the observed heterogeneity.
Low or adequate dietary vitamin E intake prior to trial entry (low intake defined as intake less than the recommended dietary intake in that setting as measured by dietary questionnaire)
Two trials (Roberts 2010; Rumbold 2006) reported on dietary vitamin E intake of participants at trial entry. One study (Roberts 2010), was classified as including participants with "adequate intake", as the median intake in the treatment and control groups was above the RDI. The other study (Rumbold 2006), was classified as including women with "low intake" as less than half of all participants met the RDI at trial entry (43% and 42% in the treatment and control groups, respectively. One trial (Villar 2009), was designed specifically to assess the effect of vitamin E in combination with vitamin C in populations with poor nutrition, however the dietary intake of vitamin E and other micronutrients of participants was not assessed. This trial was classified as including participants with "low nutritional status", the remaining 18 trials were classified as "dietary intake unclear". Three studies (Chappell 1999; McCance 2010; Poston 2006), assessed plasma concentrations of vitamin E at baseline, and one of these trials (McCance 2010), reported information about pre‐eclampsia according to baseline vitamin E status.
There were no clear differences in the risks of stillbirth, neonatal death, perinatal death, preterm birth or intrauterine growth restriction between women supplemented with vitamin E in combination with other supplements compared with placebo or no control, in any of the subgroups based on dietary intake of vitamin E (Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 4.6). ) F Furthermore, the test for subgroup differences were not significant for any of these outcomes, suggesting that the treatment effects due not differ substantively between trials in these subgroups.
For the outcome pre‐eclampsia (Analysis 4.5), in a subgroup group of women with low baseline vitamin E status, the risk was reduced in women supplemented with vitamin E in combination with other supplements compared with placebo, although the result did not reach statistical significance (average RR 0.35, 95% CI 0.12 to 1.02; one trial, 95 participants). A reduced risk of pre‐eclampsia was also observed among women supplemented with vitamin E in the trials where the baseline dietary intake was unclear (average RR 0.74, 95% CI 0.56 to 0.98, 10 trials, 6928 participants; I² = 52%). However, there was no observed reduction in the risk of pre‐eclampsia in vitamin E supplemented women with low intake (average RR 1.20, 95% CI 0.82 to 1.75, one trial, 1877 participants), or from populations with low nutritional status (average RR 1.03, 95% CI 0.85 to 1.25, one trial, 1355 participants). There was no clear difference in the risk of pre‐eclampsia between treatment groups in women with adequate intake (RR 1.07, 95% CI 0.93 to 1.24, one trial, 9969 participants), or moderate/high baseline vitamin E status (average RR 0.77, 95% CI 0.53 to 1.12, one trial, 572 participants). The test of subgroup differences was significant for this outcome (Chi² = 11.63, P = 0.02, I² = 65.6%).
The use of vitamin E in combination with other dietary supplements
Three trials supplemented women with vitamin E alone (Anthony 1996; Sawhney 2000; Shahraki 2006), however none of these trials reported any clinically meaningful information. Seventeen trials gave women vitamin E in combination with vitamin C, and two of these trials also supplemented women additionally with either allopurinol (Gulmezoglu 1997), or aspirin and fish oil (Rivas 2000). The remaining trial supplemented women with a vitamin E rich fraction of palm oil, which is likely to have contained other nutritional agents, however, no further information was provided about the content of the supplement. Therefore, as there were no trials available to assess the effect of vitamin E supplementation alone, subgroup analyses were not performed.
Women's risk status for adverse pregnancy outcomes (as defined by the authors)
Nine trials supplemented women who were at increased risk or high risk of pre‐eclampsia (Beazley 2005; Chappell 1999; Kalpdev 2011; McCance 2010; Poston 2006; Rivas 2000; Spinnato 2007; Villar 2009; Xu 2010), three trials supplemented women with established pre‐eclampsia (Anthony 1996; Gulmezoglu 1997; Sawhney 2000), and two trials supplemented women with established preterm PROM (Borna 2005; Gungorduk 2014). For this subgroup analysis, all 14 of these studies were classified as including women at 'high/increased risk' of adverse pregnancy outcomes. Five trials supplemented nulliparous or primiparous women (Huria 2010; Mahdy 2004; Nasrolahi 2006; Roberts 2010; Rumbold 2006), one trial supplemented pregnant women with leg cramps (Shahraki 2006), and a further trial supplemented with planned caesarean section (Pressman 2003). These remaining seven trials were classified as including women at 'low/moderate risk' of adverse pregnancy outcomes.
For the outcomes stillbirth, neonatal death, perinatal death, preterm birth, clinical pre‐eclampsia and intrauterine growth restriction, there were no clear differences in the effects of vitamin E supplementation in combination with other supplements versus placebo or no control for women classified as 'high/increased risk' and for those classified as 'low/moderate' risk (Analysis 5.1; Analysis 5.2; Analysis 5.3; Analysis 5.4; Analysis 5.5; Analysis 5.6). Furthermore, the tests for subgroup differences were not significant for any of these outcomes. For the outcomes pre‐eclampsia and preterm birth, substantial heterogeneity was present in the analyses of both of these subgroups, suggesting that heterogeneity between included studies may be due to other factors rather than just differences in baseline risk of adverse pregnancy outcomes.
Discussion
Summary of main results
The results of this review, which included 21 trials involving over 21,000 women and their babies, do not support routine vitamin E supplementation in combination with other supplements in pregnancy. We found no clear differences between women supplemented with vitamin E compared with placebo or control for the risk of any primary maternal or infant outcomes including fetal, perinatal or neonatal death, preterm birth, pre‐eclampsia or intrauterine growth restriction. Supplementation was associated with a reduced risk of placental abruption, which warrants further investigation. However, there was also some evidence of harm, as supplementation appeared to increase the risk of term prelabour rupture of membranes (PROM) as well as self‐reported abdominal pain. There was no convincing evidence that vitamin E supplementation in combination with other supplements results in any other important benefits or harms.
Overall completeness and applicability of evidence
In this review, three trials assessed vitamin E supplementation alone in pregnancy; however, the data from these trials could not be used in the meta‐analysis. Seventeen trials assessed vitamin E in conjunction with vitamin C, and one further trial gave with a vitamin E rich fraction of palm oil. Therefore, there was no information available to assess whether vitamin E supplementation alone may be beneficial or harmful for women, hence any treatment effects seen here may not be directly attributable to vitamin E.
This review provides reliable information about the impact of vitamin E supplementation in combination with other supplements on a range of maternal, perinatal and infant health outcomes. Pre‐eclampsia was the most commonly reported outcome among included studies (14 trials, 20,878 participants). This is not surprising as 14 trials assessed vitamin E supplementation in combination with other supplements for the prevention of pre‐eclampsia. Other commonly reported outcomes were preterm birth (11 trials, 20,565 participants), intrauterine growth restriction (11 trials, 20,202 participants), birthweight (10 trials, 16,888 participants), fetal and neonatal death (nine trials, 19,023 participants), eclampsia (eight trials, 19,471 participants), neonatal respiratory distress syndrome (eight trials, 18,574 women) and admission to the neonatal intensive care unit (eight trials, 17,782 participants).
However, no trials reported any maternal and infant haematological measures (except hyperbilirubinaemia reported by one trial), vitamin K deficiency bleeding, peripheral neuropathy, maternal satisfaction with care or any possible long‐term benefits or harms of supplementation for the mother. One trial (Poston 2006) reported on various measures of respiratory function (wheezing, asthma) in children aged up to two years, however, whether antenatal supplementation influences the health of children beyond two years of age is unknown .There were also scarce available data on side effects of vitamin E supplementation. One trial reported an increased risk of low abdominal pain in the vitamin supplemented group compared with a placebo control. There were no other clear differences between women supplemented with vitamin E compared with placebo or no control for any other potential side effects assessed, including elevated liver enzymes, acne, transient weakness and skin rash.
We detected substantial heterogeneity for the outcomes perinatal death, preterm birth, pre‐eclampsia, birthweight, and preterm PROM. For perinatal death, excluding the trial by Villar 2009 reduced the heterogeneity to zero. Therefore, the observed heterogeneity may reflect different characteristics of participating women or differential access to maternity care, as the Villar 2009 trial involved women of low income in developing countries at risk of poor nutritional status, who may have a generally higher risk of perinatal mortality than women in the other trials who were predominantly from Western, developed, countries.
For preterm birth and pre‐eclampsia, the identified heterogeneity appears to be explained in part by variation in the quality of included studies. For example, in the sensitivity analyses, when studies at high or unclear risk of bias were excluded the magnitude of the heterogeneity was reduced markedly. Furthermore, for preterm birth, removing the trial by McCance 2010 further reduced the heterogeneity (down to I2 = 5%). The heterogeneity that appears to be associated with McCance 2010 may reflect a higher baseline risk of preterm birth among participants in this trial compared with other trials, as McCance 2010 included women with type 1 diabetes, a known risk factor for preterm birth (Hanson 1993). Indeed the rate of preterm birth in the control group of this trial was 41%, the rate in the control group of other included studies ranged from 4% to 45% (median 23%).
In the sensitivity analyses for pre‐eclampsia, removing the trial by Chappell 1999 reduced the heterogeneity to zero. It is possible that heterogeneity associated with Chappell 1999 may reflect differences in underlying risk, however the rate of pre‐eclampsia in the control group (17%) was similar to that observed in other included trials (range 3% to 25%, median 15%). As Chappell 1999 was a small, positive trial, we explored the possibility of reporting bias for this outcome using a funnel plot (see Figure 4). The distribution of the results in Figure 4 are skewed, indicating that small studies reporting negative findings may be missing which could indicate reporting bias.
For preterm PROM, removing the trials by Spinnato 2007 and Xu 2010 reduced the heterogeneity to zero and the point estimate changed from RR = 1.27 to 1.02. The cause of the heterogeneity associated with these two studies is unclear. Both were judged to be at low overall risk of bias, and participants did not appear to be at high risk of preterm PROM, as the rate in the control group of both trials was lower than the rate observed in other included trials (7% to 18% versus 20% to 37%). One possibility is that there was a greater proportion of women with a history of PROM (either preterm or term) in the vitamin E group; however, this cannot be examined as information about the history of PROM among multiparous participants is not available. As these two trials are the only studies that contribute data for the outcome term PROM, the finding of an increased risk of term PROM among vitamin E supplemented women should be interpreted with caution. It should be noted that another included trial (Poston 2006), reported that there was no difference in the risk of either preterm or term PROM between treatment groups, however, individual data were not reported so this trial did not contribute to the meta‐analysis for those outcomes. Further observational research investigating the role of vitamin E in the development of preterm and term PROM is warranted.
We also undertook pre‐specified subgroup analyses exploring the effect of variation in baseline risk of adverse pregnancy outcomes. Approximately two‐thirds of all trials included women considered to be at high or increased risk of adverse outcomes (mostly pre‐eclampsia). For all of the primary outcomes, the effect sizes did not vary substantially between women at high/increased risk and women at low/moderate risk, suggesting that there are no benefits of supplementation in particular subgroups based on underlying risk.
We also undertook other subgroup analyses to explore the impact of variation in timing of commencement of supplementation (i.e. gestation at trial entry) and adequacy of dietary intake of vitamin E prior to trial entry. While there was substantial variation in the gestation at trial entry across all of the included studies, the subgroup analyses did not reveal any substantial differences in the effect size between trials enrolling women prior to 20 weeks’, after 20 weeks’ or that included women both prior to and after 20 weeks’ gestation. This suggests that there is no benefit of commencing supplementation either earlier or later in pregnancy.
Whether vitamin E supplementation is beneficial for women with low or inadequate vitamin E intake is unclear. Only two studies reported information specifically about women's dietary intake of vitamin E at trial entry, and in the subgroup analyses including these trials, there were no apparent benefits of vitamin E supplementation either in women with low or adequate intake. One study (Villar 2009) was undertaken in women from populations with a presumed low dietary intake of vitamin E, based on dietary information collected in previous studies of clinic attendees. There was no clear difference in the pattern of risks of adverse outcomes in these women either. One trial (McCance 2010), reported information about pre‐eclampsia according to baseline plasma vitamin E status. In this trial, there appeared to be a reduced risk of pre‐eclampsia in women with a low baseline vitamin E intake, although the result was of borderline statistical significance and should be interpreted with caution due to the small number of women in this subgroup (n = 95).
Subgroup analyses exploring the impact of vitamin E dosage and use of vitamin E combined with other supplements were planned but could not be undertaken due to insufficient data in each subgroup.
Quality of the evidence
The overall risk of bias is low to unclear for most of the studies, however, there were some high quality, large trials that were heavily weighted in the analysis. Five trials were judged to be at high risk of bias.
The quality of the evidence using GRADE was high for preterm birth, intrauterine growth restriction and placental abruption, moderate for stillbirth and clinical pre‐eclampsia, and low for preterm PROM (summary of findings Table for the main comparison). The outcomes were downgraded due to wide confidence interval crossing the line of no effect, statistical heterogeneity, and publication bias.
Potential biases in the review process
We followed the Cochrane Pregnancy and Childbirth Group search strategies, which includes a search of the Trials Register that is updated weekly to monthly from a range of databases as well as handsearches from selected journals and proceedings of major conferences. Therefore, it is unlikely that studies that have been missed, although it is possible that studies that have not been published could be missing. Should any further studies be identified, we will include them in future updates of the review. We also followed the Cochrane Pregnancy and Childbirth Group recommended review process to reduce potential biases, which included having at least two review authors independently assessing identified studies, extracting data and evaluating risk of bias.
Agreements and disagreements with other studies or reviews
The findings of this review are in agreement with several meta‐analyses examining the effects of vitamin C and E supplementation for the prevention of pre‐eclampsia and other maternal and perinatal complications (Basaran 2010; Conde‐Agudelo 2011).
The finding of a 36% reduction in the relative risk of placental abruption among vitamin E supplemented women compared with placebo or no control warrants further investigation. There is some limited evidence of serum markers of oxidative stress as well as low serum levels of vitamin E in women with placental abruption (Incebiyik 2015; Sharma 1986), suggesting a biologically plausible role for vitamin E supplementation. However, lower serum levels of other antioxidants including vitamin C have also been demonstrated (Sharma 1985), therefore, it is unclear whether the result observed in this review is due to vitamin E or C or the combination of both agents. Further observational research examining the underlying pathways to placental abruption is required, before any firm conclusions can be drawn about this finding.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Funnel plot of comparison: 1 Any vitamin E supplementation, outcome: 1.9 Preterm birth (less than 37 weeks' gestation).
Funnel plot of comparison: 1 Any vitamin E supplementation, outcome: 1.10 Clinical pre‐eclampsia (random‐effects model).
Funnel plot of comparison: 1 Any vitamin E supplementation, outcome: 1.11 Intrauterine growth restriction (various definitions).
Comparison 1 Any vitamin E supplementation, Outcome 1 Stillbirth.
Comparison 1 Any vitamin E supplementation, Outcome 2 Neonatal death.
Comparison 1 Any vitamin E supplementation, Outcome 3 Perinatal death.
Comparison 1 Any vitamin E supplementation, Outcome 4 Infant death.
Comparison 1 Any vitamin E supplementation, Outcome 7 Hyperbilirubinemia.
Comparison 1 Any vitamin E supplementation, Outcome 9 Preterm birth (less than 37 weeks' gestation).
Comparison 1 Any vitamin E supplementation, Outcome 10 Clinical pre‐eclampsia (random‐effects model).
Comparison 1 Any vitamin E supplementation, Outcome 11 Intrauterine growth restriction (various definitions).
Comparison 1 Any vitamin E supplementation, Outcome 12 Birthweight.
Comparison 1 Any vitamin E supplementation, Outcome 13 Prelabour rupture of fetal membranes.
Comparison 1 Any vitamin E supplementation, Outcome 14 Maternal death.
Comparison 1 Any vitamin E supplementation, Outcome 15 Elective delivery and caesarean section.
Comparison 1 Any vitamin E supplementation, Outcome 16 Bleeding episodes.
Comparison 1 Any vitamin E supplementation, Outcome 17 Measures of serious maternal morbidity.
Comparison 1 Any vitamin E supplementation, Outcome 20 Gestational age at birth.
Comparison 1 Any vitamin E supplementation, Outcome 21 Congenital malformations.
Comparison 1 Any vitamin E supplementation, Outcome 22 Apgar score less than seven at five minutes.
Comparison 1 Any vitamin E supplementation, Outcome 24 Respiratory distress syndrome.
Comparison 1 Any vitamin E supplementation, Outcome 25 Chronic lung disease or bronchopulmonary dysplasia.
Comparison 1 Any vitamin E supplementation, Outcome 26 Periventricular haemorrhage and periventricular leukomalacia.
Comparison 1 Any vitamin E supplementation, Outcome 27 Bacterial sepsis.
Comparison 1 Any vitamin E supplementation, Outcome 28 Necrotising enterocolitis.
Comparison 1 Any vitamin E supplementation, Outcome 29 Retinopathy of prematurity.
Comparison 1 Any vitamin E supplementation, Outcome 33 Side effects of vitamin E supplementation.
Comparison 1 Any vitamin E supplementation, Outcome 34 Use of health service resources ‐ maternal.
Comparison 1 Any vitamin E supplementation, Outcome 35 Use of health service resources ‐ infant.
Comparison 2 Any vitamin E supplementation (sensitivity analyses by trial quality), Outcome 1 Stillbirth.
Comparison 2 Any vitamin E supplementation (sensitivity analyses by trial quality), Outcome 2 Neonatal death.
Comparison 2 Any vitamin E supplementation (sensitivity analyses by trial quality), Outcome 3 Perinatal death.
Comparison 2 Any vitamin E supplementation (sensitivity analyses by trial quality), Outcome 4 Preterm birth (< 37 weeks' gestation).
Comparison 2 Any vitamin E supplementation (sensitivity analyses by trial quality), Outcome 5 Clinical pre‐eclampsia.
Comparison 2 Any vitamin E supplementation (sensitivity analyses by trial quality), Outcome 6 Intrauterine growth restriction.
Comparison 3 Any vitamin E supplementation (subgroup analyses based on gestation at entry), Outcome 1 Stillbirth.
Comparison 3 Any vitamin E supplementation (subgroup analyses based on gestation at entry), Outcome 2 Neonatal death.
Comparison 3 Any vitamin E supplementation (subgroup analyses based on gestation at entry), Outcome 3 Perinatal death.
Comparison 3 Any vitamin E supplementation (subgroup analyses based on gestation at entry), Outcome 4 Preterm birth.
Comparison 3 Any vitamin E supplementation (subgroup analyses based on gestation at entry), Outcome 5 Clinical pre‐eclampsia.
Comparison 3 Any vitamin E supplementation (subgroup analyses based on gestation at entry), Outcome 6 Intrauterine growth restriction.
Comparison 4 Any vitamin E supplementation (subgroup analyses by dietary intake), Outcome 1 Stillbirth.
Comparison 4 Any vitamin E supplementation (subgroup analyses by dietary intake), Outcome 2 Neonatal death.
Comparison 4 Any vitamin E supplementation (subgroup analyses by dietary intake), Outcome 3 Perinatal death.
Comparison 4 Any vitamin E supplementation (subgroup analyses by dietary intake), Outcome 4 Preterm birth (less than 37 weeks' gestation).
Comparison 4 Any vitamin E supplementation (subgroup analyses by dietary intake), Outcome 5 Clinical pre‐eclampsia (random‐effects model).
Comparison 4 Any vitamin E supplementation (subgroup analyses by dietary intake), Outcome 6 Intrauterine growth restriction (less than third centile or the most extreme centile reported).
Comparison 5 Any vitamin E supplementation (subgroup analyses by risk of adverse pregnancy outcomes at trial entry), Outcome 1 Stillbirth.
Comparison 5 Any vitamin E supplementation (subgroup analyses by risk of adverse pregnancy outcomes at trial entry), Outcome 2 Neonatal death.
Comparison 5 Any vitamin E supplementation (subgroup analyses by risk of adverse pregnancy outcomes at trial entry), Outcome 3 Perinatal death.
Comparison 5 Any vitamin E supplementation (subgroup analyses by risk of adverse pregnancy outcomes at trial entry), Outcome 4 Preterm birth (less than 37 weeks' gestation).
Comparison 5 Any vitamin E supplementation (subgroup analyses by risk of adverse pregnancy outcomes at trial entry), Outcome 5 Clinical pre‐eclampsia (random‐effects model).
Comparison 5 Any vitamin E supplementation (subgroup analyses by risk of adverse pregnancy outcomes at trial entry), Outcome 6 Intrauterine growth restriction (less than third centile or the most extreme centile reported).
| Any vitamin E supplementation versus placebo, no placebo or other supplements | ||||||
| Population: pregnant women receiving vitamin E supplementation or control, living in areas where there is either inadequate dietary intake of vitamin E or where there is presumed adequate intake. | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Any vitamin E supplementation | |||||
| Stillbirth | Study population | RR 1.17 | 19023 | ⊕⊕⊕⊝ | ||
| 9 per 1000 | 11 per 1000 | |||||
| Moderate | ||||||
| 14 per 1000 | 16 per 1000 | |||||
| Preterm birth (less than 37 weeks' gestation) | Study population | RR 0.98 | 20565 | ⊕⊕⊕⊕ | ||
| 159 per 1000 | 156 per 1000 | |||||
| Moderate | ||||||
| 235 per 1000 | 230 per 1000 | |||||
| Clinical pre‐eclampsia (random‐effects model) | Study population | RR 0.91 | 20878 | ⊕⊕⊕⊝ | ||
| 95 per 1000 | 87 per 1000 | |||||
| Moderate | ||||||
| 146 per 1000 | 133 per 1000 | |||||
| Intrauterine growth restriction (various definitions) | Study population | RR 0.98 | 20202 | ⊕⊕⊕⊕ | ||
| 106 per 1000 | 104 per 1000 | |||||
| Moderate | ||||||
| 119 per 1000 | 117 per 1000 | |||||
| Prelabour rupture of fetal membranes ‐ preterm | Study population | RR 1.27 | 1999 | ⊕⊕⊝⊝ | ||
| 29 per 1000 | 37 per 1000 | |||||
| Moderate | ||||||
| 26 per 1000 | 33 per 1000 | |||||
| Bleeding episodes (placental abruption) | Study population | RR 0.64 | 14922 | ⊕⊕⊕⊕ | ||
| 9 per 1000 | 6 per 1000 | |||||
| Moderate | ||||||
| 19 per 1000 | 12 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Wide confidence interval crossing the line of no effect. 3 Publication bias detected. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stillbirth Show forest plot | 9 | 19023 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.88, 1.56] |
| 2 Neonatal death Show forest plot | 9 | 18617 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.58, 1.13] |
| 3 Perinatal death Show forest plot | 6 | 16923 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.77, 1.54] |
| 4 Infant death Show forest plot | 1 | 2694 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.02 [0.12, 74.12] |
| 5 Haemolytic anemia | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Reticulocytosis | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 7 Hyperbilirubinemia Show forest plot | 1 | 725 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.59, 1.04] |
| 8 Haemoglobin levels | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8.1 Maternal | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 Infant | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 9 Preterm birth (less than 37 weeks' gestation) Show forest plot | 11 | 20565 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.88, 1.09] |
| 10 Clinical pre‐eclampsia (random‐effects model) Show forest plot | 14 | 20878 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.79, 1.06] |
| 11 Intrauterine growth restriction (various definitions) Show forest plot | 11 | 20202 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.91, 1.06] |
| 11.1 Birthweight < 10th centile | 8 | 10161 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.90, 1.06] |
| 11.2 IUGR definition unclear | 1 | 216 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.45, 1.97] |
| 11.3 Birthweight < 1 SD for gestational age | 1 | 44 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.5 [0.28, 8.12] |
| 11.4 Birthweight < 3rd centile | 1 | 9781 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.79, 1.27] |
| 12 Birthweight Show forest plot | 10 | 16888 | Mean Difference (IV, Random, 95% CI) | 22.17 [‐23.01, 67.36] |
| 13 Prelabour rupture of fetal membranes Show forest plot | 5 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 13.1 Preterm | 5 | 1999 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.93, 1.75] |
| 13.2 Term | 2 | 2504 | Risk Ratio (M‐H, Random, 95% CI) | 1.77 [1.37, 2.28] |
| 14 Maternal death Show forest plot | 7 | 17120 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.14, 2.51] |
| 15 Elective delivery and caesarean section Show forest plot | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 15.1 Prelabour caesarean section | 2 | 1932 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.85, 1.56] |
| 15.2 Any caesarean section | 6 | 15297 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.97, 1.07] |
| 15.3 Induction of labour | 1 | 1877 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.97, 1.26] |
| 16 Bleeding episodes Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 16.1 Placental abruption | 7 | 14922 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.44, 0.93] |
| 16.2 Antepartum haemorrhage | 2 | 12256 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.85, 1.82] |
| 17 Measures of serious maternal morbidity Show forest plot | 8 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 17.1 Eclampsia | 8 | 19471 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.82, 3.41] |
| 17.2 Renal failure or insufficiency | 2 | 1933 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.55, 4.02] |
| 17.3 Disseminated intravascular coagulation | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.36 [0.02, 8.41] |
| 17.4 Pulmonary oedema | 4 | 12569 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.40 [0.16, 1.03] |
| 18 Peripheral neuropathy | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 18.1 Maternal | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 18.2 Infant | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Maternal satisfaction with care | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 20 Gestational age at birth Show forest plot | 7 | 13783 | Mean Difference (IV, Random, 95% CI) | 0.15 [‐0.12, 0.43] |
| 21 Congenital malformations Show forest plot | 4 | 5511 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.83, 1.63] |
| 22 Apgar score less than seven at five minutes Show forest plot | 3 | 3531 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.42, 1.27] |
| 23 Vitamin K deficiency bleeding or haemorrhagic disease of the newborn | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 24 Respiratory distress syndrome Show forest plot | 8 | 18574 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.89, 1.08] |
| 25 Chronic lung disease or bronchopulmonary dysplasia Show forest plot | 3 | 3262 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.10, 4.69] |
| 26 Periventricular haemorrhage and periventricular leukomalacia Show forest plot | 6 | 17787 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.58, 1.42] |
| 27 Bacterial sepsis Show forest plot | 5 | 13324 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.73, 1.67] |
| 28 Necrotising enterocolitis Show forest plot | 7 | 18514 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.36, 1.55] |
| 29 Retinopathy of prematurity Show forest plot | 6 | 18270 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.72, 1.93] |
| 30 Disability at childhood follow‐up | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 31 Poor childhood growth | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 32 Adverse events related to vitamin E supplementation | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 33 Side effects of vitamin E supplementation Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 33.1 Acne | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.21 [0.14, 75.68] |
| 33.2 Transient weakness | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.36 [0.27, 106.78] |
| 33.3 Skin rash | 1 | 56 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.21 [0.14, 75.68] |
| 33.4 Any side effects (symptoms not reported separately by group status) | 1 | 707 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.16 [0.39, 3.41] |
| 33.5 Abdominal pain | 1 | 1877 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.66 [1.16, 2.37] |
| 33.6 Elevated liver enzymes (defined by authors) | 3 | 14209 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.71, 1.41] |
| 34 Use of health service resources ‐ maternal Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 34.1 Admission to intensive care unit | 2 | 3718 | Risk Ratio (M‐H, Random, 95% CI) | 0.60 [0.16, 2.30] |
| 34.2 Hospitalisations in pregnancy | 2 | 2407 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.30, 1.80] |
| 35 Use of health service resources ‐ infant Show forest plot | 10 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 35.1 Admission to intensive care unit | 8 | 17594 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.95, 1.08] |
| 35.2 Use of mechanical ventilation | 6 | 8531 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.84, 1.25] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stillbirth Show forest plot | 8 | 18777 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.89, 1.58] |
| 1.1 Low overall risk of bias | 8 | 18777 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.89, 1.58] |
| 2 Neonatal death Show forest plot | 7 | 18314 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.57, 1.24] |
| 2.1 Low overall risk of bias | 7 | 18314 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.57, 1.24] |
| 3 Perinatal death Show forest plot | 5 | 16677 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.82, 1.73] |
| 3.1 Low overall risk of bias | 5 | 16677 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.82, 1.73] |
| 4 Preterm birth (< 37 weeks' gestation) Show forest plot | 8 | 20205 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.91, 1.07] |
| 4.1 Low overall risk of bias | 8 | 20205 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.91, 1.07] |
| 5 Clinical pre‐eclampsia Show forest plot | 8 | 19698 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.89, 1.10] |
| 5.1 Low overall risk of bias | 8 | 19698 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.89, 1.10] |
| 6 Intrauterine growth restriction Show forest plot | 8 | 19842 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.91, 1.06] |
| 6.1 Low overall risk of bias | 8 | 19842 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.91, 1.06] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stillbirth Show forest plot | 9 | 19023 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.88, 1.56] |
| 1.1 Less than or equal to 20 week's gestation | 3 | 13084 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.06 [0.73, 1.55] |
| 1.2 Greater than 20 weeks' gestation | 2 | 302 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.35, 1.70] |
| 1.3 Both prior to and after 20 weeks' gestation | 4 | 5637 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.61 [0.96, 2.70] |
| 2 Neonatal death Show forest plot | 9 | 18617 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.58, 1.13] |
| 2.1 Less than or equal to 20 weeks' gestation | 3 | 12977 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.53, 1.39] |
| 2.2 Greater than 20 weeks' gestation | 3 | 343 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.51, 1.68] |
| 2.3 Both prior to and after 20 weeks' gestation | 3 | 5297 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.58 [0.28, 1.22] |
| 3 Perinatal death Show forest plot | 6 | 16923 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.77, 1.54] |
| 3.1 Less than or equal to 20 weeks' gestation | 2 | 12332 | Risk Ratio (M‐H, Random, 95% CI) | 1.71 [0.42, 6.87] |
| 3.2 Greater than 20 weeks' gestation | 2 | 302 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.49, 1.82] |
| 3.3 Both prior to and after 20 weeks' gestation | 2 | 4289 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.60, 2.14] |
| 4 Preterm birth Show forest plot | 11 | 20565 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.88, 1.09] |
| 4.1 Less than or equal to 20 weeks' gestation | 5 | 13465 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.77, 1.20] |
| 4.2 Greater than 20 weeks' gestation | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 4.3 Both prior to and after 20 weeks' gestation | 6 | 7100 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.85, 1.10] |
| 5 Clinical pre‐eclampsia Show forest plot | 14 | 20878 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.79, 1.06] |
| 5.1 Less than or equal to 20 weeks' gestation | 5 | 13299 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.91, 1.16] |
| 5.2 Greater than 20 weeks' gestation | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 5.3 Both prior to and after 20 weeks' gestation | 7 | 6886 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.73, 1.12] |
| 5.4 Gestation at trial entry unknown | 2 | 693 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.13, 0.79] |
| 6 Intrauterine growth restriction Show forest plot | 11 | 20202 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.91, 1.06] |
| 6.1 Less than or equal to 20 week's gestation | 5 | 13285 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.84, 1.10] |
| 6.2 Greater than 20 weeks' gestation | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6.3 Both prior to and after 20 weeks' gestation | 6 | 6917 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.90, 1.08] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stillbirth Show forest plot | 9 | 19023 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.88, 1.56] |
| 1.1 Low dietary intake | 1 | 1867 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.34 [0.47, 3.84] |
| 1.2 Adequate dietary intake | 1 | 9855 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.67, 1.66] |
| 1.3 Dietary intake unclear | 7 | 7301 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.85, 1.84] |
| 2 Neonatal death Show forest plot | 9 | 18617 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.58, 1.13] |
| 2.1 Low dietary intake | 1 | 1853 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.25 [0.03, 2.24] |
| 2.2 Adequate dietary intake | 1 | 9781 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.41, 1.31] |
| 2.3 Dietary intake unclear | 7 | 6983 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.60, 1.37] |
| 3 Perinatal death Show forest plot | 6 | 16923 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.77, 1.54] |
| 3.1 "Low nutritional status" | 1 | 1515 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.59, 1.17] |
| 3.2 Adequate dietary intake | 1 | 9969 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.48, 2.46] |
| 3.3 Dietary intake unclear | 4 | 5439 | Risk Ratio (M‐H, Random, 95% CI) | 1.26 [0.75, 2.11] |
| 4 Preterm birth (less than 37 weeks' gestation) Show forest plot | 11 | 20565 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.88, 1.09] |
| 4.1 "Low nutritional status" | 1 | 1343 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.74, 1.03] |
| 4.2 Low dietary intake | 1 | 1877 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.73, 1.43] |
| 4.3 Adequate dietary intake | 1 | 9969 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.87, 1.09] |
| 4.4 Dietary intake unclear | 8 | 7376 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.83, 1.18] |
| 5 Clinical pre‐eclampsia (random‐effects model) Show forest plot | 14 | 20796 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.76, 1.03] |
| 5.1 "Low nutritional status" | 1 | 1355 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.85, 1.25] |
| 5.2 Low baseline vitamin E status (≤ 5 µmol/mmol cholesterol) | 1 | 95 | Risk Ratio (M‐H, Random, 95% CI) | 0.35 [0.12, 1.02] |
| 5.3 Moderate/high baseline antioxidant status (> 5 µmol/mmol cholesterol) | 1 | 572 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.53, 1.12] |
| 5.4 Low dietary intake | 1 | 1877 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.82, 1.75] |
| 5.5 Adequate dietary intake | 1 | 9969 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [0.93, 1.24] |
| 5.6 Dietary intake unclear | 10 | 6928 | Risk Ratio (M‐H, Random, 95% CI) | 0.74 [0.56, 0.98] |
| 6 Intrauterine growth restriction (less than third centile or the most extreme centile reported) Show forest plot | 11 | 20202 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.91, 1.06] |
| 6.1 "Low nutritional status" | 1 | 1165 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.75, 1.12] |
| 6.2 Low dietary intake | 1 | 1853 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.66, 1.16] |
| 6.3 Adequate dietary intake | 1 | 9781 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.79, 1.27] |
| 6.4 Dietary intake unclear | 8 | 7403 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.91, 1.10] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Stillbirth Show forest plot | 9 | 19023 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.88, 1.56] |
| 1.1 High/increased risk | 7 | 7301 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.85, 1.84] |
| 1.2 Low/moderate risk | 2 | 11722 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.09 [0.72, 1.66] |
| 2 Neonatal death Show forest plot | 9 | 18617 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.58, 1.13] |
| 2.1 High/increased risk | 7 | 6983 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.60, 1.37] |
| 2.2 Low/moderate risk | 2 | 11634 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.39, 1.17] |
| 3 Perinatal death Show forest plot | 6 | 16923 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.77, 1.54] |
| 3.1 High/increased risk | 5 | 6954 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.73, 1.67] |
| 3.2 Low/moderate risk | 1 | 9969 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.48, 2.46] |
| 4 Preterm birth (less than 37 weeks' gestation) Show forest plot | 11 | 20565 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.88, 1.09] |
| 4.1 High/increased risk | 8 | 8503 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.87, 1.13] |
| 4.2 Low/moderate risk | 3 | 12062 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.64, 1.23] |
| 5 Clinical pre‐eclampsia (random‐effects model) Show forest plot | 14 | 20878 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.79, 1.06] |
| 5.1 High/increased risk | 9 | 8123 | Risk Ratio (M‐H, Random, 95% CI) | 0.90 [0.76, 1.06] |
| 5.2 Low/moderate risk | 5 | 12755 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.56, 1.27] |
| 6 Intrauterine growth restriction (less than third centile or the most extreme centile reported) Show forest plot | 11 | 20202 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.91, 1.06] |
| 6.1 High/increased risk | 8 | 8352 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.91, 1.08] |
| 6.2 Low/moderate risk | 3 | 11850 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.80, 1.13] |
