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Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction

  1. Maria Makrides1,*,
  2. Lelia Duley2,
  3. Sjurdur F Olsen3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 19 JUL 2006

Assessed as up-to-date: 18 APR 2006

DOI: 10.1002/14651858.CD003402.pub2


How to Cite

Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003402. DOI: 10.1002/14651858.CD003402.pub2.

Author Information

  1. 1

    Women's and Children's Health Research Institute, Child Nutrition Research Centre, North Adelaide, SA, Australia

  2. 2

    University of Nottingham, Nottingham Clinical Trials Unit, Nottingham, UK

  3. 3

    Institute of Public Health, Aarhus C, Denmark

*Maria Makrides, Child Nutrition Research Centre, Women's and Children's Health Research Institute, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA, 5006, Australia. maria.makrides@health.sa.gov.au.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 19 JUL 2006

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Characteristics of included studies [ordered by study ID]
Angola 1992

Methods3 arm trial: evening primrose + fish oils, magnesium oxide, and olive oil placebo. Women "randomly assigned using a random number table". Outcome assessments partially blinded - olive oil and evening primrose oil + fish oil capsules identical, but both different to magnesium oxide. The number of exclusions was not stated.


Participants100 primiparous and multiparous women, aged 14-40 years and </= 16 weeks' gestation. 76% had a recent history of malaria or fever of unknown origin, 34% had a history of sickle cell trait or disease, 37% had a history of anaemia, 21% had a history of pregnancy hypertension or other hypertension and 4% had a previous preterm delivery.


InterventionsTreatment: 8 capsules/day evening primrose oil + fish oil, providing a total of 296 mg GLA, 144 mg EPA and 80 mg DHA/day.
Control: 8 capsules olive oil/day.


OutcomesWomen: PIH, oedema, PE, eclampsia.
Babies: birthweight (< 2000b and > 2000b).


NotesNo estimate of sample size is given.
Reported dietary intake of women at study entry was poor. 50 women allocated magnesium oxide excluded from this review.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskB - Unclear

Denmark 1992

Methods3 arm trial in a ratio of 2/1/1: fish oil, olive oil and no supplement. Each woman assigned a study number corresponding to a sealed, opaque envelope containing a randomisation number, this identified either a particular package of oil capsules or no treatment. The olive oil capsules were identical to the fish oil capsules. Outcome assessment was blinded, but 85% of women in the fish oil group correctly identified their group allocation, whereas for olive oil 50% identified the correct oil. There were no post-randomisation exclusions.


Participants533 women at approximately 30 weeks' gestation, aged 18-44 years. Excluded if history of placental abruption, a serious bleed in the current pregnancy, use of prostaglandin inhibitors, multiple pregnancy, fish allergy or regular intake of fish oil.


InterventionsTreatment: fish oil (2.7 g n-3 fatty acids/day) given as 4 x 1 g capsules/day.
Control: either 4 x 1 g capsules olive oil/day or no supplement.


OutcomesWomen: systolic and diastolic blood pressure, PIH, PE.
Babies: duration of gestation, birthweight, birth length.


NotesSample size estimates were done but not reported in the papers because they were regarded as post-festum by authors (personal communication).
Women completed baseline information regarding fish intake.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Low riskA - Adequate

England 1995

MethodsRandom numbers were generated by computer and kept in sealed, opaque, numbered envelopes in the hospital pharmacy. Pharmacy staff allocated the trial treatments. Placebo capsules were identical to treatment capsules. Outcome assessments were blinded, but 44% of a subgroup of women identified that they were in the fish oil group. There was only 0.4% post-randomisation exclusions.


Participants232 women at 19-26 weeks with high-risk singleton pregnancy: history of 1 or more small babies (birthweight < 3rd percentile), history of pregnancy hypertension, history of unexplained stillbirth, or primigravida with abnormal uterine Doppler at 24 weeks' gestation.


InterventionsTreatment: fish oil (2.7 g of MaxEPA/day) given as 9 capsules/day. This provided 1.62 g EPA and 1.08 g DHA/day.
Control: matching air filled capsules.
Treatment stopped at 38 weeks' gestation.


OutcomesWomen: PIH, PE.
Babies: birthweight < 3rd percentile.


NotesSample size estimate is given for proteinuric hypertension.
All women were asked to avoid non-steroidal anti-inflammatory drugs.
Compliance: 50% of women in the fish oil group and 57% of women in the placebo group took < 70% of capsules.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Low riskA - Adequate

Europe 2000

MethodsMulticentre study with 6 different subsets (A to F) of eligibility criteria. The 6 subsets had a standard protocol, and were mutually exclusive. The 4 subsets labelled A-D were included in this review. "Randomisation identified a package number at the relevant centre, where packages were ordered in a random way as to oil type". Placebo capsules were identical looking but contained olive oil. Outcome assessments were blinded, but a questionnaire completed by a subgroup of women indicated that 80% of women in the fish oil group could guess their allocation. There were 3.2% post-randomisation exclusions.


ParticipantsSubset A to D recruited 1477 women who were at least 16 weeks' gestation. Subset A included 232 women with a previous preterm birth. Subset B included 280 women with previous IUGR. Subset C included 386 women with previous PIH. Subset D included 579 women with twins. All subsets excluded women with diabetes mellitus, severe fetal malformation, previous placental abruption, drug or alcohol abuse, use of non-steroidal anti-inflammatory drugs, use of fish oil or fish allergy.


InterventionsTreatment: fish oil (1.3 g EPA and 0.9 g DHA/day), given as 4 capsules/day.
Control: matching olive oil capsules.


OutcomesSubset A: preterm birth, low birthweight.
Subset B: small-for-gestational age, low birthweight.
Subset C: PIH and PE.
Subset D: Preterm birth, small for gestational age, low birthweight.
For the combined subsets: prolonged gestation, maternal morbidity and mortality, infant morbidity.


NotesSample size estimates were modified during the course of the study.

We excluded subsets E and F because these were "therapeutic" subsets and included women with pre-eclampsia (subset E) or suspected IUGR (subset F).


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Low riskA - Adequate

Netherlands 1994

Methods"Randomisation was performed by the hospital pharmacy". Placebo capsules were identical to treatment capsules. Outcome assessments were blinded, but there was no comment whether a significant proportion of women could guess their treatment. There were 7.3% post-randomisation exclusions.


Participants63 women at 12-14 weeks' gestation with a history of IUGR, +/- PIH in the previous (index) pregnancy.


InterventionsTreatment: 3 g EPA/day, given as 12 capsules/day. Each capsule contained 250 mg EPA. No information about the DHA content of the capsules.
Control: 12 capsules coconut oil/day.


OutcomesPrimary outcomes: pregnancy induced hypertension and birthweight < 10th percentile.


NotesSample size estimate was based on the first randomised study of aspirin in high-risk pregnancies.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskB - Unclear

USA 2003

MethodsTrial comparing DHA-enriched eggs vs ordinary eggs. Participants were assigned to an egg group using a computer-generated randomization schedule. Ordinary eggs were the control. Outcome assessments were blinded. 17% post-randomisation exclusions.


Participants350 women with singleton pregnancies, aged 16-36 years. 24-28 weeks' gestation at enrolment and excluded if diabetic. Majority of women were socially disadvantaged and were black (73%).


InterventionsTreatment: DHA-enriched eggs. Each egg had 133 mg DHA. Women were asked to eat 12 eggs per week but reported eating 5.5 per week.
Control: ordinary eggs. Each egg had 33 mg DHA. Women were asked to eat 12 eggs per week but reported eating 5.4 per week.


OutcomesDuration of gestation, birthweight.


NotesInitial sample size was 285. Because there were no published data for low-level DHA supplementation on which to base a power analysis, a blinded reveiw of the data were undertaken after that first 100 births to refine power analysis. Sample size was increased to 350 after the blinded analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskB - Unclear

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Australia 2004Did not report any outcomes of interest to this review. Main focus was the effect of marine oil supplementation during pregnancy on neonatal allergen-specific immune responses.

Colombia 1993The intervention (linoleic acid) is not a direct prostaglandin precursor.

Colombia 1998The intervention (linoleic acid) is not a direct prostaglandin precursor.

Denmark 1994Not a randomised controlled trial.

England 1984The intervention (linoleic acid) is not a direct prostaglandin precursor.

England 1986Women who "developed significant hypertension in the third trimester" were recruited.
Trial does not appear to be randomised.

Finland 1993Women had pre-eclampsia.

France 1985Women had pre-eclampsia

Netherlands 2000Did not report any outcomes of interest to this review. Main focus was the effect of DHA+AA supplementation on plasma and erythrocyte phospholipids in mid-pregnancy.

Netherlands 2004The intervention (alpha-linolenic acid) is not a direct prostaglandin precursor.

Norway 2001Completeness of follow up < 80%. 341 of 590 women assessed at birth. There was post-randomisation exclusion of women with pregnancy outcomes of primary interest to this review, including "premature birth" and "anomalies in the infants that required special attention". No differences between groups for length of gestation and birthweight.
84 children of 590 mothers assessed at 4 years of age. Children from the cod liver oil group had higher IQ than children from the control group.

Scotland 2003Completeness of follow up < 80%. Assessed 63 of 100 women at birth. There was post-randomisation exclusion of women with pregnancy outcomes of primary interest to this review. No differences between groups for length of gestation, birthweight and visual evoked potentials in early infancy.

Slovenia 1994Trial compared n-3 fatty acids with aspirin. There was no placebo or no treatment group.

South Africa 1989Women had pre-eclampsia.

Venezuela 2000Fish oil used in combination with aspirin and vitamins C and E.

 
Characteristics of ongoing studies [ordered by study ID]
DOMInO

Trial name or titleRandomised trial of DHA in pregnancy to prevent postnatal depressive symptoms and enhance neurodevelopment in children.

Methods

ParticipantsWomen with a singleton pregnancy, no known fetal abnormality, and not taking medication where tuna oil is contraindicated.

InterventionsTuna oil capsules providing 1 g DHA + 300 mg EPA or a matching placebo vegetable oil blend daily from 20 weeks.

OutcomesEPDS score > 12 at 6 weeks and 6 months postpartum. Bayley Scales of infant development at 18 months in 600 randomly selected infants.

Starting dateNovember 2005.

Contact informationMaria Makrides, Child Health Research Institute.

NotesAustralian Clinical Trials Registry
ACTRN012605000569606.

Mexico

Trial name or titleRandomized controlled trial of prenatal DHA supplementation to improve child growth and development in infancy.

Methods

ParticipantsWomen with a singleton, uncomplicated pregnancy who are planning to breastfeed.

InterventionsAlgal oil capsules providing 200 mg DHA or matching placebo daily.

OutcomesLength of gestation, birthweight, birth length, growth in infancy, mental and motor development to 18 months of age.

Starting dateJune 2004.

Contact informationUsha Ramakrishnan, Emory University.

Notes

NICHD

Trial name or titleA randomized trial of omega-3 fatty acid supplementation to prevent preterm birth in pregnancies at high risk.

Methods

ParticipantsWomen with a singleton pregnancy and previous preterm birth.

Interventions800 mg DHA+1200 mg EPA or matching placebo daily from 16-22 weeks.
All women also receive weekly injections of 17 alpha hydroxyprogesterone caproate.

OutcomesBirth < 37 completed weeks' gestation including any miscarriages occurring after randomisation.

Starting dateFebruary 2005.

Contact informationCatherine Spong, NICHD
Elizabeth Thom, George Washington University
Margaret Harper, Wake Forest University.

NotesClinicalTrials.gov Identifier NCT00135902.

 
Comparison 1. Prostagladin precursor supplementation versus none or placebo - all women

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

 1 High blood pressure (without proteinuria)51831Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.90, 1.33]

 2 Pre-eclampsia (hypertension with proteinuria)41683Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.59, 1.27]

 3 Eclampsia or other serious maternal morbidity1100Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.70]

 4 Maternal death11477Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Maternal antepartum hospitalisation163Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.67, 2.28]

 6 Mother's length stay in hospital (days)11477Mean Difference (IV, Fixed, 95% CI)-0.81 [-2.87, 1.25]

 7 Antepartum vaginal bleeding21976Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.71, 1.56]

 8 Maternal anaemia1846Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.91, 1.48]

 9 Maternal side-effects3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    9.1 Belching
31386Risk Ratio (M-H, Fixed, 95% CI)3.55 [2.78, 4.52]

    9.2 Unpleasant taste
31354Risk Ratio (M-H, Fixed, 95% CI)6.17 [4.03, 9.44]

    9.3 Nausea
31352Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.74, 1.60]

    9.4 Vomiting
21263Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.53, 1.69]

    9.5 Stomach pain
2477Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.54, 4.41]

    9.6 Diarrhoea
21251Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.42, 1.12]

    9.7 Constipation
11077Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.08, 2.15]

    9.8 Nasal bleeding
21506Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.71, 1.24]

 10 Caesarean section41119Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.80, 1.41]

11 Length of labour (hours)00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Blood loss at delivery (mls)22009Mean Difference (IV, Fixed, 95% CI)13.20 [-9.85, 36.25]

 13 Vaginal blood loss after delivery1533Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.49, 3.41]

 14 Miscarriage (< 24 weeks)11477Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.20, 2.45]

 15 Stillbirth (= or > 24 weeks)42802Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.46, 1.57]

 16 Neonatal death32303Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.29]

 17 Length of gestation (days)31621Mean Difference (IV, Fixed, 95% CI)2.55 [1.03, 4.07]

 18 Preterm birth (< 37 weeks)51916Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.79, 1.07]

 19 Early preterm birth (< 34 weeks)2860Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.49, 0.99]

 20 Prolonged gestation (> 42 weeks)21970Risk Ratio (M-H, Random, 95% CI)1.68 [0.77, 3.66]

 21 Small-for-gestational age11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]

 22 Low birthweight (< 2500 g)52302Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.88, 1.12]

23 Very low birthweight (< 1500 g)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 24 Birthweight (gm)32440Mean Difference (IV, Fixed, 95% CI)47.24 [1.05, 93.44]

 25 Birth length (cm)2824Mean Difference (IV, Fixed, 95% CI)0.48 [0.13, 0.83]

 26 Congenital malformation1533Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.15, 2.49]

 27 Baby admitted to neonatal care22261Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.81, 1.09]

 28 Baby's length of stay in hospital (days)11970Mean Difference (IV, Fixed, 95% CI)-0.32 [-1.63, 0.99]

 29 Neonatal morbidity - bleeding disorders (eg IVH)11974Risk Ratio (M-H, Fixed, 95% CI)2.39 [0.62, 9.22]

 30 Neonatal morbidity - non-bleeding disorders (eg RDS)175Risk Ratio (M-H, Fixed, 95% CI)2.5 [0.11, 59.46]

31 Childhood disability00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 2. Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry

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

 1 Pre-eclampsia (hypertension with proteinuria)41683Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.59, 1.27]

    1.1 < 16 weeks' gestation at trial entry
1100Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.08, 1.97]

    1.2 = or > 16 weeks' gestation at trial entry
31583Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.61, 1.37]

 2 Length of gestation (days)31621Mean Difference (IV, Fixed, 95% CI)2.55 [1.03, 4.07]

   2.1 < 16 weeks' gestation at trial entry
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 = or > 16 weeks' gestation at trial entry
31621Mean Difference (IV, Fixed, 95% CI)2.55 [1.03, 4.07]

 3 Preterm birth (< 37 weeks)51916Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.79, 1.07]

    3.1 < 16 weeks' gestation at trial entry
163Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.35, 1.70]

    3.2 = or > 16 weeks' gestation at trial entry
41853Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.79, 1.09]

 4 Prolonged gestation (> 42 weeks)21970Risk Ratio (M-H, Random, 95% CI)1.68 [0.77, 3.66]

   4.1 < 16 weeks' gestation at trial entry
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 = or > 16 weeks' gestation at trial entry
21970Risk Ratio (M-H, Random, 95% CI)1.68 [0.77, 3.66]

 5 Birthweight (gm)32440Mean Difference (IV, Fixed, 95% CI)47.24 [1.05, 93.44]

   5.1 < 16 weeks' gestation at trial entry
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 = or > 16 weeks' gestation at trial entry
32440Mean Difference (IV, Fixed, 95% CI)47.24 [1.05, 93.44]

 6 Low birthweight (< 2500 g)52302Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.89, 1.13]

    6.1 < 16 weeks' gestation at trial entry
2163Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.60, 2.09]

    6.2 = or > 16 weeks' gestation at trial entry
32139Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.88, 1.13]

 7 Small-for-gestational age11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]

   7.1 < 16 weeks' gestation at trial entry
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    7.2 = or > 16 weeks' gestation at trial entry
11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]

 8 Stillbirth (= or > 24 weeks)42802Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.46, 1.57]

    8.1 < 16 weeks' gestation at trial entry
163Risk Ratio (M-H, Fixed, 95% CI)2.91 [0.12, 68.81]

    8.2 = or > 16 weeks' gestation at trial entry
32739Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.42, 1.51]

 9 Neonatal death32303Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.29]

    9.1 < 16 weeks' gestation at trial entry
163Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.04, 2.94]

    9.2 = or > 16 weeks' gestation at trial entry
22240Risk Ratio (M-H, Fixed, 95% CI)1.91 [0.52, 7.00]

 
Comparison 3. Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy

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

 1 Pre-eclampsia (hypertension with proteinuria)41683Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.59, 1.28]

    1.1 Singleton pregnancy
41186Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.43, 1.04]

    1.2 Multiple pregnancy
1497Risk Ratio (M-H, Fixed, 95% CI)2.38 [0.93, 6.10]

 2 Length of gestation (days)31621Mean Difference (IV, Fixed, 95% CI)2.58 [1.06, 4.10]

    2.1 Singleton pregnancy
31052Mean Difference (IV, Fixed, 95% CI)3.03 [1.38, 4.68]

    2.2 Multiple pregnancy
1569Mean Difference (IV, Fixed, 95% CI)0.10 [-3.77, 3.97]

 3 Preterm birth (< 37 weeks)51916Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.78, 1.07]

    3.1 Singleton pregnancy
51347Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.61, 1.04]

    3.2 Multiple pregnancy
1569Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.84, 1.21]

 4 Prolonged gestation (> 42 weeks)1533Risk Ratio (M-H, Random, 95% CI)1.19 [0.73, 1.93]

    4.1 Singleton pregnancy
1533Risk Ratio (M-H, Random, 95% CI)1.19 [0.73, 1.93]

   4.2 Multiple pregnancy
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Birthweight (gm)32440Mean Difference (IV, Fixed, 95% CI)47.99 [1.81, 94.18]

    5.1 Singleton pregnancy
31318Mean Difference (IV, Fixed, 95% CI)72.11 [11.73, 132.50]

    5.2 Multiple pregnancy
11122Mean Difference (IV, Fixed, 95% CI)14.0 [-57.68, 85.68]

 6 Birthweight < 2500 g52302Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.88, 1.12]

    6.1 Singleton pregnancy
51180Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.77, 1.24]

    6.2 Multiple pregnancy
11122Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.87, 1.15]

 7 Small-for-gestational age11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]

    7.1 Singleton pregnancy
1263Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.81, 1.69]

    7.2 Multiple pregnancy
11111Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.93, 1.35]

 8 Stillbirth (= or > 24 weeks)3828Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.17, 3.41]

    8.1 Singleton pregnancy
3828Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.17, 3.41]

   8.2 Multiple pregnancy
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Neonatal death32303Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.29]

    9.1 Singleton pregnancy
31724Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.32, 3.24]

    9.2 Multiple pregnancy
1579Risk Ratio (M-H, Fixed, 95% CI)2.01 [0.18, 22.01]

 
Comparison 4. Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk

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

 1 Pre-eclampsia (hypertension with proteinuria)41683Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.59, 1.28]

    1.1 Low/moderate risk at trial entry
31130Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.52, 1.98]

    1.2 High risk at trial entry
2553Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.50, 1.29]

 2 Length of gestation (days)31621Mean Difference (IV, Fixed, 95% CI)2.58 [1.06, 4.10]

    2.1 Low/moderate risk at trial entry
31393Mean Difference (IV, Fixed, 95% CI)2.23 [0.67, 3.80]

    2.2 High risk at trial entry
1228Mean Difference (IV, Fixed, 95% CI)8.5 [2.05, 14.95]

 3 Preterm birth (< 37 weeks)51916Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.78, 1.07]

    3.1 Low/moderate risk at trial entry
31393Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.80, 1.13]

    3.2 High risk at trial entry
3523Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.60, 1.12]

 4 Prolonged gestation (> 42 weeks)1533Risk Ratio (M-H, Random, 95% CI)1.19 [0.73, 1.93]

    4.1 Low/moderate risk at trial entry
1533Risk Ratio (M-H, Random, 95% CI)1.19 [0.73, 1.93]

   4.2 High risk at trial entry
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Birthweight (gm)32440Mean Difference (IV, Fixed, 95% CI)48.01 [1.81, 94.20]

    5.1 Low/moderate risk at trial entry
31946Mean Difference (IV, Fixed, 95% CI)55.79 [4.83, 106.74]

    5.2 High risk at trial entry
1494Mean Difference (IV, Fixed, 95% CI)12.11 [-97.34, 121.56]

 6 Low birthweight (< 2500 g)42202Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.89, 1.13]

    6.1 Low/moderate risk at trial entry
21413Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.87, 1.13]

    6.3 High risk at trial entry
3789Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.80, 1.33]

 7 Small-for-gestational age11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]

    7.1 Low/moderate risk at trial entry
11111Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.93, 1.35]

    7.2 High risk at trial entry
1263Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.81, 1.69]

 8 Stillbirth (= or > 24 weeks)3828Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.17, 3.41]

    8.1 Low/moderate risk at trial entry
1533Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.06, 15.96]

    8.2 High risk at trial entry
2295Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.11, 4.08]

 9 Neonatal death32303Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.29]

    9.1 Low/moderate risk at trial entry
1579Risk Ratio (M-H, Fixed, 95% CI)2.01 [0.18, 22.01]

    9.2 High risk at trial entry
31724Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.32, 3.24]

 
Comparison 5. Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement

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

 1 Pre-eclampsia (hypertension with proteinuria)41683Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.59, 1.27]

    1.1 Fish oil
31583Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.61, 1.37]

   1.2 Evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Fish oil + evening primrose oil
1100Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.08, 1.97]

 2 Length of gestation (days)31621Mean Difference (IV, Fixed, 95% CI)2.55 [1.01, 4.09]

    2.1 Fish oil
31621Mean Difference (IV, Fixed, 95% CI)2.55 [1.01, 4.09]

   2.2 Evening primrose oil
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

   2.3 Fish oil + evening primrose oil
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Preterm birth (< 37 weeks)51916Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.79, 1.07]

    3.1 Fish oil
51916Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.79, 1.07]

   3.2 Evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   3.3 Fish oil + evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Prolonged gestation (> 42 weeks)21970Risk Ratio (M-H, Random, 95% CI)1.68 [0.77, 3.66]

    4.1 Fish oil
21970Risk Ratio (M-H, Random, 95% CI)1.68 [0.77, 3.66]

   4.2 Evening primrose oil
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   4.3 Fish oil + evening primrose oil
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Birthweight (gm)32440Mean Difference (IV, Fixed, 95% CI)47.24 [1.05, 93.44]

    5.1 Fish oil
32440Mean Difference (IV, Fixed, 95% CI)47.24 [1.05, 93.44]

   5.2 Evening primrose oil
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

   5.3 Fish oil + evening primrose oil
00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Low birthweight (< 2500 g)51180Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.77, 1.24]

    6.1 Fish oil
41080Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.79, 1.28]

   6.2 Evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.3 Fish oil + evening primrose oil
1100Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.08, 1.97]

 7 Small-for-gestational age11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]

    7.1 Fish oil
11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]

   7.2 Evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   7.3 Fish oil + evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Stillbirth (= or > 24 weeks)42802Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.46, 1.57]

    8.1 Fish oil
42802Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.46, 1.57]

   8.2 Evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   8.3 Fish oil + evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Neonatal death32303Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.29]

    9.1 Fish oil
32303Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.29]

   9.2 Evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

   9.3 Fish oil + evening primrose oil
00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]