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

  • Review
  • Intervention

Authors


Abstract

Background

Population studies have shown that higher intakes of marine foods during pregnancy are associated with longer gestations, higher infant birthweights and a low incidence of pre-eclampsia. It is suggested that the fatty acids of marine foods may be the underlying cause of these associations.

Objectives

To estimate the effects of marine oil, and other prostaglandin precursor, supplementation during pregnancy on the risk of pre-eclampsia, preterm birth, low birthweight and small-for-gestational age.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group Trials Register (December 2005), The Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 2) and MEDLINE (1966 to April 2005).

Selection criteria

All randomised trials comparing oral marine oil, or other prostaglandin precursor, supplementation during pregnancy with either placebo or no treatment. Trials were excluded if their aim was to treat women with established pre-eclampsia or suspected intrauterine growth restriction.

Data collection and analysis

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

Main results

Six trials, involving 2783 women, are included in this review. Three of these were rated as high quality, including the largest trial with 1477 women. Women allocated a marine oil supplement had a mean gestation that was 2.6 days longer than women allocated to placebo or no treatment (weighted mean difference (WMD), 2.55 days, 95% confidence interval (CI) 1.03 to 4.07 days; 3 trials, 1621 women). This was not reflected in a clear difference between the two groups in the relative risk (RR) of birth before 37 completed weeks, although women allocated marine oil did have a lower risk of giving birth before 34 completed weeks' gestation (RR 0.69, 95% CI 0.49 to 0.99; 2 trials, 860 women). Birthweight was slightly greater in infants born to women in the marine oil group compared with control (WMD 47 g, 95% CI 1 g to 93 g; 3 trials, 2440 women). However, there were no overall differences between the groups in the proportion of low birthweight or small-for-gestational age babies. There was no clear difference in the relative risk of pre-eclampsia between the two groups.

Authors' conclusions

There is not enough evidence to support the routine use of marine oil, or other prostaglandin precursor, supplements during pregnancy to reduce the risk of pre-eclampsia, preterm birth, low birthweight or small-for-gestational age.

アブストラクト

子癇前症や子宮内胎児発育遅延がない妊婦に対する魚油などのプロスタグランジン前駆体補充

背景

集団研究では、妊娠中に魚介類を多く摂取すると、妊娠期間が長くなり、乳児の出生時体重が重くなり、子癇前症の罹患率が低下することが示されてきている。集団研究では、妊娠中に魚介類を多く摂取すると、妊娠期間が長くなり、乳児の出生時体重が重くなり、子癇前症の罹患率が低下することが示されてきている。

目的

魚油などのプロスタグランジン前駆体の妊娠中の補充について、子癇前症、早産、低出生時体重、および不当軽量児のリスクへの影響を推定すること。

検索戦略

Cochrane Pregnancy and Childbirth Group Trials Register(2005年12月)、The Cochrane Central Register of Controlled Trials(The Cochrane Library 2005年2号)、およびMEDLINE(1966年~2005年4月)を検索した。

選択基準

妊娠中における、魚油などのプロスタグランジン前駆体の経口補充と、プラセボまたは無治療を比較したすべてのランダム化試験。妊娠中における、魚油などのプロスタグランジン前駆体の経口補充と、プラセボまたは無治療を比較したすべてのランダム化試験。

データ収集と分析

2名のレビュー著者が独立して試験を選択し、データ抽出と試験の質を評価した。

主な結果

本レビューでは、女性2783例を対象とした6件の試験を選択した。これらのうち女性1477例を対象としたもっとも規模が大きい3件の試験について、質が高いと評価した。魚油サプリメントに割り付けられた女性では、プラセボまたは無治療に割り付けられた女性と比較して、平均妊娠期間が2.6日長かった(重み付け平均差(WMD)、2.55日、95%信頼区間(CI)1.03~4.07日;3件の試験、女性1621例)。これは、満37週以下の出産の相対リスク(RR)における2群間の明確な差にはならなかったが、魚油に割り付けられた女性では満34週以下の出産のリスクが低下した(RR 0.69、95%CI 0.49 ~0.99;2件の試験、女性860例)。コントロール群と比較して、魚油群の女性から生まれた乳児は出生時体重がやや重かった(WMD 47 g、95%CI 1 g~93 g;3件の試験、女性2440例)。しかし、低出生時体重や不当軽量児の割合に、両群間で全体的な差はなかった。子癇前症の相対リスクに両群間で明確な差はなかった。

著者の結論

子癇前症、早産、低出生時体重、または不当軽量児のリスクを低下させるために、妊娠中における魚油などのプロスタグランジン前駆体の日常的な補充を支持するには、エビデンスが不十分である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.29]《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

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

Not enough evidence to say if fish oil supplementation in pregnancy helps reduce the risk of pre-eclampsia and small-for-date babies.

Pre-eclampsia in the mother and a baby being born too soon or too small are relatively common complication of pregnancy that can sometimes seriously affect the health of the baby and the mother. Omega-3 fatty acids found in fish/marine oils may prevent these complications. This review identified six trials involving 2755 women. The findings were that fish/marine oil supplements taken in pregnancy increase the length of pregnancy by two to three days, slightly increase a baby's birth weight and slightly reduce the number of babies born before 34 weeks gestation. However, these small effects did not reduce the overall risk of a baby being born too soon or too small, nor the mother developing pre-eclampsia. It is likely that a large number of women participating in trials is needed to address this question fully, and to answer the question is supplementation harmless. Further research is needed.

平易な要約

子癇前症や子宮内胎児発育遅延がない妊婦に対する魚油などのプロスタグランジン前駆体補充

妊婦が魚油を補充することが、子癇前症や不当軽量児のリスクを低下させるのに役立つことを示す十分なエビデンスはない。

母親の子癇前症、乳児の早産や低体重は比較的よくみられる妊娠合併症で、乳児や母親の健康に深刻な影響を与えることが時々ある。魚や魚油に含まれるオメガ-3脂肪酸には、これらの合併症を予防する可能性がある。本レビューでは、女性2755例を対象とした6件の試験を同定した。妊娠中に魚や魚油を補充すると、妊娠期間が2~3日長くなり、乳児の出生時体重がやや増加し、34週以下で生まれる乳児数がやや減少した。しかし、これらの影響は小さく、乳児の早産や低体重、および母親の子癇前症の全体的なリスクは低下しなかった。この課題に十分取り組み、補充が無害であることを示すには、多くの女性が試験に参加する必要があると考えられる。さらなる研究が必要である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.29]《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Background

Pre-eclampsia, preterm birth and intrauterine growth restriction (IUGR) are relatively common complications of pregnancy and are all associated with increased morbidity for both mother and child.

Pre-eclampsia is characterised by high blood pressure and protein in the urine, but can also affect the kidneys, liver and blood-clotting systems. Rare but serious and life-threatening complications include eclampsia, which is characterised by one or more convulsions, and HELLP syndrome, which is the combination of haemolysis, elevated liver enzymes and lower platelets. The outcome for pre-eclampsia for both woman and child is usually good, but for a few women it can lead to substantial morbidity (Pritchard 1984) and occasionally death (DH 1998), particularly if eclampsia develops.

Preterm birth and IUGR are associated with increased infant morbidity and on occasion result in death. Although most babies born with weights below 2500 g survive with good long-term outcome, around 12% are either stillborn or die in the neonatal period, as in South Australia for example (SA Health Commission). The causes of most preterm births in developed countries are unexplained, although pre-eclampsia is a known antecedent in up to 19% of preterm births (Hewitt 1988).

Reducing the frequency of pre-eclampsia, preterm birth and IUGR would improve the health of mothers and their babies, as well as leading to more efficient use of the limited resources available for health services.

The use of fish oil supplements during the second half of pregnancy has been proposed as a possible strategy to prevent pre-eclampsia and preterm birth and to increase birthweight. The hypotheses that fish oil could prevent or improve these conditions were initially developed following population comparisons. The high birthweights (Olsen 1985) and long duration of pregnancies (Olsen 1986) observed in the fish-eating community of the Faroe Islands, together with an inspiring case report (Olsen 1987a), led to the suggestion that fatty acids from marine food could delay spontaneous delivery and thereby increase birthweight (Olsen 1986). The relatively high birthweight for gestational age observed in this population led to the suggestion that fat from marine animals might also increase fetal growth (Andersen 1989; Olsen 1987b). Likewise, the low incidence of pre-eclampsia observed in Greenland Inuits provided basis for the first suggestion that fish oil could prevent this condition (Dyerberg 1985).

These hypotheses have been tested in a number of observational epidemiological studies, several of which have been reviewed elsewhere (Olsen 1993; Olsen 1994). One trial involving 5644 women, not included in this systematic review because it employed alternate rather than random allocation to intervention, deserves mention here. In the late 1930s the People's League of Health conducted a trial evaluating a multivitamin and mineral supplement during pregnancy, which included a small amount of fish oil (League of Health; Olsen 1990). A 31% decrease in proteinuric hypertension (or pre-eclampsia) was reported for women allocated supplementation compared with no supplementation. Women in the treated group were also 20% less likely to give birth to a baby before 40 weeks' gestation compared with the treated group (Olsen 1990).

Marine oils are a rich source of the n-3 long chain polyunsaturated fatty acids (LCPUFA) eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). These fatty acids are precursors to the 3-series prostaglandins and have been shown to modulate inflammatory and vascular effects (Simopoulos 1991). Since pre-eclampsia and gestational hypertension are associated with vasoconstriction and endothelial damage, it is plausible that marine oil fatty acids, especially EPA, can down regulate these responses through direct competition with the thromboxane A2 precursor, arachidonic acid. This mechanism has also been postulated to explain the hypotensive properties of marine oil treatment in normotensive and hypertensive non-pregnant women (Morris 1993). Alternatively, marine oil fatty acids could delay birth in two ways. Firstly, they could delay initiation of labour and cervical ripening by inhibiting the production of prostaglandins F2a and E2. Secondly, they may relax the myometrium by increasing the production of prostacyclins (PGI2 and PGI3).

Other agents, such as evening primrose oil, contain a fatty acid called gamma-linolenic acid that is a precursor to the 1-series prostaglandins. These prostaglandins have a similar hypothesis for their mode action as those derived from n-3 (marine oil) fatty acids. They are therefore included in this review.

Several randomised trials of prostaglandin precursor supplementation during pregnancy have now been undertaken to determine whether these supplements have a clinically worthwhile benefit for either the woman or her child. This review aims to estimate the overall benefits and hazards of prostaglandin precursor supplementation during pregnancy.

Objectives

To estimate the effects of marine oil, and other prostaglandin precursor, supplementation during pregnancy on the risk of pre-eclampsia, preterm birth, low birthweight and small-for-gestational age (SGA), and on other substantive measures of maternal morbidity, and of morbidity and mortality for the child.

Methods

Criteria for considering studies for this review

Types of studies

All randomised trials, with adequate concealment of the allocation, of dietary marine oil or other prostaglandin precursor supplementation during pregnancy. Trials with other methods of allocation, where biases could not be eliminated, were excluded.

Types of participants

All pregnant women, regardless of their risk for pre-eclampsia, preterm birth or IUGR.

Women at high risk of pre-eclampsia, preterm birth or IUGR were defined as women with previous severe pre-eclampsia, diabetes, chronic hypertension, renal disease, autoimmune disease, previous preterm birth, previous IUGR or report smoking more than 30 cigarettes per day. All other women were defined as having low or moderate risk.

Women with established pre-eclampsia or suspected IUGR at trial entry were excluded.

Types of interventions

Marine oil (fish or algal oils), orally administered, compared with placebo or no marine oil treatment. Trials that used foods supplemented with marine oil were included. Treatment with other oils, such as evening primrose or borage, that have fatty acids that may be capable of generating prostaglandins were also included. Trials with a single dose treatment were excluded. Trials in which marine oil, or other prostaglandin precursors, were tested in combination with other nutrients or drugs that may affect pre-eclampsia, preterm birth or IUGR were also excluded.

Types of outcome measures

For the woman
  • Hypertension

  • Pre-eclampsia*

  • Eclampsia

  • Other complications of eclampsia

  • Admission to hospital

  • Caesarean section

  • Haemorrhage

  • Length of labour

  • Serious morbidity (such as renal failure, liver failure, eclampsia, death)

  • Length of gestation*

  • Side-effects (gastrointestinal and non-gastrointestinal)

  • Prolonged gestation (> 42 weeks)*

For babies
  • Stillbirths*

  • Neonatal deaths*

  • Preterm birth (< 37 completed weeks)*

  • Neonatal morbidity (such as intraventricular haemorrhage, respiratory distress syndrome)

  • Birthweight*

  • Low birthweight (< 2.5 kg)*

  • SGA (< 10th percentile)*

  • Admission to a neonatal intensive care unit

Long term follow up included measures of neurological and developmental outcome (such as cerebral palsy).

For health service resources
  • Admission and length of stay in hospital and intensive care facilities

  • Use of community health services

Outcomes marked with * are the primary outcomes and those used for subgroup analyses.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group Trials Register by contacting the Trials Search Co-ordinator (December 2005).

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

  1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. monthly searches of MEDLINE;

  3. handsearches of 30 journals and the proceedings of major conferences;

  4. weekly current awareness search of a further 37 journals.

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

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

In addition, we searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 2) and MEDLINE (1966 to April 2005) using the search strategy in Appendix 1.

We did not apply any language restrictions.

Data collection and analysis

The review was conducted following the procedures outlined in the Cochrane Handbook (Higgins 2005). Potentially eligible trials were evaluated for inclusion and methodological quality, without consideration of their results. Each was separately assessed by two of the authors. Discrepancies were resolved by discussion. There was no blinding of authorship.

We assigned quality scores for concealment of allocation to each trial: A = adequate, B = unclear, C = inadequate. Trials with non-random allocation, where biases could not be eliminated, were excluded.

In addition, we assigned quality scores to each trial for blinding of outcome assessment and completeness of follow up as follows.

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

For completeness of follow up:
(A) less than 3% of participants excluded;
(B) 3% to 9.9% of participants excluded;
(C) 10% to 19.9% of participants excluded.

If 20% or more of participants were excluded, we excluded the data for that outcome.

Data were independently extracted by two review authors and cross-checked. Discrepancies were resolved by discussion. Whenever possible, we sought unpublished data from investigators.

Subgroup analyses

Prespecified subgroup analyses were based on:

  1. type of supplementation: marine (fish or algal) oil or other prostaglandin precursors;

  2. gestation at trial entry: before or after 16 weeks' gestation;

  3. type of pregnancy: singleton or multiple;

  4. risk status at trial entry: high or low/moderate risk of pre-eclampsia, preterm birth or IUGR;

  5. dietary intake of marine oil at trial entry: high, medium or low dietary intake.

Subgroup analyses were only conducted for the main outcomes of pre-eclampsia, preterm birth, length of gestation, prolonged gestation, birthweight, low birthweight, SGA, stillbirth and neonatal death. If possible interaction tests were undertaken to determine whether marine oil supplementation has differential effects in different subgroups. It was only possible to undertake interaction analysis for the gestational age at trial entry subgroups. There were insufficient data in each subgroup to conduct an analysis by dietary intake of marine oil at trial entry.

Results

Description of studies

A total of 2755 women from six trials have been included in this review. All six trials had a randomised design and have compared a supplement or food that contains marine fatty acids with either placebo or no treatment. Four of the trials used an oil derived from the body of the fish, while another used a combination of evening primrose oil and fish (body) oil (Angola 1992). The sixth and most recently published trial assessed consumption of eggs enriched with DHA (USA 2003). This enrichment was achieved by feeding laying hens an algal oil (USA 2003). The allocated dose of the active ingredients in the marine oils (EPA and DHA) ranged from 133 mg/day (USA 2003) to 3 g/day (Europe 2000). The most commonly used dose was 2.7 g of EPA and DHA per day (Denmark 1992; England 1995; Europe 2000), and these trials also included the majority of women (2242). Most trials commenced supplementation after 16 weeks' gestation (Denmark 1992; England 1995; Europe 2000; USA 2003). Three of the six trials included women with high-risk pregnancies (England 1995; Europe 2000; Netherlands 1994). The main outcome measures reported across trials were preterm birth, pre-eclampsia and birthweight. Data regarding neonatal outcome and later childhood outcomes are scarce.

The Europe trial 2000 also included two subsets of women with pre-eclampsia or suspected IUGR (Europe 2000). These women were excluded from this review. Three other studies were excluded because no relevant outcome data were reported (Australia 2004), losses to follow up were greater than 20% (Norway 2001; Scotland 2003) or the intervention was not a direct prostaglandin precursor (Netherlands 2004).

Risk of bias in included studies

Three trials (2242 women) reported adequate allocation concealment (Denmark 1992; England 1995; Europe 2000). All trials, except one (Angola 1992), also used a placebo or control treatment with an identical appearance to the supplement. However, trials that report information regarding the success of blinding indicate that the majority of women taking marine oil could guess their group allocation, largely because of belching and an unpleasant taste associated with taking the fish oil supplements (Denmark 1992; England 1995; Europe 2000). Most trials reported outcome for at least 83% of all women recruited.

Effects of interventions

(1) Pre-eclampsia and high blood pressure (comparisons 01-01, 01-02)

There were no clear differences in the relative risk (RR) of high blood pressure (RR 1.09, 95% confidence interval (CI) 0.90 to 1.33; 5 trials, 1831 women) or the incidence of pre-eclampsia (RR 0.86, 95% CI 0.59 to 1.27; 4 trials, 1683 women) between marine oil treated and control groups.

Subgroup analyses relating to pre-eclampsia (comparisons 02-01, 03-01, 04-01, 05-01)

Treatment and control groups did not clearly differ in the incidence of pre-eclampsia regardless of the timing of supplementation, whether women were exclusively treated with marine oil, or whether women had high risk pregnancies for pre-eclampsia, preterm birth or IUGR. For women with singleton pregnancies who were allocated marine oil, the relative risk of pre-eclampsia was 0.67 (95% CI 0.43, 1.04; 4 trials, 1186 women) compared with placebo or no treatment. Only one study reported data for women with multiple pregnancies, and for women allocated marine oil the relative risk of pre-eclampsia was 2.38 (95% CI 0.93 to 6.10; 1 trial, 497 women) compared with control.

(2) Duration of gestation (comparisons 01-17, 01-18, 01-19, 01-20)

Women allocated a marine oil supplement had a mean gestation that was 2.6 days longer than women allocated placebo or no treatment (weighted mean difference (WMD) 2.55 days, 95% CI 1.03 to 4.07 days; 3 trials, 1621 women). This was not reflected in a clear difference between the two groups in the relative risk of birth before 37 completed weeks (RR 0.92, 95% CI 0.79 to 1.07; 5 trials, 1916 women). However, women allocated marine oil did have a lower risk of giving birth before 34 completed weeks' gestation compared with placebo (RR 0.69, 95% CI 0.49 to 0.99; 2 trials, 860 women). Two trials reported data for the risk of prolonging gestation beyond 42 weeks. As there was substantial heterogeneity, this outcome was analysed using the random-effects model (RR 1.68, 95% CI 0.77 to 3.66; 2 trials, 1970 women).

Subgroup analyses relating to length of gestation, preterm birth and prolonged gestation (comparisons 02-02, 02-03, 02-04, 03-02, 03-03, 03-04, 04-02, 04-03, 04-04, 05-02, 05-03, 05-04)

Trials reporting length of gestation all commenced supplementation after 16 weeks' gestation and treated women with marine oil only. Women with singleton pregnancies who were allocated marine oil had pregnancies that were 3.0 days longer than control women (WMD 3.03 days, 95% CI 1.38 to 4.68 days; 3 trials, 1052 women), but for women with multiple pregnancies there was no clear difference in length of gestation between the two groups. This lengthening of gestation appeared to be slightly greater for women with high risk pregnancies (for high risk WMD 8.5 days, 95% CI 2.05 to 14.95 days; 1 trial, 255 women; for low/moderate risk WMD 2.23 days, 95% CI 0.67 to 3.80 days; 3 trials, 1393 women).

There were no overall differences in the relative risk of preterm birth between marine oil and control treatment in any of the subgroups investigated.

Trials that reported data regarding prolonged gestation all commenced supplementation after 16 weeks' gestation and used marine oil supplements. Only one trial reported data for prolonging gestation beyond 42 weeks in women with singleton and low/moderate risk pregnancies (RR 1.19, 95% CI 0.73 to 1.93; 1 trial, 533 women). These data were analysed using a random-effects model because of significant heterogeneity in the primary analysis. No data were available for women with high-risk pregnancies or women with multiple pregnancies.

(3) Birth size (comparisons 01-21, 01-22, 01-23, 01-24, 01-25)

Birthweight (WMD 47 g, 95% CI 1 to 93 g; 3 trials, 2440 women) and birth length (WMD 0.48 cm, 95% CI 0.13 to 0.83 cm; 2 trials, 824 women) were slightly greater in infants born to women in the marine oil group compared with control. However, there were no overall differences between the groups in the relative risk for low birthweight or SGA babies. No trials reported data relating to very low birthweight babies.

Subgroup analyses relating to birthweight, low birthweight and small-for-gestational age (comparisons 02-05, 02-06, 02-07, 03-05, 03-06, 03-07, 04-05, 04-06, 04-07, 05-05, 05-06, 05-07)

Trials reporting birthweight all commenced treatment after 16 weeks' gestation. Women with singleton pregnancies allocated marine oil had babies with slightly higher birthweight than those allocated to control (WMD 72 g, 95% CI 11 to 133 g; 3 trials with 1318 women), while there was no clear difference for women with multiple pregnancies (WMD 14 g, 95% CI -57 to 86 g; 1 trial with 1122 women). There was no clear difference between treatment and control groups for women with high risk pregnancies (WMD 12 g, 95% CI -97 to 122 g; 1 trial with 494 women), while treated women with low/moderate risk pregnancies had babies with a higher mean birthweight compared with control (WMD 56 g, 95% CI 5 to 107 g; 3 trials with 1946 women).

The relative risk of giving birth to a low birthweight (less than 2500 g) or SGA baby did not differ between treatment and control groups in any subgroup.

(4) Infant mortality and morbidity (comparisons 01-14, 01-15, 01-16, 01-26, 01-27, 01-28, 01-29, 01-30)

Even taken together, there were too few baby deaths for any reliable conclusions about the overall effects of marine oils and other prostaglandin precursors.

There were no clear differences between the groups in the mean length of infant hospital stay or the relative risks of admission to neonatal care, congenital malformation, neonatal bleeding disorders and neonatal non-bleeding disorders.

Subgroup analyses relating to stillbirth and neonatal death (comparisons 02-08, 02-09, 03-08, 03-09, 04-08, 04-09, 05-08, 05-09)

Similarly, there were insufficient data on stillbirth and neonatal death for any reliable conclusion about the possible effects in any of the prespecified subgroups.

(5) Maternal mortality and morbidity (comparisons 01-03, 01-04, 01-05, 01-06, 01-10)

There were no maternal deaths in the one trial reporting this outcome (1477 women).

There were no clear differences between the groups in any measure of maternal morbidity, such as length of hospital stay, caesarean section and eclampsia or other serious maternal morbidity.

(6) Maternal side-effects (comparisons 01-07, 01-08, 01-09, 01-12, 01-13)

Women allocated marine oil were more than three times more likely to report belching (RR 3.55, 95% CI 2.78 to 4.52; 3 trials, 1386 women) and six times more likely to complain of an unpleasant taste (RR 6.17, 95% CI 4.03 to 9.44; 3 trials, 1354 women) than those allocated control oil. There were no clear differences in nausea, vomiting, stomach pain, diarrhoea and constipation between women in the two groups.

Also, there were no differences in any bleeding complications such as nasal bleeding, antepartum vaginal bleeding, maternal anaemia, vaginal blood loss after birth and blood loss at birth between women in the two groups.

(7) Long-term childhood outcome (comparisons 01-31)

No included trials reported data regarding long-term childhood outcomes.

Discussion

Data from this systematic review indicate a small but consistent increase in the mean length of gestation associated with marine oil, and other prostaglandin precursor, supplementation during pregnancy. This small increase of two to three days in the mean length of gestation did not translate into a reduction in the risk of birth before 37 weeks' completed gestation, although there does appear to be a reduction in the relative risk of birth before 34 completed weeks. However, the numbers of women for whom this outcome is reported are relatively small, and most had high risk pregnancies. Therefore, there is a potential to be misled by both bias and random error.

Although an increased length of gestation is desirable if it reduces the risk of preterm birth, it may not be so desirable if it also prolongs gestation beyond term. The data in this review are insufficient for any reliable conclusions about the possible effect on prolonged gestation.

Marine oil supplementation was associated with a small increase in birthweight that appears commensurate with the two to three day increase in the mean duration of gestation. The clinical importance of these findings is questionable, however, as they are not reflected in any overall impact on the relative risk of a baby being low birthweight or small-for-gestational age. These findings were consistent across all subgroup analyses. This suggests that marine oil supplementation in pregnancy may not improve fetal growth, and that the small increase in birthweight may be mediated by the small increase in the length of gestation.

The point estimate for the effect of marine oils or other prostaglandin precursors on pre-eclampsia was a 14% reduction in relative risk, with 95% confidence intervals for the true effects being anything from a 39% reduction to a 33% increase, compared with control. Although subgroup analysis by singleton and multiple pregnancy suggests that any reduction in the risk of pre-eclampsia may be confined to women with a singleton pregnancy, only one trial contributed to both the singleton and multiple pregnancy subgroups and the remainder of trials only included women with singleton pregnancies. This imbalance in the subgroups and the limited number of women with multiple pregnancies may result in bias and random error.

The doses of EPA and DHA derived from the marine oils used in the trials in this review ranged from 133 mg/day to 3 g/day, although most trials involving the majority of women assessed a dose of 2.7 g of EPA and DHA per day. Such a dose would be difficult to achieve from food sources. As an example, this would require a woman to eat 300 g of cooked salmon daily. Although the doses appear high compared with what may be achievable through the diet, the marine oil interventions appeared safe. There were no increases in bleeding or haemorrhage either before or after birth. The only side-effects associated with fish oil supplementation were belching and unpleasant taste, and these are relatively minor.

More recent literature has suggested that increasing DHA supply in pregnancy may improve maternal mood as well as improve the neural development of the infant. Prospective cohort studies have indicated a strong association between the dietary dose of DHA in pregnancy and the prevalence of depressive symptoms in the postnatal period (Hibbeln 2003). Similarly cohort studies have related DHA status of the mother at the end of pregnancy or DHA status in cord blood with changes in neonatal sleeping patterns (Cheruku 2002), altered attention (Colombo 2004) and motor development (Bakker 2003). There have only been two published randomised trials to assess the effect of fish oil intervention in pregnancy on the subsequent developmental outcome of children (Norway 2001; Scotland 2003) and both trials have been excluded from this review because of methodological issues. Nevertheless, the data relating to maternal mood and childhood development have generated substantial interest that has seen the recent initiation of several trials to assess the impact of DHA supply in pregnancy on maternal mood (DOMInO) and childhood development (DOMInO; Mexico; NICHD).

Authors' conclusions

Implications for practice

There is not enough evidence to support the routine use of marine oil, or other prostaglandin precursor, supplements during pregnancy to reduce the risk of pre-eclampsia, preterm birth, low birthweight or small-for-gestational age.

Implications for research

The review suggests that marine oil supplementation may be of most benefit in prolonging gestation in women with high-risk pregnancies. Further large randomised trials are required to confirm whether or not there are clinically important benefits for mother and child, and to provide reliable information about potential adverse effects. Such trials should include assessment of the longer-term effects, for example on maternal mood in the postnatal period and childhood development.

Acknowledgements

Sjurdur Olsen and Marie Louise Osterdal provided unpublished data for the Europe 2000 trial.

Data and analyses

Download statistical data

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-effects3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 Belching31386Risk Ratio (M-H, Fixed, 95% CI)3.55 [2.78, 4.52]
9.2 Unpleasant taste31354Risk Ratio (M-H, Fixed, 95% CI)6.17 [4.03, 9.44]
9.3 Nausea31352Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.74, 1.60]
9.4 Vomiting21263Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.53, 1.69]
9.5 Stomach pain2477Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.54, 4.41]
9.6 Diarrhoea21251Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.42, 1.12]
9.7 Constipation11077Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.08, 2.15]
9.8 Nasal bleeding21506Risk 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]
Analysis 1.1.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 1 High blood pressure (without proteinuria).

Analysis 1.2.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 2 Pre-eclampsia (hypertension with proteinuria).

Analysis 1.3.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 3 Eclampsia or other serious maternal morbidity.

Analysis 1.4.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 4 Maternal death.

Analysis 1.5.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 5 Maternal antepartum hospitalisation.

Analysis 1.6.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 6 Mother's length stay in hospital (days).

Analysis 1.7.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 7 Antepartum vaginal bleeding.

Analysis 1.8.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 8 Maternal anaemia.

Analysis 1.9.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 9 Maternal side-effects.

Analysis 1.10.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 10 Caesarean section.

Analysis 1.12.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 12 Blood loss at delivery (mls).

Analysis 1.13.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 13 Vaginal blood loss after delivery.

Analysis 1.14.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 14 Miscarriage (< 24 weeks).

Analysis 1.15.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 15 Stillbirth (= or > 24 weeks).

Analysis 1.16.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 16 Neonatal death.

Analysis 1.17.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 17 Length of gestation (days).

Analysis 1.18.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 18 Preterm birth (< 37 weeks).

Analysis 1.19.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 19 Early preterm birth (< 34 weeks).

Analysis 1.20.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 20 Prolonged gestation (> 42 weeks).

Analysis 1.21.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 21 Small-for-gestational age.

Analysis 1.22.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 22 Low birthweight (< 2500 g).

Analysis 1.24.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 24 Birthweight (gm).

Analysis 1.25.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 25 Birth length (cm).

Analysis 1.26.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 26 Congenital malformation.

Analysis 1.27.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 27 Baby admitted to neonatal care.

Analysis 1.28.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 28 Baby's length of stay in hospital (days).

Analysis 1.29.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 29 Neonatal morbidity - bleeding disorders (eg IVH).

Analysis 1.30.

Comparison 1 Prostagladin precursor supplementation versus none or placebo - all women, Outcome 30 Neonatal morbidity - non-bleeding disorders (eg RDS).

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 entry1100Risk Ratio (M-H, Fixed, 95% CI)0.4 [0.08, 1.97]
1.2 = or > 16 weeks' gestation at trial entry31583Risk 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 entry00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 = or > 16 weeks' gestation at trial entry31621Mean 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 entry163Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.35, 1.70]
3.2 = or > 16 weeks' gestation at trial entry41853Risk 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 entry00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.2 = or > 16 weeks' gestation at trial entry21970Risk 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 entry00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 = or > 16 weeks' gestation at trial entry32440Mean 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 entry2163Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.60, 2.09]
6.2 = or > 16 weeks' gestation at trial entry32139Risk 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 entry00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7.2 = or > 16 weeks' gestation at trial entry11374Risk 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 entry163Risk Ratio (M-H, Fixed, 95% CI)2.91 [0.12, 68.81]
8.2 = or > 16 weeks' gestation at trial entry32739Risk 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 entry163Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.04, 2.94]
9.2 = or > 16 weeks' gestation at trial entry22240Risk Ratio (M-H, Fixed, 95% CI)1.91 [0.52, 7.00]
Analysis 2.1.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 1 Pre-eclampsia (hypertension with proteinuria).

Analysis 2.2.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 2 Length of gestation (days).

Analysis 2.3.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 3 Preterm birth (< 37 weeks).

Analysis 2.4.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 4 Prolonged gestation (> 42 weeks).

Analysis 2.5.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 5 Birthweight (gm).

Analysis 2.6.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 6 Low birthweight (< 2500 g).

Analysis 2.7.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 7 Small-for-gestational age.

Analysis 2.8.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 8 Stillbirth (= or > 24 weeks).

Analysis 2.9.

Comparison 2 Prostaglandin precursor supplementation versus none or placebo - subgroups by gestation at trial entry, Outcome 9 Neonatal death.

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 pregnancy41186Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.43, 1.04]
1.2 Multiple pregnancy1497Risk 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 pregnancy31052Mean Difference (IV, Fixed, 95% CI)3.03 [1.38, 4.68]
2.2 Multiple pregnancy1569Mean 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 pregnancy51347Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.61, 1.04]
3.2 Multiple pregnancy1569Risk 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 pregnancy1533Risk Ratio (M-H, Random, 95% CI)1.19 [0.73, 1.93]
4.2 Multiple pregnancy00Risk 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 pregnancy31318Mean Difference (IV, Fixed, 95% CI)72.11 [11.73, 132.50]
5.2 Multiple pregnancy11122Mean 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 pregnancy51180Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.77, 1.24]
6.2 Multiple pregnancy11122Risk 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 pregnancy1263Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.81, 1.69]
7.2 Multiple pregnancy11111Risk 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 pregnancy3828Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.17, 3.41]
8.2 Multiple pregnancy00Risk 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 pregnancy31724Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.32, 3.24]
9.2 Multiple pregnancy1579Risk Ratio (M-H, Fixed, 95% CI)2.01 [0.18, 22.01]
Analysis 3.1.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 1 Pre-eclampsia (hypertension with proteinuria).

Analysis 3.2.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 2 Length of gestation (days).

Analysis 3.3.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 3 Preterm birth (< 37 weeks).

Analysis 3.4.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 4 Prolonged gestation (> 42 weeks).

Analysis 3.5.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 5 Birthweight (gm).

Analysis 3.6.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 6 Birthweight < 2500 g.

Analysis 3.7.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 7 Small-for-gestational age.

Analysis 3.8.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 8 Stillbirth (= or > 24 weeks).

Analysis 3.9.

Comparison 3 Prostaglandin precursor supplementation versus none or placebo - subgroups by singleton or multiple pregnancy, Outcome 9 Neonatal death.

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 entry31130Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.52, 1.98]
1.2 High risk at trial entry2553Risk 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 entry31393Mean Difference (IV, Fixed, 95% CI)2.23 [0.67, 3.80]
2.2 High risk at trial entry1228Mean 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 entry31393Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.80, 1.13]
3.2 High risk at trial entry3523Risk 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 entry1533Risk Ratio (M-H, Random, 95% CI)1.19 [0.73, 1.93]
4.2 High risk at trial entry00Risk 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 entry31946Mean Difference (IV, Fixed, 95% CI)55.79 [4.83, 106.74]
5.2 High risk at trial entry1494Mean 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 entry21413Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.87, 1.13]
6.3 High risk at trial entry3789Risk 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 entry11111Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.93, 1.35]
7.2 High risk at trial entry1263Risk 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 entry1533Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.06, 15.96]
8.2 High risk at trial entry2295Risk 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 entry1579Risk Ratio (M-H, Fixed, 95% CI)2.01 [0.18, 22.01]
9.2 High risk at trial entry31724Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.32, 3.24]
Analysis 4.1.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 1 Pre-eclampsia (hypertension with proteinuria).

Analysis 4.2.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 2 Length of gestation (days).

Analysis 4.3.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 3 Preterm birth (< 37 weeks).

Analysis 4.4.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 4 Prolonged gestation (> 42 weeks).

Analysis 4.5.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 5 Birthweight (gm).

Analysis 4.6.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 6 Low birthweight (< 2500 g).

Analysis 4.7.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 7 Small-for-gestational age.

Analysis 4.8.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 8 Stillbirth (= or > 24 weeks).

Analysis 4.9.

Comparison 4 Prostaglandin precursor supplementation versus none or placebo in singleton pregnancy - subgroups by risk, Outcome 9 Neonatal death.

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 oil31583Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.61, 1.37]
1.2 Evening primrose oil00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Fish oil + evening primrose oil1100Risk 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 oil31621Mean Difference (IV, Fixed, 95% CI)2.55 [1.01, 4.09]
2.2 Evening primrose oil00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2.3 Fish oil + evening primrose oil00Mean 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 oil51916Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.79, 1.07]
3.2 Evening primrose oil00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Fish oil + evening primrose oil00Risk 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 oil21970Risk Ratio (M-H, Random, 95% CI)1.68 [0.77, 3.66]
4.2 Evening primrose oil00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Fish oil + evening primrose oil00Risk 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 oil32440Mean Difference (IV, Fixed, 95% CI)47.24 [1.05, 93.44]
5.2 Evening primrose oil00Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 Fish oil + evening primrose oil00Mean 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 oil41080Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.79, 1.28]
6.2 Evening primrose oil00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6.3 Fish oil + evening primrose oil1100Risk 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 oil11374Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.96, 1.34]
7.2 Evening primrose oil00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
7.3 Fish oil + evening primrose oil00Risk 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 oil42802Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.46, 1.57]
8.2 Evening primrose oil00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8.3 Fish oil + evening primrose oil00Risk 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 oil32303Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.29]
9.2 Evening primrose oil00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
9.3 Fish oil + evening primrose oil00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 5.1.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 1 Pre-eclampsia (hypertension with proteinuria).

Analysis 5.2.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 2 Length of gestation (days).

Analysis 5.3.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 3 Preterm birth (< 37 weeks).

Analysis 5.4.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 4 Prolonged gestation (> 42 weeks).

Analysis 5.5.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 5 Birthweight (gm).

Analysis 5.6.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 6 Low birthweight (< 2500 g).

Analysis 5.7.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 7 Small-for-gestational age.

Analysis 5.8.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 8 Stillbirth (= or > 24 weeks).

Analysis 5.9.

Comparison 5 Prostaglandin precursor supplementation versus placebo - subgroups by type of supplement, Outcome 9 Neonatal death.

Appendices

Appendix 1. Search strategy

  1. PREGNANCY*:ME

  2. PREGNANCY-COMPLICATIONS*:ME

  3. PREGNANCY TRIMESTERS*:ME

  4. PREGNANCY-MULTIPLE*:ME

  5. PREGNAN*

  6. #1 OR #2 OR #3 OR #4 OR #5

  7. PREECLAMP*

  8. PRE-ECLAMP*

  9. (PRE NEXT ECLAMP*)

  10. ECLAMP*

  11. HYPERTENS*

  12. #7 OR #8 OR #9 OR #10 OR #11

  13. PRIMROSE NEAR OIL

  14. EVENING NEAR OIL

  15. PROSTAGLANDIN* NEAR PRECURSOR*

  16. FISH NEAR OIL*

  17. N-3 NEAR POLYUNSATURATED NEAR "FATTY ACID*"

  18. LCPUFA

  19. EICOSAPENTAENOIC NEXT ACID

  20. EICOSAPENTANOIC NEXT ACID

  21. 5-8-11-14-17-EICOSAPENTAENOIC ACID*:ME

  22. EPA

  23. DOCOSAHEXAENOIC NEXT ACID

  24. DOCOSAHEXANOIC NEXT ACID

  25. DOCOSAHEXAENOIC-ACIDS*:ME

  26. DHA

  27. #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 or #25 or #26

  28. #6 AND #12

  29. #28 AND #27

What's new

DateEventDescription
11 September 2012AmendedContact details updated.

History

Protocol first published: Issue 4, 2001
Review first published: Issue 3, 2006

DateEventDescription
17 September 2008AmendedConverted to new review format.

Contributions of authors

M Makrides (MM) and SF Olsen (SFO) assessed the trials for inclusion and extracted the data. MM wrote the protocol and review with contributions from L Duley and SFO.

Declarations of interest

Sjurdur Olsen was the principal investigator of the Denmark 1992 and Europe 2000 trials. Maria Makrides is the principal investigator of the ongoing DOMInO trial.

Sources of support

Internal sources

  • Child Health Research Institute, Australia.

  • Women's & Children's Hospital, Australia.

External sources

  • Department for International Development, UK.

  • Medical Research Council, UK.

  • National Health and Medical Research Council, Australia.

  • Danish National Research Foundation, Denmark.

Differences between protocol and review

The title has been updated from 'Fish oil and other prostaglandin precursor supplementation during pregnancy for reducing pre-eclampsia, preterm birth, low birth weight and intrauterine growth restriction' to 'Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia and intrauterine growth restriction' to more clearly identify the types of interventions and types of participants included.

Characteristics of studies

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.
Notes

Sample 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

  1. a

    DHA: docosahexaenoic acid
    EPA: eicosapentaenoic acid
    GLA: gamma linolenic acid
    IUGR: intrauterine growth restriction
    PE: pre-eclampsia
    PIH: pregnancy-induced hypertension

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
  1. a

    DHA: docosahexaenoic acid

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

  1. a

    DHA: docosahexaenoic acid
    EPA: eicosapentaenoic acid
    EPDS: Edinburgh Postnatal Depression Scale

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.

Ancillary