Maternal prenatal and/or postnatal n‐3 long chain polyunsaturated fatty acids (LCPUFA) supplementation for preventing allergies in early childhood
Abstract
Background
Allergies have become more prevalent globally over the last 20 years. Dietary consumption of n‐3 (or omega 3) long chain polyunsaturated fatty acids (LCPUFA) has declined over the same period of time. This, together with the known role of n‐3 LCPUFA in inhibiting inflammation, has resulted in speculation that n‐3 LCPUFA may prevent allergy development. Dietary n‐3 fatty acids supplements may change the developing immune system of the newborn before allergic responses are established, particularly for those with a genetic predisposition to the production of the immunoglobulin E (IgE) antibody. Individuals with IgE‐mediated allergies have both the signs and symptoms of the allergic disease and a positive skin prick test (SPT) to the allergen.
Objectives
To assess the effect of n‐3 LCPUFA supplementation in pregnant and/or breastfeeding women on allergy outcomes (food allergy, atopic dermatitis (eczema), allergic rhinitis (hay fever) and asthma/wheeze) in their children.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (6 August 2014), PubMed (1966 to 01 August 2014), CINAHL via EBSCOhost (1984 to 01 August 2014), Scopus (1995 to 01 August 2014), Web of Knowledge (1864 to 01 August 2014) and ClinicalTrials.gov (01 August 2014) and reference lists of retrieved studies.
Selection criteria
We included randomised controlled trials (RCTs) evaluating the effect of n‐3 LCPUFA supplementation of pregnant and/or lactating women (compared with placebo or no treatment) on allergy outcomes of the infants or children. Trials using a cross‐over design and trials examining biochemical outcomes only were not eligible for inclusion.
Data collection and analysis
Two review authors independently assessed eligibility and trial quality and performed data extraction. Where the review authors were also investigators on trials selected, an independent reviewer assessed trial quality and performed data extraction.
Main results
Eight trials involving 3366 women and their 3175 children were included in the review. In these trials, women were supplemented with n‐3 LCPUFA during pregnancy (five trials), lactation (two trials) or both pregnancy and lactation (one trial). All trials randomly allocated women to either a n‐3 LCPUFA supplement or a control group. The risk of bias varied across the eight included trials in this review with only two trials with a low risk of selection, performance and attrition bias.
N‐3 LCPUFA supplementation showed a clear reduction in the primary outcome of any allergy (medically diagnosed IgE mediated) in children aged 12 to 36 months (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.98; two RCTs; 823 children), but not beyond 36 months (RR 0.86, 95% CI 0.61 to 1.20; one RCT, 706 children). For any allergy (medically diagnosed IgE mediated and/or parental report), no clear differences were seen in children either at 12 to 36 months (RR 0.89, 95% CI 0.71 to 1.11; two RCTs, 823 children) or beyond 36 months of age (RR 0.96, 95% CI 0.84 to 1.09; three RCTs, 1765 children).
For the secondary outcomes of specific allergies there were no clear differences for food allergies at 12 to 36 months and beyond 36 months, but a clear reduction was seen for children in their first 12 months with n‐3 LCPUFA (both for medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report). There was a clear reduction in medically diagnosed IgE‐mediated eczema with n‐3 LCPUFA for children 12 to 36 months of age, but not at any other time point for both medically diagnosed IgE mediated and medically diagnosed IgE mediated and/or parental report. No clear differences for allergic rhinitis or asthma/wheeze were seen at any time point for both medically diagnosed IgE mediated, and medically diagnosed IgE mediated and/or parental report.
There was a clear reduction in children's sensitisation to egg and sensitisation to any allergen between 12 to 36 months of age when mothers were supplemented with n‐3 LCPUFA.
In terms of safety for the mother and child, n‐3 LCPUFA supplementation during pregnancy did not show increased risk of postpartum haemorrhage or early childhood infections.
Authors' conclusions
Overall, there is limited evidence to support maternal n‐3 LCPUFA supplementation during pregnancy and/or lactation for reducing allergic disease in children. Few differences in childhood allergic disease were seen between women who were supplemented with n‐3 LCPUFA and those who were not.
PICOs
Plain language summary
Fish oil (n‐3 or omega‐3) for pregnant mothers or breastfeeding mothers to prevent allergies in their young children
Fish and fish oil are the major sources of omega‐3 long chain fatty acids. Dietary marine omega‐3 fatty acid supplements during pregnancy may change the immune system of the newborn before allergic responses are established, particularly for those with a genetic predisposition to the production of the immunoglobulin E (IgE) antibody. Individuals with IgE‐mediated allergies have both the signs and symptoms of the allergic disease and a positive skin prick test (SPT) to the allergen.
Allergy is an important public health problem that places a burden on individuals, society and healthcare costs. Allergic diseases include food allergies, eczema (atopic dermatitis), asthma or wheeze and hay fever (allergic rhinitis). Many childhood allergies continue into adulthood.
Pregnant women, especially those from Western countries, are not eating as much fish and allergic diseases have been increasing over the time that pregnant women have been eating less fish. The unborn baby gets nutrition from his or her mother and so the mother's diet is important. Supplementing women with omega‐3 fatty acids from marine origin may be important in preventing their children from developing allergies.
In this review of randomised controlled studies, we evaluated the effects of adding marine omega‐3 fatty acids to women’s diets during pregnancy or lactation on allergic diseases in their children. We analysed eight trials that involved 3366 women and 3175 children. The women were randomly assigned to receive a marine omega‐3 supplement (as fish oil capsules, or added to foods) or no treatment during pregnancy (five trials), during breast feeding (two trials) or both pregnancy and breast feeding (one trial). Overall, the methodological quality of the trials varied, with only two trials being at low risk of bias.
Overall, the results showed little effect of maternal marine omega‐3 supplementation during pregnancy and/or breast feeding for the reduction of allergic disease in the children. However there were reductions in some outcomes such as food allergy during the baby's first year and eczema with marine omega‐3 supplementation in women with a baby at high risk of allergy. Currently, there is not enough evidence to say that omega‐3 supplements from marine origin during pregnancy and/or breast feeding for mothers will reduce allergies in their children.
In terms of safety for the mother and child, omega‐3 fatty acids supplementation from marine origin during pregnancy did not show increased risk of excessive bleeding after the baby was born (postpartum haemorrhage) or early childhood infections.
Authors' conclusions
Background
Description of the condition
Over the past 20 years the prevalence of allergies in industrialised countries has increased fivefold, from approximately 4% to an estimated 20% (Asher 2006; Pawanker 2011). Allergic diseases include food allergies, atopic dermatitis (eczema), asthma and allergic rhinitis (hay fever) (Arkwright 2008). The pattern of allergy expression differs with age (Spergel 2003). Food allergies and eczema are common in children under three years of age, while asthma and allergic rhinitis are more common between the ages of three and 15 years (Saarinen 1995). Regardless of these changing patterns of allergic disease in childhood, many childhood allergies persist, with 50% of childhood asthma sufferers and 80% of allergic rhinitis sufferers continuing to experience allergic symptoms into adulthood (Asher 2006; Barbee 1998; Greisner 1998; Spergel 2010).
Atopy is defined as a genetic predisposition to the production of specific immunoglobulin E (IgE) antibodies to allergens and atopic people are more liable to have immune reactions that lead to allergies (Sears 1996). One of the principal methods of determining specific IgE sensitisation to an allergen is the skin prick test (SPT). To perform a SPT, a drop of allergen extract is placed on the skin and a small prick is made through the drop. This allows a small amount of allergen to enter the skin. If allergic to the tested allergen, a small lump (wheal) will appear at the site of testing within 15 to 20 minutes. A test is positive if there is a mean wheal diameter of 3 mm or greater (Bousquet 2012). A positive SPT to an allergen, along with clinical allergy symptoms, forms the basis for IgE‐mediated allergy diagnosis (Johansson 2001; Johansson 2004).
The risk of allergy is 30% greater if one first degree relative (parent or sibling) is atopic, but if both parents are atopic then the allergy risk increases to 70% (Sears 1996). Allergic responses are reactions to an extrinsic substance (allergen) that is mediated by an immunological response (Arkwright 2008). This immunological response may cause mild to severe reactions in different individuals and can be life threatening (Arkwright 2008). Thus allergy is an important public health problem which places a burden on individuals, society and the healthcare system (Gupta 2004).
Environmental factors seem to have had an important influence on the increasing incidence of allergies. Possible contributing factors include lack of breastfeeding, higher socio‐economic conditions with higher standards of hygiene, fewer respiratory infections, greater use of antibiotics early in life, fewer older siblings in the household, less contact with farm animals, general lack of microbial exposure and changes in dietary patterns (Gupta 2004; Strong 2005).
Among the changes in dietary patterns, it has been hypothesised that the balance of long chain polyunsaturated fatty acids (LCPUFA), specifically the n‐3 (omega 3) to n‐6 (omega 6) ratio, may be a factor in the increased incidence of childhood allergies (Calder 2000; Calder 2010b; Prescott 2004). Furthermore, maternal fish consumption during pregnancy has also reduced due to precautionary public health advice regarding the consumption of specific fish which may contain methyl mercury (Oken 2003).
Description of the intervention
Fish and fish oil are the major sources of n‐3 LCPUFA, while vegetable oils are the major source of n‐6 LCPUFA. Recent data suggest that dietary consumption of n‐3 LCPUFA has declined in Western diets to favour the intake of n‐6 fatty acids (Meyer 2003). Epidemiological data suggest that a higher fish intake during pregnancy is associated with fewer symptoms of allergic diseases in the offspring in early childhood (Calvani 2006; Romieu 2007; Sausenthaler 2007; Willers 2007). Thus, supplementing maternal diets with n‐3 LCPUFA may be an important factor in reducing the incidence of allergic diseases.
How the intervention might work
Dietary n‐3 LCPUFA supplementation during pregnancy and lactation has been suggested to modulate the immune system of the fetus, neonate or infant before allergic responses are established (Denburg 2005). The early programming of fetal immune responses to allergens possibly begins in the epithelial tissue where antigen (allergen) proteins first encounter antigen‐presenting cells (Prescott 2007). The pattern of cytokine production by antigen‐presenting cells determines the pattern of T‐helper (Th) cells differentiation (Prescott 2007). T cells producing Type 1 T cells (Th1), develop under the influence of interleukin (IL)‐12 and IL‐2, whereas T cells producing Type 2 T cells (Th2), develop in the relative absence of pro‐Th2 factors such as IL‐4 (Snijdewint 1993). The differences in T cell phenotypes also determine the pattern of B‐cell antibody production with Th2 cytokines (IL‐4, IL‐5, and IL‐13), prompting IgE production and allergic inflammation, whereas Th1 cytokines (IFN‐γ) largely inhibit this in favour of low level IgG production (Calder 2006; Calder 2010a). Th2 cytokines are also important in determining whether these immune responses result in clinically relevant diseases such as asthma, allergic rhinitis or allergic dermatitis (Calder 2003; Georas 2005; Prescott 2007). A well regulated placental balance between the Th1 and Th2 responses is important for developing a robust immune system during pregnancy (Wilczynski 2005).
Maternal n‐3 LCPUFA intervention studies support this immune programming hypothesis (Krauss‐Etschmann 2007; Lauritzen 2005; Lee 2013; Romero 2013). Two studies investigated Th1/Th2 related molecules in cord blood (Krauss‐Etschmann 2008; Romero 2013), and the other investigated cytokine production in children at two and a half years of age (Lauritzen 2005). These studies showed that allergy‐related immune parameters were lower in the offspring of women who had n‐3 LCPUFA supplementation during pregnancy or lactation (Krauss‐Etschmann 2008; Lauritzen 2005; Romero 2013). The other study also showed that maternal n‐3 LCPUFA supplementation during pregnancy was associated with balancing Th1/Th2 and modulating IFNγ and IL13 in infants (Lee 2013).
Supporting evidence from mechanistic (Denburg 2005; Prescott 2007) and small scale intervention studies show that allergy markers and allergy mechanisms are influenced by n‐3 LCPUFA (Dunstan 2003; Prescott 2007a). Also there were studies in which maternal or postnatal consumption of n‐3 LCPUFA through oily fish or fish oil had an effect on allergy outcomes in children (Hodge 1996; Romieu 2007), as well as a transient effect on allergy outcomes (Mihrshahi 2004; Oddy 2004).
Why it is important to do this review
Allergy is an important public health problem that places a burden on individuals, society and healthcare costs (Gupta 2004; Kemp 1999; Pawanker 2011). Consequently, allergy prevention is a major global challenge (Strong 2005) and the World Allergy Organization (WAO) recommends that allergy preventative strategies are urgently needed (Asher 2004). It is uncertain if n‐3 LCPUFA supplementation during pregnancy or lactation reduces allergic disease in children. For these reasons, we need clear evidence from intervention studies. Therefore, in this systematic review we aim to evaluate the effects of maternal n‐3 LCPUFA supplementation during pregnancy and/or lactation on allergy outcomes in children.The safety aspects of n‐3 LCPUFA also need to be considered; it is postulated that high doses of n‐3 LCPUFA may have antithrombotic antiplatelet properties which may lead to bleeding (Simopoulos 1991), as well as immune cell alterations which may have an effect on infections (Calder 2007).
Objectives
To assess the effect of maternal n‐3 LCPUFA supplementation during pregnancy and/or lactation on the allergy outcomes of their children.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs) focusing on n‐3 LCPUFA supplementation of pregnant and/or lactating women (compared with placebo or no treatment) and assessed allergy outcomes of the infants or children. Quasi‐RCTs and RCTs using a cluster‐randomised design were eligible for inclusion but none were identified. Trials published in abstract form only were not identified for inclusion. In future updates we will only consider abstracts for inclusion if unpublished data can be obtained from the trails. Trials using a cross‐over design and trials examining biochemical outcomes only were not eligible for inclusion.
Types of participants
Women and their children, with either a normal or high risk of developing allergic disease, were included. A fetus or a child with a first degree relative with medically diagnosed allergies, or a positive a SPT, or a positive radioallergosorbent test (RAST) was defined as being at high risk of allergies. Infants were also considered at high risk of allergies if their cord blood IgE level was above 0.70 IU/mL.
Types of interventions
We considered all randomised comparisons of n‐3 LCPUFA supplementation given to pregnant or lactating women (either with or without arachidonic acid), with placebo or no supplementation as a control, regardless of dose regimens and duration of intervention. Trials in which fish was the intervention were included if appropriately controlled, for example, if the diet was appropriately adjusted to match the protein contribution of fish.
Types of outcome measures
Primary outcome measures included children with allergy, including food allergy, atopic dermatitis (eczema), asthma/wheeze, allergic rhinitis (hay fever) or any allergies (children with one or more of the allergy types). Outcomes were assessed as short term (occurring at less than 12 months of age), medium term (occurring from 12 to less than 36 months of age) and long term (36 months of age and older). Outcomes were also assessed by combining short‐term, medium‐term and long‐term results to assess the cumulative incidence.
Primary outcomes
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Medically diagnosed any allergy with sensitisation, i.e. IgE‐mediated allergies where both the signs and symptoms of the allergic disease and a positive SPT and/or RAST test are present.
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Medical diagnosis or parental report (using validated questionnaire) of any allergy, +/‐ IgE sensitisation.
Secondary outcomes
Secondary outcome measures included children with specific forms of allergy, including food allergy, atopic dermatitis (eczema), asthma/wheeze, allergic rhinitis (hay fever) with IgE sensitisation and +/‐ IgE sensitisation, SPT results, and parent‐reported allergies using non‐validated questionnaires. Secondary safety outcomes included infant safety (e.g. infections) and maternal safety (e.g. postpartum haemorrhage or infection) due to the theoretical risk associated with higher doses of n‐3 LCPUFA.
Search methods for identification of studies
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (6 August 2014).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
In addition, we searched PubMed (1966 to 01 August 2014) (Appendix 1), CINAHL via EBSCOhost (1984 to 01 August 2014) (Appendix 2), Scopus (1995 to 01 August 2014) (Appendix 3), Web of Knowledge (1864 to 01 August 2014) (Appendix 4) and ClinicalTrials.gov (01 August 2014) (Appendix 5).
Searching other resources
We searched reference lists of retrieved studies.
We did not apply any language or date restrictions.
Data collection and analysis
Selection of studies
Two review authors Anoja W Gunaratne (AWG) and Carmel T Collins (CTC) independently assessed the eligibility of trials identified by the search. Disagreements were resolved through discussion or, if required, by consultation with the third review author Maria Makrides (MM).
Data extraction and management
Two review authors (AWG, CTC) independently extracted the data from eligible trials using the agreed form. Discrepancies were resolved through discussion or through consultation with the third author (MM) if required. When information was unclear or incomplete, we attempted to contact authors of the original reports to provide further details. We entered data into Review Manager software 5.3 (RevMan 2014) and checked them for accuracy.
Assessment of risk of bias in included studies
Two review authors (AWG, CTC) independently assessed the risk of bias for each trial using the criteria outlined inthe Cochrane Handbook for Systematic Reviews of Interventions (Handbook) (Higgins 2011). We resolved any disagreement by discussion or by involving a third assessor (MM). MM and CTC are Investigators on two trials, Makrides 2009 and Makrides 2010 included in the review. These trials were independently assessed for risk of bias and data extracted by AWG and an independent researcher third party Karen Best (KB).
(1) Random sequence generation (checking for possible selection bias)
For each included trial, we described the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it would produce comparable groups.
We assessed the method as:
low risk of bias (any truly random process, e.g. random number table, computer random number generator); high risk of bias (any non‐random process, e.g. odd or even date of birth, hospital or clinic record number); unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
For each included trial, we described the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen before recruitment, during recruitment or changed after assignment.
We assessed the methods as:
low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We described the methods used, if any, to blind trial participants and personnel from knowledge of which intervention a participant received for each trial. We considered that trials were at low risk of bias if they were blinded, or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
low, high or unclear risk of bias for participants; low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We described the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received for each included trial. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods used to blind outcome assessment as:
low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We described the completeness of data, including attrition and exclusions from the analysis, for each included trial and for each outcome or class of outcomes. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants). We also outlined the reasons for attrition or exclusion, where reported, and whether missing data were balanced across groups or related to outcomes. We included missing data in the analyses where sufficient information was reported or could be supplied by the trial authors.
We assessed methods as:
low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups); high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation); unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We described our investigation of possible selective outcome reporting bias and our results for each included trial.
We assessed the methods as having a:
low risk of bias – where it is clear that all of the trial’s pre‐specified outcomes and all expected outcomes of interest to the review were reported; high risk of bias – where not all the trial’s pre‐specified outcomes had been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest were reported incompletely and so could not be used; or trial failed to include results of a key outcome that would have been expected to have been reported; unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We described any important concerns we had about other possible sources of bias for each included trial.
We assessed whether each trial was free of other problems that could put it at risk of bias, as low, high or unclear risk of other bias.
(7) Overall risk of bias
We made explicit judgements about whether trials were at high risk of bias according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses – seeSensitivity analysis.
Measures of treatment effect
Dichotomous data
Results are presented as summary risk ratio with 95% confidence intervals.
Continuous data
We planned to present the results of continuous data as the mean difference, if outcomes were measured in the same way between trials. We would have used the standardised mean difference to combine trials that measured the same outcome but used different methods.
Unit of analysis issues
Cluster‐randomised trials
We did not identify any cluster‐randomised trials for inclusion in this review. If we identify cluster‐randomised trials in future updates of this review, we will include them in the analyses along with individually‐randomised trials. We will adjust their sample size using the methods described in the Handbook (Higgins 2011) using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a trial of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we will synthesis the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the trial designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.
Cross‐over trials
Cross‐over trials are not an appropriate design for this review.
Other unit of analysis issues
Trials with more than two treatment groups
Trials using one or more treatment groups (multi‐arm trials) were combined to create a single pair‐wise comparison where appropriate. We used the methods described in the Handbook (Higgins 2011) to ensure that we did not double count participants.
Dealing with missing data
We noted levels of attrition within the included trials. We used sensitivity analyses to explore the impact of including trials with high levels of missing data on the overall assessment of treatment effect. For all outcomes, we carried out analyses (as far as possible) on an intention‐to‐treat basis. This meant that we attempted to include all participants randomised to each group in the analyses with all participants analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator used for each outcome was the number randomised minus the number with missing outcomes. In studies where there were missing data, we imputed results, if the imputed results differed little from the raw data.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta‐analysis using the T², I² and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either the T² was greater than zero or there was a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
In future updates, if there are 10 or more studies in the meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
We carried out statistical analyses using the Review Manager software 5.2 (RevMan 2014). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that trials were estimating the same underlying treatment effect: that is, where trials were examining the same intervention and the trials’ populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. We did not combine trials if the average treatment effect was not clinically meaningful.
Where we used random‐effects analyses, the results are presented as the average treatment effect with 95% confidence intervals and estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
Substantial heterogeneity was investigated using subgroup analyses and sensitivity analyses. We considered whether an overall summary was meaningful, and if it was, used random‐effects analyses.
We planned to carry out the following subgroup analyses.
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Timing of supplementation
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n‐3 LCPUFA supplementation during pregnancy versus placebo or no supplementation during pregnancy
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n‐3 LCPUFA supplementation during lactation versus placebo or no supplementation during lactation
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n‐3 LCPUFA supplementation during pregnancy and lactation versus placebo or no supplementation during pregnancy and lactation
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Allergy risk
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Maternal n‐3 LCPUFA supplementation in women whose infants were at high risk of allergic disease versus placebo or no supplementation
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Maternal n‐3 LCPUFA supplementation in women whose infants were not considered as at high risk of allergic disease versus placebo or no supplementation
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Infant maturity
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Maternal n‐3 LCPUFA supplementation in term born infants versus placebo or no supplementation
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Maternal n‐3 LCPUFA supplementation in preterm born infants versus placebo or no supplementation
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We restricted subgroup analyses to the primary outcomes.
Sensitivity analysis
We planned to carry out sensitivity analyses for the review's primary outcomes to investigate the effect of trial quality by removing those trials rated as ‘high' or 'unclear' risk of selection, performance or attrition bias to establish whether it was likely to impact on the findings.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Results of the search
Electronic searches yielded 2290 records. The Cochrane Pregnancy and Childbirth Trials Register search (06 August 2014), retrieved 144 reports. Other electronic databases, PubMed (1966 to 01 August 2014), CINAHL via EBSCOhost (1984 to 01 August 2014), Scopus (1995 to 01 August 2014), Web of Knowledge (1864 to 01 August 2014) and ClinicalTrials.gov (01 August 2014) retrieved 159, 18,1817, 140 and 12 reports respectively. Two additional reports included the doctoral thesis (submitted) of AWG and an unpublished honours dissertation supervised by MM and CTC.
Of the 2292 records, we removed duplicates and irrelevant reports and identified 141 titles and abstracts by considering the inclusion criteria. Sixteen trials (with 43 reports) were excluded, leaving eight trials (with 94 reports) for inclusion in this review. Four trials (with four reports) are ongoing (Bisgaard 2012; Duchen 2012; Laitinen 2013; Liu 2013.) See Figure 1.
Study flow diagram.
Included studies
See: Characteristics of included studies.
We identified eight randomised controlled trials with 3366 women (3175 children) who were supplemented with oily fish, or n‐3 LCPUFA supplements during pregnancy and/or during lactation and assessed allergic outcomes in their children.
Study design
All eight trials were parallel randomised controlled trials published in English. Six trials had two parallel groups (Dunstan 2003; Furuhjelm 2009; Makrides 2009; Noakes 2012; Makrides 2010; Ramakrishnan 2010), one trial included two parallel groups and a high fish intake non‐randomised reference group (Lauritzen 2005), and one trial had three parallel groups including intervention, placebo and no oil group (Olsen 1992).
Full details of the included trials are provided in the Characteristics of included studies table.
Participants
Of the 3366 women included in the review, 667 were supplemented during the postnatal period only (Lauritzen 2005; Makrides 2009), 145 received supplementation in both the prenatal and postnatal period (Furuhjelm 2009) and the remaining 2554 women were only supplemented in the prenatal period (Dunstan 2003; Noakes 2012; Olsen 1992; Makrides 2010; Ramakrishnan 2010). Women with a fetus at high risk of allergies (n = 1072) were included in four trials (Dunstan 2003; Furuhjelm 2009; Noakes 2012; Makrides 2010) while the remainder included women with a fetus at both high and normal risk of allergies (Lauritzen 2005; Makrides 2009; Olsen 1992; Ramakrishnan 2010), see 'types of participants for definition of high risk'. In one trial, only preterm infants were included (Makrides 2009).
Sample sizes
The sample sizes of the included trials ranged from 98 (Dunstan 2003) to 1094 (Ramakrishnan 2010). Four trials had approximately 100 to 150 mothers (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Noakes 2012) and four trials had > 500 participants (Makrides 2009; Makrides 2010; Olsen 1992; Ramakrishnan 2010).
Study location
Three trials (Dunstan 2003; Makrides 2009; Makrides 2010) were undertaken in Australia, two (Lauritzen 2005; Olsen 1992) in Denmark, one (Furuhjelm 2009) in Sweden, one (Ramakrishnan 2010) in Mexico, and one (Noakes 2012) in the UK. Most of the trials were conducted in high‐income, well‐developed industrialised countries except one trial (Ramakrishnan 2010) which was conducted in a upper‐middle income country.
Intervention
Six trials used n‐3 LCPUFA capsules (Dunstan 2003; Furuhjelm 2009; Makrides 2009; Makrides 2010; Olsen 1992; Ramakrishnan 2010), one used muesli bars containing microencapsulated fish oil as a source of n‐3 LCPUFA (Lauritzen 2005), and the remaining trial used oily fish (Noakes 2012). The daily dosage of n‐3 LCPUFA varied between 400 mg and 4500 mg; providing between 331 mg and 2070 mg of docosahexaenoic acid (DHA) and 100 mg and 1600 mg of eicosapentaenoic acid (EPA). Control groups received olive oil in three trials (Dunstan 2003; Lauritzen 2005; Olsen 1992), soy oil in two trials (Furuhjelm 2009; Makrides 2009), a blend of vegetable oils (rapeseed, sunflower, and palm in equal proportions) in one trial, (Makrides 2010), or a blend of corn and soy oil in one trial (Ramakrishnan 2010). Olsen 1992 included a third randomised group who did not receive any supplementation and the control group in Noakes 2012 also received no supplementation.
The prenatal supplementation trials commenced supplementation between 18 to 20 weeks (Ramakrishnan 2010), at 20 (Dunstan 2003; Makrides 2010; Noakes 2012) and 30 (Olsen 1992) weeks of gestation and continued until delivery. One trial supplemented in both the prenatal and postnatal period, commencing from 25 weeks' gestation and continuing until the infant reached four months of age (Furuhjelm 2009). In the two postnatal supplementation trials, supplementation commenced within one week after delivery (Lauritzen 2005; Makrides 2009). The duration of supplementation was four months in Lauritzen 2005 while in Makrides 2009 trial in preterm infants, supplementation continued until the infant reached 40 weeks postmenstrual age (a median duration of 9.4 weeks supplementation).
Outcome measures
The allergy outcomes were determined by parental reports of doctor diagnosed allergy in one trial (Lauritzen 2005), parental reports of allergy symptoms in one trial (Ramakrishnan 2010) and parental reports of allergy symptoms and parental reports of doctor diagnosed allergy in one trial (Makrides 2009). Allergy was medically diagnosed in the remaining trials (Dunstan 2003; Furuhjelm 2009; Noakes 2012; Olsen 1992; Makrides 2010). In Olsen 1992, the medical diagnosis of allergy was obtained from the Danish Medical registries. Parent reports of allergy outcome data were collected using a non‐validated questionnaire and validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire in Makrides 2009 trial. Parent reports of allergy outcome data were collected using a non‐validated questionnaire in Ramakrishnan 2010 trial. Additionally, Makrides 2010 trial also had parent reports of allergy outcome data using a non‐validated questionnaire. The data that were collected using non‐validated questionnaires were only included in the secondary outcomes.
The age of assessments differed in the trials. Assessments were conducted at one month and three months (Ramakrishnan 2010), six months (Furuhjelm 2009; Noakes 2012; Makrides 2010; Ramakrishnan 2010), 12 months (Dunstan 2003; Furuhjelm 2009; Makrides 2009; Makrides 2010), 18 months corrected age (Makrides 2009; Ramakrishnan 2010), 24 months (Furuhjelm 2009), 30 months (Lauritzen 2005), three to five years corrected age (Makrides 2009) (subgroup), 36 months (Makrides 2010), seven years of age (Makrides 2009), and 16 years of age (Olsen 1992). Of the five trials that used medical diagnosis of allergies (Dunstan 2003; Furuhjelm 2009; Noakes 2012; Olsen 1992; Makrides 2010), four performed skin prick tests (SPT) (Dunstan 2003; Furuhjelm 2009; Noakes 2012; Makrides 2010) and included children at high risk of allergy. Two trials (Furuhjelm 2009; Noakes 2012) reported SPT results for children under 12 months of age, three trials (Dunstan 2003; Furuhjelm 2009; Makrides 2010), reported SPT between 12 to 36 months of age, and one trial (Makrides 2010) reported SPT in children at 36 months of age.
IgE‐mediated allergies were reported in Furuhjelm 2009 and Makrides 2010. Two trials (Furuhjelm 2009; Noakes 2012) used blood samples for IgE detection in infants and one trial (Noakes 2012) reported the results at birth and six months of age while the other trial (Furuhjelm 2009) analysed the serum IgE levels at three and 12 months of age, but results were not reported.
The type of allergies reported in the trials differed. Five trials (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2009; Makrides 2010) reported food allergy. Six trials (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2009; Noakes 2012; Makrides 2010) reported eczema. All trials (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2009; Noakes 2012; Olsen 1992; Makrides 2010; Ramakrishnan 2010) reported asthma or wheeze. Three trials (Furuhjelm 2009; Makrides 2009; Makrides 2010) reported allergic rhinitis and four trials (Furuhjelm 2009; Makrides 2009; Olsen 1992; Makrides 2010) reported any allergy.
Two trials (Olsen 1992; Makrides 2010) reported postpartum haemorrhage. Makrides 2010 (n = 2399) was the primary trial from which the Palmer 2012 participants were recruited (see table of included studies); the incidence of postpartum haemorrhage is reported for the primary trial. Four trials (Noakes 2012; Makrides 2009; Makrides 2010; Ramakrishnan 2010) reported early childhood infections. Infection outcomes (in‐hospital proven late onset sepsis) for Makrides 2009 are reported for the whole sample (n = 657). Ramakrishnan 2010 also reported fever in infants.
Excluded studies
See: Characteristics of excluded studies.
We excluded 16 randomised controlled trials where the intervention was n‐3 LCPUFA supplementation but allergy outcomes of the infants and/or children were not reported (Bergmann 2008; Campos‐Martinez 2012; Carlson 2013 : Colombo 2004; Courville 2011; Granot 2011; Hauner 2009; Helland 2001; Innis 2007; Judge 2007; Karlsson 2010; Knudsen 2006; Krauss‐Etschmann 2007; Martin‐Alvarez 2012: Pena‐Quintana 2011; Ribeiro 2012). Many of these trials are included in the Cochrane Systematic Review currently being updated (Makrides 2006).
Characteristics of ongoing studies
See: Characteristics of ongoing studies.
There are four ongoing trials (Bisgaard 2012; Duchen 2012; Laitinen 2013; Liu 2013).
Risk of bias in included studies
Overall, the eight included studies had various levels of risk of bias for methodological quality. See Figure 2 and Figure 3 for details.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Allocation
All of the eight trials were at low risk of bias for sequence generation.
Six trials reported adequate allocation concealment methods (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2009; Makrides 2010: Olsen 1992) and two trials (Noakes 2012; Ramakrishnan 2010) had an unclear risk of bias as the method of allocation concealment was not described.
Blinding
Women, care providers and research personnel were blinded in six trials (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2009; Makrides 2010; Ramakrishnan 2010). In two trials (Noakes 2012; Olsen 1992), women who were randomised to the 'no supplement' group could not be blinded.
Outcome assessments were performed by assessors who were blinded to the trial supplementations in all eight trials (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2009; Makrides 2010: Noakes 2012; Olsen 1992; Ramakrishnan 2010).
Incomplete outcome data
All trials reported withdrawals and dropouts. We assessed four trials (Makrides 2009; Makrides 2010: Olsen 1992; Ramakrishnan 2010) as having a low risk of attrition bias. Makrides 2009 reported 6% of participant losses to follow‐up at 18 months, 8% at three to five years of age and 10.5% at seven years of age. Olsen 1992 reported 1% of participant losses to follow‐up at 16 years of age. Makrides 2010 reported participant follow‐up losses of 3.5% and 9.6% at one and three years of age respectively. Ramakrishnan 2010 reported 25% participants losses to follow‐up at six months, but balanced between group, and reasons for withdrawals were reported (intervention (23%) and control (24%)). Dunstan 2003, Furuhjelm 2009, Lauritzen 2005 and Noakes 2012 were assessed as having a high risk of attrition bias. Dunstan 2003 reported a loss of 15% to follow‐up and participant exclusion after randomisation, which differed between intervention (n = 12, 23%) and control (n = 3, 6.5%). More women in the intervention group discontinued treatment because of nausea (n = 7, 13.5%) than in the control (n = 1, 2%). Furuhjelm 2009 reported a 19% loss of participants to follow‐up (n = 16), with 23% in the treatment group (n = 9) and 12% in the placebo group excluded from the analysis because they did not complete the 15‐week intervention. Lauritzen 2005 had large follow‐up losses of more than 47%, with no reasons reported for the withdrawals (treatment n = 25, 40%; control n = 32, 53%). Noakes 2012 also had large follow‐up losses (30%) at six months with no reasons reported (treatment n = 16, 23%; control n = 23, 37%).
Selective reporting
All trials (Dunstan 2003; Lauritzen 2005; Makrides 2009; Noakes 2012; Olsen 1992; Ramakrishnan 2010) except two (Furuhjelm 2009; Makrides 2010) were assessed as having a high risk of reporting bias, as expected outcomes of interest to this review were not reported or were not reported completely.
Other potential sources of bias
There were no obvious other potential sources of bias identified in four trials (Furuhjelm 2009; Lauritzen 2005; Noakes 2012; Ramakrishnan 2010). There was an unclear risk of bias in the two trials that included subgroups of their original trials (Makrides 2009; Makrides 2010). In Olsen 1992 the placebo group and no oil group were combined in this review. We conducted analyses with the n‐3 LCPUFA supplementation group compared to olive oil control group separately to n‐3 LCPUFA supplementation group compared to no supplement control group, and found that although the direction of effect differed it made little difference to the meta‐analysis therefore for this review the control groups were combined. Dunstan 2003 was rated as having an unclear risk of bias because preterm infants were excluded from their analysis after randomisation.
Effects of interventions
N‐3 LCPUFA supplementation versus placebo or no supplementation
Primary outcomes ‐ any allergy
| Allergy (IgE mediated) | Assessed Age | No of studies | No of participants | n‐3 LCPUFA | Placebo | Effect Estimate RR [95% CI] | ||
| Events | Total | Events | Total | |||||
| Food allergy | < 12 months | 1 | 117 | 1 | 52 | 10 | 65 | 0.13 [0.02 to 0.95] ٭ |
| 12‐36 months | 2 | 825 | 13 | 422 | 20 | 403 | 0.58 [0.18 to 1.88] R | |
| ≥ 36 months | 1 | 706 | 14 | 368 | 9 | 338 | 1.43 [0.63 to 3.26] | |
| Eczema | < 12 months | 1 | 117 | 4 | 52 | 13 | 65 | 0.38 [0.13 to 1.11] |
| 12‐36 months | 2 | 823 | 29 | 422 | 45 | 401 | 0.61 [0.39 to 0.95] ٭ | |
| ≥ 36 months | 1 | 706 | 44 | 368 | 48 | 338 | 0.84 [0.57 to 1.23] | |
| Allergic rhinitis | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 825 | 1 | 422 | 3 | 403 | 0.47 [0.07 to 3.06] | |
| ≥ 36 months | 1 | 706 | 18 | 368 | 20 | 338 | 0.83 [0.44 to 1.54] | |
| Asthma | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 824 | 3 | 422 | 4 | 402 | 0.86 [0.21 to 3.49] | |
| ≥ 36 months | 1 | 706 | 6 | 368 | 5 | 338 | 1.10 [0.34 to 3.58] | |
| Any allergies | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 823 | 36 | 422 | 52 | 401 | 0.66 [0.44 to 0.98] ٭ | |
| ≥ 36 months | 1 | 706 | 55 | 368 | 59 | 338 | 0.86 [0.61 to 1.20] | |
*significant P < 0.05, ٭٭ significant P < 0.005, NE = Not estimable , R= Random‐effects estimate
| Allergy (IgE mediated or not) | Assessed Age | No of studies | No of participants | n‐3 LCPUFA | Placebo | Effect Estimate RR [95% CI] | ||
| Events | Total | Events | Total | |||||
| Food allergy | < 12 months | 1 | 117 | 1 | 52 | 10 | 65 | 0.13 [0.02, 0.95] ٭ |
| 12‐36 months | 4 | 973 | 19 | 499 | 26 | 474 | 0.72 [0.40 to 1.30] | |
| ≥ 36 months | 1 | 706 | 14 | 368 | 9 | 338 | 1.43 [0.63 to 3.26] | |
| Eczema | < 12 months | 2 | 203 | 16 | 100 | 20 | 103 | 0.76 [0.22 to 2.62]R |
| 12‐36 months | 4 | 973 | 118 | 499 | 122 | 474 | 0.96 [0.69 to 1.33]R | |
| ≥ 36 months | 2 | 1237 | 122 | 628 | 131 | 609 | 0.88 [0.68 to 1.13]R | |
| Allergic rhinitis | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 805 | 10 | 414 | 18 | 391 | 0.53 [0.25 to 1.12] | |
| ≥ 36 months | 2 | 1169 | 114 | 593 | 109 | 576 | 1.03 [0.81 to 1.30] | |
| Asthma | < 12 months | 1 | 83 | 11 | 46 | 7 | 37 | 1.26 [0.54 to 2.94] |
| 12‐36 months | 4 | 955 | 106 | 491 | 105 | 464 | 0.93 [0.73 to 1.18] | |
| ≥ 36 months | 3 | 1697 | 165 | 856 | 171 | 841 | 0.94 [0.78 to 1.13] | |
| Any allergies | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 823 | 109 | 422 | 117 | 401 | 0.89 [0.71 to 1.11] | |
| ≥ 36 months | 3 | 1765 | 270 | 891 | 274 | 874 | 0.96 [0.84 to 1.09] | |
*significant P < 0.05, ٭٭ significant P < 0.005, NE= Not estimable , R= Random‐effects estimate
We considered any allergy that included children with one or more allergy types including food allergy, atopic dermatitis (eczema), asthma/wheeze, allergic rhinitis (hay fever) as primary outcomes of the review. Allergic disease was considered in two ways. Firstly, the effect of n‐3 LCPUFA supplementation on IgE‐mediated allergic disease, then the effect of supplementation on all allergic disease (+/‐ IgE sensitivity) was analysed, for each of the allergic diseases under study. The effect of supplementation was analysed at various points in the child's life – short term (up to 12 months of age), medium term (12 to 36 months), and long term (36 months and beyond). We were unable to report cumulative incidences due to variation in reporting between studies.
Any allergies (Analysis 1.1; Analysis 1.2)
N‐3 LCPUFA supplementation showed a clear reduction in IgE‐mediated allergies in 12 to 36 months of age children when compared with the control group (Analysis 1.1; Furuhjelm 2009; Makrides 2010, 823 children, risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.98). No clear differences were found in IgE‐mediated allergies between treatments in 36 months of age or older children (Makrides 2010, 706 children, RR 0.86, 95% CI 0.0.61 to 1.20). No included trials reported on combined IgE‐mediated allergies in infants under 12 months of age.
When all allergies (+/‐ IgE sensitivity) were considered, n‐3 LCPUFA supplementation did not show clear differences in allergies in children at 12 to 36 months (Furuhjelm 2009, Makrides 2010, RR 0.89, 95% CI 0.71 to 1.11, 823 children) or 36 months and beyond (Makrides 2009, Makrides 2010, Olsen 1992, RR 0.96, 95% CI 0.84 to 1.09, 1765 children) (Analysis 1.2). No included trials reported on combined +/‐ IgE‐mediated allergies in infants under 12 months of age.
Secondary outcomes
As secondary outcomes, we considered specific forms of allergy including food allergy, atopic dermatitis (eczema), asthma/wheeze and allergic rhinitis (hay fever) (IgE‐mediated and +/‐ IgE sensitivity).
Food allergy (Analysis 2.1; Analysis 2.2)
N‐3 LCPUFA supplementation reduced the incidence of IgE‐mediated food allergies in children up to 12 months of age (Furuhjelm 2009, 117 infants, RR 0.13, 95% 0.02 to 0.95; Analysis 2.1), but there were no clear differences found between the intervention and control groups at any other age (12 to 36 months Furuhjelm 2009; Makrides 2010, 825 children, average RR 0.58, 95% CI 0.18 to 1.88; > 36 months of age Makrides 2010, 706 children, RR 1.43, 95% CI 0.63 to 3.26). A random‐effects analysis was used as substantial heterogeneity was noted at the 12‐ to 36‐month time point (Tau² = 0.39; P = 0.15; I² = 51%) (Analysis 2.1). The heterogeneity may be due to the duration of the intervention, the dose used and the difference in assessment ages.
When food allergies +/‐ IgE sensitivity were considered (Analysis 2.2), results showed few differences from those for IgE‐mediated allergies (Analysis 2.1) with no differences in the direction of findings from those for IgE‐mediated allergies (up to 12 months of age, Furuhjelm 2009, 117 infants, RR 0.13, 95% CI 0.02 to 0.95; between 12 to 36 months, Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2010, 973 children, RR 0.72, 95% CI 0.40 to 1.30; > 36 months of age Makrides 2010, 706 children, RR 1.43, 95% CI 0.63 to 3.26).
Eczema (Analysis 2.3; Analysis 2.4)
N‐3 LCPUFA supplementation reduced the incidence of IgE‐mediated eczema in children at 12 to 36 months of age (Furuhjelm 2009; Makrides 2010; 823 children, RR 0.61, 95% CI 0.39 to 0.95, Analysis 2.3). There were no clear differences between groups at the other time points (< 12 months Furuhjelm 2009; 117 children, RR 0.38, 95% CI 0.13 to 1.11 or > 36 months of age Makrides 2010, 706 children, RR 0.84, 95% CI 0.57 to 1.23)
When eczema outcomes +/‐ IgE sensitivity were considered (Analysis 2.4), results showed few differences from those for IgE‐mediated eczema (Analysis 2.3), however the direction of effect was reversed for the 12‐ to 36‐month age group (up to 12 months of age (Furuhjelm 2009; Noakes 2012, 203 infants, average RR 0.76, 95% CI 0.22 to 2.62; between 12 to 36 months, Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Makrides 2010, 973 children, average RR 0.96, 95% CI 0.69 to 1.33; > 36 months of age, Makrides 2009; Makrides 2010, 1237 children, average RR 0.88, 95% CI 0.68 to 1.13). A random‐effects analysis was used all time points as substantial heterogeneity was noted at the 12‐month time point (Tau² = 0.57; P = 0.06; I² = 71%) (Analysis 2.4).
Allergic rhinitis (Analysis 2.5; Analysis 2.6)
No clear difference was seen between n‐3 LCPUFA and control groups in either IgE‐mediated allergic rhinitis (Analysis 2.5: 12 to 36 months, Furuhjelm 2009; Makrides 2010, 825 children, RR 0.47, 95% CI 0.07 to 3.06; > 36 months of age, Makrides 2010, 706 children, RR 0.83, 95% CI 0.44 to 1.54 or allergic rhinitis +/‐ IgE sensitivity (Analysis 2.6:12 to 36 months, Furuhjelm 2009, Makrides 2010, 805 children, RR 0.53, 95% CI 0.25 to 1.12; > 36 months of age, Makrides 2009, Makrides 2010, 1169 children, RR 1.03, 95% CI 0.81 to 1.30) across any age group. No included trials reported allergic rhinitis outcomes in infants under 12 months of age.
Asthma (Analysis 2.7; Analysis 2.8)
No clear differences were found between n‐3 LCPUFA and control groups in children with either IgE‐mediated asthma (Analysis 2.7; 12 to 36 months, Furuhjelm 2009; Makrides 2010, 824 children, RR 0.86, 95% CI 0.21 to 3.49; > 36 months of age, Makrides 2010, 706 children, RR 1.10, 95% CI 0.34 to 3.58), or asthma +/‐ IgE sensitivity (Analysis 2.8; < 12 months, Noakes 2012, 83 infants, RR 1.26, 95% CI 0.54 to 2.94; 12 to 36 months, Dunstan 2003, Furuhjelm 2009, Lauritzen 2005, Makrides 2010, 955 children, RR 0.93, 95% CI 0.73 to 1.18; > 36 months of age, Makrides 2009, Makrides 2010, Olsen 1992, 1697 children, RR 0.94, 95% CI 0.78 to 1.13) across any age group. No included trials reported IgE‐mediated asthma outcomes in infants under 12 months of age.
Maternal safety (Analysis 3.1)
There was no clear difference in postpartum haemorrhage (defined as > 500 mL of blood loss post delivery) in women supplemented with n‐3 LCPUFA compared with those in the control group (Analysis 3.1; Makrides 2010; Olsen 1992, n = 2932, average RR 0.73, 95% CI 0.49 to 1.10). Given the substantial heterogeneity between trials, a random‐effects model was used (Tau² = 0.05, P = 0.11; I² = 60%; Analysis 3.1). Postpartum infection was not reported in any of the included trials.
Infant safety (Analysis 3.2)
Infant safety was assessed using early childhood infections. Four trials reported this outcome (Makrides 2009; Makrides 2010; Noakes 2012; Ramakrishnan 2010, 2280 infants) with no clear difference between the n‐3 LCPUFA and control group (RR 0.99; 95% CI 0.87 to 1.12). Ramakrishnan 2010 reported fever in 834 infants and found no differences between groups (RR 0.99; 95% CI 0.74 to 1.31; Analysis 3.2).
Sensitisation to allergens (Analysis 4.1 to Analysis 4.9)
See: Table 3.
| Skin prick results | Assessed Age | No of studies | No of participants | n‐3 LCPUFA | Placebo | Fixed Effect estimate RR [95% CI] | ||
| Events | Total | Events | Total | |||||
| Egg | < 12 months | 2 | 203 | 7 | 100 | 17 | 103 | 0.44 [0.19 to 1.04] |
| 12‐36 months | 3 | 893 | 46 | 455 | 82 | 438 | 0.55 [0.39 to 0.77] ٭٭ | |
| ≥ 36 months | 1 | 706 | 11 | 368 | 16 | 338 | 0.63 [0.30 to 1.34] | |
| Cow’s milk | < 12 months | 2 | 205 | 5 | 102 | 7 | 103 | 0.75 [0.24 to 2.29]R |
| 12‐36 months | 3 | 897 | 9 | 457 | 13 | 440 | 0.68 [0.20 to 2.34]R | |
| ≥ 36 months | 0 | 0 | NE | |||||
| Peanut | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 778 | 18 | 403 | 28 | 375 | 0.61 [0.34 to 1.08] | |
| ≥ 36 months | 1 | 706 | 13 | 368 | 20 | 338 | 0.60 [0.30 to 1.18] | |
| Wheat | < 12 months | 1 | 117 | 1 | 52 | 0 | 65 | 3.74 [0.16 to 89.85] |
| 12‐36 months | 2 | 783 | 3 | 401 | 2 | 382 | 1.40 [0.29 to 6.84] | |
| ≥ 36 months | 1 | 706 | 6 | 368 | 2 | 338 | 2.76 [0.56 to 13.56] | |
| Fish | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 1 | 666 | 3 | 349 | 0 | 317 | 6.36 [0.33 to 122.65] | |
| ≥ 36 months | 1 | 706 | 2 | 368 | 1 | 338 | 1.84 [0.17 to 20.17] | |
| Inhalant allergens (pollens) | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 779 | 2 | 400 | 5 | 379 | 0.44 [0.08 to 2.30] | |
| ≥ 36 months | 1 | 580 | 21 | 303 | 25 | 277 | 0.77 [0.44 to 1.34] | |
| House dust mite | <12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 738 | 3 | 384 | 4 | 354 | 0.76 [0.18 to 3.28] | |
| ≥36 months | 1 | 580 | 22 | 303 | 24 | 277 | 0.84 [0.48 to 1.46] | |
| Cat | < 12 months | 1 | 86 | 1 | 48 | 1 | 38 | 0.79 [0.05 to 12.25] |
| 12‐36 months | 2 | 738 | 8 | 384 | 7 | 354 | 1.07 [0.39 to 2.94] | |
| ≥ 36 months | 1 | 706 | 25 | 368 | 12 | 338 | 1.91 [0.98 to 3.75] | |
| Any allergen (one or more allergen) | < 12 months | 2 | 201 | 14 | 100 | 25 | 101 | 0.59 [0.32 to 1.09] |
| 12‐36 months | 3 | 892 | 68 | 455 | 93 | 437 | 0.70 [0.53 to 0.94] ٭ | |
| ≥ 36 months | 1 | 706 | 91 | 368 | 88 | 338 | 0.95 [0.74 to 1.22] | |
*significant P < 0.05, ٭٭ significant P < 0.005, NE = Not estimable
Sensitisation is the strongest predictor of IgE‐mediated allergy and was defined by a positive skin prick test to an allergen (de Jong 2011). Sensitisation to egg (Analysis 4.1) was reduced in the n‐3 LCPUFA group compared with the control in 12‐ to 36 month‐old children (Dunstan 2003; Furuhjelm 2009; Makrides 2010, 893 children, RR 0.55; 95% CI 0.39 to 0.77). No clear differences between groups were seen in egg sensitisation in children up to 12 months of age (Furuhjelm 2009; Noakes 2012) or in children 36 months or older (Makrides 2010).
Sensitisation to cows' milk was not different between the treatment groups at any age of assessment (Analysis 4.2), although no trials contained data for children aged 36 months or older. Given the substantial heterogeneity at 12 to 36 months, a random‐effects model was used (Tau² = 0.48; P = 0.19; I² = 40%).
There were no clear differences between groups in peanut sensitisation at any time point (Analysis 4.3; no trials in infants under 12 months of age),
The effect of n‐3 LCPUFA supplementation on wheat sensitisation was not different from the control group at any age (Analysis 4.4) and similar results were seen with sensitisation to fish (Analysis 4.5; no trials up to 12 months of age), inhalant allergens (pollens) (Analysis 4.6; no trials up to 12 months of age), dust mites (Analysis 4.7; no trials up to 12 months of age) and cats (Analysis 4.8).
When all allergens were considered (Analysis 4.9), no clear differences were found between treatments for infants up to 12 months and beyond 36 months. However, n‐3 LCPUFA showed a clear reduction in sensitisation in 12 to 36 months of age children (Dunstan 2003; Furuhjelm 2009; Makrides 2010, 892 children, RR 0.70; 95% CI 0.53 to 0.94).
Parent's report of allergies from non‐validated questionnaires (Analysis 5.1 to Analysis 5.5)
Three trials (Makrides 2009; Makrides 2010; Ramakrishnan 2010), included parents' reports of allergy collected using non‐validated questionnaires. No clear differences were found between n‐3 LCPUFA supplementation and control at any age in the incidence of parental reports of food allergies (Analysis 5.1), eczema (Analysis 5.2), allergic rhinitis (Analysis 5.3), asthma/wheeze (Analysis 5.4), or any allergies (Analysis 5.5).
Subgroup analysis
Data were reported at last time point only in the subgroup analysis comparisons.
Timing of supplementation (Analysis 6.1 to Analysis 6.2)
Five trials included in the review confined supplementation with n‐3 LCPUFA to the prenatal period only (Dunstan 2003; Noakes 2012; Olsen 1992; Makrides 2010; Ramakrishnan 2010). Ramakrishnan 2010 collected allergy outcome data using a non‐validated questionnaire, therefore these data did not meet the inclusion criteria for the primary outcome. Two of the included trials supplemented women with n‐3 LCPUFA in the postnatal period only (Lauritzen 2005; Makrides 2009), and only one trial (Furuhjelm 2009) supplemented women with n‐3 LCPUFA through both prenatal and postnatal periods.
There were no significant subgroup differences for any of the outcomes (Analysis 6.1; Analysis 6.2).
Allergy risk of the offspring (Analysis 5.1 to Analysis 5.5)
Four trials (Dunstan 2003; Furuhjelm 2009; Noakes 2012; Makrides 2010) provided n‐3 LCPUFA supplements to women whose fetuses were at high risk of allergy development with two reporting only IgE‐mediated allergies (Furuhjelm 2009; Makrides 2010). Three trials studied the effect of n‐3 LCPUFA supplementation on allergy in women with fetuses or women with infants who were not selected on the basis of allergy risk (Lauritzen 2005; Makrides 2009; Olsen 1992). There were no significant subgroup differences for any outcome (Analysis 7.1).
Infant maturity
Subgroup analyses based on infant maturity were not able to be conducted. Although data from preterm children were available for Makrides 2009, it was not possible to separate out children according to their gestational age in the remaining included trials (Furuhjelm 2009; Lauritzen 2005; Noakes 2012; Olsen 1992; Makrides 2010). Dunstan 2003 excluded preterm infants after randomisation.
Sensitivity analysis
Sensitivity analyses were conducted for the primary outcome removing trials with high or unclear risk of selection, performance or attrition bias; Makrides 2009 and Makrides 2010 were the only trials with low risk of bias across these parameters. Removing trials with high or unclear risk of bias changed the direction for IgE‐mediated any allergy at 12 to 36 months time point, but not beyond the 36 months time point, or for medically diagnosed IgE mediated and/or parental report any allergy outcome at any time points (Analysis 8.1; Analysis 8.2).
Discussion
Summary of main results
Eight trials involving 3366 women with 3175 children were included in this review. Supplementation occurred during pregnancy, lactation or both pregnancy and lactation.
Overall, the available evidence shows that maternal n‐3 LCPUFA (long chain polyunsaturated fatty acid) supplementation showed little benefit in the reduction of childhood allergic disease. There was no clear overall effect of maternal n‐3 LCPUFA supplementation on the incidence of medically diagnosed or parental reports of allergy (+/‐ IgE sensitisation) including food allergy, eczema, allergic rhinitis, asthma/wheeze or any allergy. No reduction was observed with maternal n‐3 LCPUFA supplementation on IgE‐mediated allergic rhinitis or IgE‐mediated asthma.
However, there were reductions in some outcomes such as IgE‐mediated food allergy up to 12 months of age, IgE‐mediated eczema between one and three years of age and the risk of developing any IgE‐mediated allergic disease between one and three years of age. However, this needs to be interpreted with caution as IgE‐mediated allergies were reported in only two trials, which only focused on high‐risk populations of allergy.
There was also a reduction in the incidence of sensitisation to egg and any allergen in children in the n‐3 LCPUFA group.
Overall completeness and applicability of evidence
The majority of the evidence came from children of women supplemented with n‐3 LCPUFA during pregnancy and/or lactation and from women with a fetus at high risk of allergy (who were supplemented during pregnancy). Most of the trials included in this review were conducted in high‐income industrialised countries and the findings are therefore applicable to the most affluent societies where the burden of allergy is known to be high.
IgE‐mediated allergies, where both the signs and symptoms of the allergic disease and a positive skin prick test (SPT) and/or radioallergosorbent test (RAST) were present, were reported in two trials (Furuhjelm 2009; Makrides 2010 and all trials except three (Lauritzen 2005; Makrides 2009; Ramakrishnan 2010), used medical diagnosis of allergy for the analyses (with IgE status not tested or unknown).
Most allergic responses are mediated by IgE antibodies, specific to the trigger allergen (Johansson 2001; Sicherer 2012). However, although the presence of IgE antibodies indicates a sensitised state, the most reliable diagnosis of allergic disease should take into account clinical history as well (Sicherer 2012). Thus, diagnoses involving laboratory tests (RAST), SPT and assessment of clinical symptoms are more reliable than clinical presentation or parental reports (using validated questionnaires), or laboratory reports alone.
As asthma is difficult to diagnose in young children, authors often report 'wheeze' (Lauritzen 2005; Makrides 2010; Noakes 2012; Ramakrishnan 2010); we therefore included reports of wheeze in asthma outcomes.
The selection of women differed with respect to fish intake, with three trials targeting women with a low fish intake (Dunstan 2003; Lauritzen 2005; Noakes 2012), while fish intake was not related to inclusion criteria in other trials (Furuhjelm 2009; Makrides 2009; Makrides 2010; Olsen 1992; Ramakrishnan 2010). One of the reasons for some of the mixed results in this review may be due to the mothers baseline intake of n‐3 LCPUFA not being considered in some studies.
In the two trials where there was not an assigned control and women continued their 'usual diet' (Noakes 2012; Olsen 1992), the women in these groups may have had a high intake of dietary n‐3 LCPUFA as the benefits of dietary n‐3 LCPUFA in pregnancy was promoted in the countries in which these two trials were conducted.
In relation to diet and supplementation, some studies excluded women who were known to be allergic to fish (Dunstan 2003; Olsen 1992), as a safety precaution in case they may have reacted to fish oil capsules. Consequently, not many studies looked at fish allergy and hence data in this area may be limited (Dunstan 2003; Olsen 1992).
The evidence is incomplete for subgroup comparisons on the timing of supplementation, allergy risk of infants and maturity of infants. The trial in which n‐3 LCPUFA supplementation started during pregnancy and continued through to lactation was limited by small sample size and high risk of attrition bias (Furuhjelm 2009).
Quality of the evidence
The majority of the comparisons in this review were based on data from two trials (Furuhjelm 2009; Makrides 2010). The quality of the evidence for each of the comparisons greatly depends on the quality of these two trials. However, other primary outcome data regardless of IgE mediation were based on all included trials except Ramakrishnan 2010. The risk of bias varied across the eight included trials with only two trials (Makrides 2009; Makrides 2010) with a low risk of selection, performance and attrition bias.
Women's adherence to the supplementation may also impact on the outcomes. Blood analysis was used to check adherence to the supplementation in most trials (Dunstan 2003; Furuhjelm 2009; Lauritzen 2005; Noakes 2012; Olsen 1992; Makrides 2010), and all reported a significant n‐3 LCPUFA increase in the intervention group. The use of fish, rather than fish oil as a supplement also needs consideration as it may contribute to the energy and protein content in the maternal diet and influence outcomes in a different way. In this review we included one trial (Noakes 2012) which supplemented with fish, however this trial had been designed to overcome any additional effect of the diet by using it as a replacement for white fish, chicken and some red meat; thus minimising any additional energy and protein contributions (personal communication Noakes 2012).
Potential biases in the review process
Our search strategy was comprehensive and was not limited by language or publication status. We searched the major international and local bibliographic databases, handsearched major journals and the proceedings of major conferences in the field and set weekly current awareness alerts for a further 44 journals as well as monthly BioMed Central email alerts. We used a clear inclusion criteria and thorough quality assessment methodology to appraise each trial. Two review authors (AWG, CTC) independently screened and appraised the trials, and used pre‐designed data extraction forms to extract data. Therefore, biases in the review process are unlikely. Review authors MM and CTC were investigators on two trials (Makrides 2009; Makrides 2010) included in the review. These trials were independently assessed for inclusion, risk of bias and data extracted by AWG and an independent researcher Karen Best (KB).
Agreements and disagreements with other studies or reviews
Two systematic reviews (Klemens 2011; Kremmyda 2011), have been recently published on this topic. Kremmyda 2011 aimed to determine the effect of n‐3 LCPUFA supplementation during the perinatal period on allergies (irrespective of IgE status) in children, but did not conduct a meta‐analysis. Klemens 2011 conducted a meta‐analysis and reported that n‐3 LCPUFA supplementation during pregnancy reduced the incidence of childhood asthma but had no effect on atopic dermatitis. Their analysis did not include the most recent trials (Makrides 2009; Makrides 2010; Noakes 2012; Ramakrishnan 2010). Neither of the Klemens 2011 or Kremmyda 2011 reviews separated IgE‐mediated allergies from allergies with or without IgE mediation.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ any allergy, Outcome 1 Any allergies (with sensitisation): medically diagnosed IgE mediated.
Comparison 1 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ any allergy, Outcome 2 Any allergies (+/‐ sensitisation): medically diagnosed/parental reported.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 1 Food allergies (with sensitisation): medically diagnosed IgE mediated.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 2 Food allergies (+/‐ sensitisation): medically diagnosed/parental reported.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 3 Atopic dermatitis/Eczema (with sensitisation): medically diagnosed IgE mediated.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 4 Atopic dermatitis/Eczema (+/‐ sensitisation): medically diagnosed/parental reported.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 5 Allergic rhinitis/Hay fever (with sensitisation): medically diagnosed IgE mediated.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 6 Allergic rhinitis/Hay fever (+/‐ sensitisation): medically diagnosed/parental reported.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 7 Asthma/Wheeze (with sensitisation): medically diagnosed IgE mediated.
Comparison 2 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ specific forms of allergy, Outcome 8 Asthma/Wheeze (+/‐ sensitisation): medically diagnosed/parental reported.
Comparison 3 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ maternal and infant safety, Outcome 1 Maternal safety.
Comparison 3 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ maternal and infant safety, Outcome 2 Infants safety.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 1 Skin prick test results ‐ egg.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 2 Skin prick test results ‐ cows' milk.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 3 Skin Prick Test results ‐ peanut.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 4 Skin prick test results ‐ wheat.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 5 Skin prick test results ‐ fish.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 6 Skin prick test results ‐ inhalant allergen (pollens).
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 7 Skin prick test results ‐ house dust mite.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 8 Skin prick test results ‐ cat.
Comparison 4 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ allergen sensitisation, Outcome 9 Skin prick test results ‐ any allergen.
Comparison 5 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ parent's reports of allergy (non‐validated questionnaire), Outcome 1 Food allergies: parental reported (non‐validated questionnaires).
Comparison 5 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ parent's reports of allergy (non‐validated questionnaire), Outcome 2 Eczema: parental reported (non‐validated questionnaires).
Comparison 5 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ parent's reports of allergy (non‐validated questionnaire), Outcome 3 Allergic rhinitis/Hay fever: parental reported (non‐validated questionnaires).
Comparison 5 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ parent's reports of allergy (non‐validated questionnaire), Outcome 4 Asthma/Wheeze: parental reported (non‐validated questionnaires).
Comparison 5 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ parent's reports of allergy (non‐validated questionnaire), Outcome 5 Any allergies: parental reported (non‐validated questionnaires).
Comparison 6 Timing of supplementation ‐ prenatal versus postnatal versus pre and postnatal subgroup, Outcome 1 Any allergies: last available time (with sensitisation): medically diagnosed IgE mediated.
Comparison 6 Timing of supplementation ‐ prenatal versus postnatal versus pre and postnatal subgroup, Outcome 2 Any allergies: last available time (+/‐ sensitisation): medically diagnosed/parental reported.
Comparison 7 Allergy risk ‐ high risk versus unselected risk subgroup, Outcome 1 Any allergy: last available time.
Comparison 8 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ sensitivity analysis, Outcome 1 Any allergies (with sensitisation): medically diagnosed IgE mediated.
Comparison 8 n‐3 LCPUFA supplementation versus placebo or no supplementation ‐ sensitivity analysis, Outcome 2 Any allergies (+/‐ sensitisation): medically diagnosed/parental reported.
| Allergy (IgE mediated) | Assessed Age | No of studies | No of participants | n‐3 LCPUFA | Placebo | Effect Estimate RR [95% CI] | ||
| Events | Total | Events | Total | |||||
| Food allergy | < 12 months | 1 | 117 | 1 | 52 | 10 | 65 | 0.13 [0.02 to 0.95] ٭ |
| 12‐36 months | 2 | 825 | 13 | 422 | 20 | 403 | 0.58 [0.18 to 1.88] R | |
| ≥ 36 months | 1 | 706 | 14 | 368 | 9 | 338 | 1.43 [0.63 to 3.26] | |
| Eczema | < 12 months | 1 | 117 | 4 | 52 | 13 | 65 | 0.38 [0.13 to 1.11] |
| 12‐36 months | 2 | 823 | 29 | 422 | 45 | 401 | 0.61 [0.39 to 0.95] ٭ | |
| ≥ 36 months | 1 | 706 | 44 | 368 | 48 | 338 | 0.84 [0.57 to 1.23] | |
| Allergic rhinitis | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 825 | 1 | 422 | 3 | 403 | 0.47 [0.07 to 3.06] | |
| ≥ 36 months | 1 | 706 | 18 | 368 | 20 | 338 | 0.83 [0.44 to 1.54] | |
| Asthma | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 824 | 3 | 422 | 4 | 402 | 0.86 [0.21 to 3.49] | |
| ≥ 36 months | 1 | 706 | 6 | 368 | 5 | 338 | 1.10 [0.34 to 3.58] | |
| Any allergies | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 823 | 36 | 422 | 52 | 401 | 0.66 [0.44 to 0.98] ٭ | |
| ≥ 36 months | 1 | 706 | 55 | 368 | 59 | 338 | 0.86 [0.61 to 1.20] | |
| *significant P < 0.05, ٭٭ significant P < 0.005, NE = Not estimable , R= Random‐effects estimate | ||||||||
| Allergy (IgE mediated or not) | Assessed Age | No of studies | No of participants | n‐3 LCPUFA | Placebo | Effect Estimate RR [95% CI] | ||
| Events | Total | Events | Total | |||||
| Food allergy | < 12 months | 1 | 117 | 1 | 52 | 10 | 65 | 0.13 [0.02, 0.95] ٭ |
| 12‐36 months | 4 | 973 | 19 | 499 | 26 | 474 | 0.72 [0.40 to 1.30] | |
| ≥ 36 months | 1 | 706 | 14 | 368 | 9 | 338 | 1.43 [0.63 to 3.26] | |
| Eczema | < 12 months | 2 | 203 | 16 | 100 | 20 | 103 | 0.76 [0.22 to 2.62]R |
| 12‐36 months | 4 | 973 | 118 | 499 | 122 | 474 | 0.96 [0.69 to 1.33]R | |
| ≥ 36 months | 2 | 1237 | 122 | 628 | 131 | 609 | 0.88 [0.68 to 1.13]R | |
| Allergic rhinitis | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 805 | 10 | 414 | 18 | 391 | 0.53 [0.25 to 1.12] | |
| ≥ 36 months | 2 | 1169 | 114 | 593 | 109 | 576 | 1.03 [0.81 to 1.30] | |
| Asthma | < 12 months | 1 | 83 | 11 | 46 | 7 | 37 | 1.26 [0.54 to 2.94] |
| 12‐36 months | 4 | 955 | 106 | 491 | 105 | 464 | 0.93 [0.73 to 1.18] | |
| ≥ 36 months | 3 | 1697 | 165 | 856 | 171 | 841 | 0.94 [0.78 to 1.13] | |
| Any allergies | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 823 | 109 | 422 | 117 | 401 | 0.89 [0.71 to 1.11] | |
| ≥ 36 months | 3 | 1765 | 270 | 891 | 274 | 874 | 0.96 [0.84 to 1.09] | |
| *significant P < 0.05, ٭٭ significant P < 0.005, NE= Not estimable , R= Random‐effects estimate | ||||||||
| Skin prick results | Assessed Age | No of studies | No of participants | n‐3 LCPUFA | Placebo | Fixed Effect estimate RR [95% CI] | ||
| Events | Total | Events | Total | |||||
| Egg | < 12 months | 2 | 203 | 7 | 100 | 17 | 103 | 0.44 [0.19 to 1.04] |
| 12‐36 months | 3 | 893 | 46 | 455 | 82 | 438 | 0.55 [0.39 to 0.77] ٭٭ | |
| ≥ 36 months | 1 | 706 | 11 | 368 | 16 | 338 | 0.63 [0.30 to 1.34] | |
| Cow’s milk | < 12 months | 2 | 205 | 5 | 102 | 7 | 103 | 0.75 [0.24 to 2.29]R |
| 12‐36 months | 3 | 897 | 9 | 457 | 13 | 440 | 0.68 [0.20 to 2.34]R | |
| ≥ 36 months | 0 | 0 | NE | |||||
| Peanut | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 778 | 18 | 403 | 28 | 375 | 0.61 [0.34 to 1.08] | |
| ≥ 36 months | 1 | 706 | 13 | 368 | 20 | 338 | 0.60 [0.30 to 1.18] | |
| Wheat | < 12 months | 1 | 117 | 1 | 52 | 0 | 65 | 3.74 [0.16 to 89.85] |
| 12‐36 months | 2 | 783 | 3 | 401 | 2 | 382 | 1.40 [0.29 to 6.84] | |
| ≥ 36 months | 1 | 706 | 6 | 368 | 2 | 338 | 2.76 [0.56 to 13.56] | |
| Fish | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 1 | 666 | 3 | 349 | 0 | 317 | 6.36 [0.33 to 122.65] | |
| ≥ 36 months | 1 | 706 | 2 | 368 | 1 | 338 | 1.84 [0.17 to 20.17] | |
| Inhalant allergens (pollens) | < 12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 779 | 2 | 400 | 5 | 379 | 0.44 [0.08 to 2.30] | |
| ≥ 36 months | 1 | 580 | 21 | 303 | 25 | 277 | 0.77 [0.44 to 1.34] | |
| House dust mite | <12 months | 0 | 0 | NE | ||||
| 12‐36 months | 2 | 738 | 3 | 384 | 4 | 354 | 0.76 [0.18 to 3.28] | |
| ≥36 months | 1 | 580 | 22 | 303 | 24 | 277 | 0.84 [0.48 to 1.46] | |
| Cat | < 12 months | 1 | 86 | 1 | 48 | 1 | 38 | 0.79 [0.05 to 12.25] |
| 12‐36 months | 2 | 738 | 8 | 384 | 7 | 354 | 1.07 [0.39 to 2.94] | |
| ≥ 36 months | 1 | 706 | 25 | 368 | 12 | 338 | 1.91 [0.98 to 3.75] | |
| Any allergen (one or more allergen) | < 12 months | 2 | 201 | 14 | 100 | 25 | 101 | 0.59 [0.32 to 1.09] |
| 12‐36 months | 3 | 892 | 68 | 455 | 93 | 437 | 0.70 [0.53 to 0.94] ٭ | |
| ≥ 36 months | 1 | 706 | 91 | 368 | 88 | 338 | 0.95 [0.74 to 1.22] | |
| *significant P < 0.05, ٭٭ significant P < 0.005, NE = Not estimable | ||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Any allergies (with sensitisation): medically diagnosed IgE mediated Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 1.2 12 to 36 months | 2 | 823 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.44, 0.98] |
| 1.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.61, 1.20] |
| 2 Any allergies (+/‐ sensitisation): medically diagnosed/parental reported Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2.2 12 to 36 months | 2 | 823 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.71, 1.11] |
| 2.3 Beyond 36 months | 3 | 1765 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.84, 1.09] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Food allergies (with sensitisation): medically diagnosed IgE mediated Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Up to 12 months | 1 | 117 | Risk Ratio (M‐H, Random, 95% CI) | 0.13 [0.02, 0.95] |
| 1.2 12 to 36 months | 2 | 825 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.18, 1.88] |
| 1.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Random, 95% CI) | 1.43 [0.63, 3.26] |
| 2 Food allergies (+/‐ sensitisation): medically diagnosed/parental reported Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Up to 12 months | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.13 [0.02, 0.95] |
| 2.2 12 to 36 months | 4 | 973 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.72 [0.40, 1.30] |
| 2.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.63, 3.26] |
| 3 Atopic dermatitis/Eczema (with sensitisation): medically diagnosed IgE mediated Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Up to 12 months | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.38 [0.13, 1.11] |
| 3.2 12 to 36 months | 2 | 823 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.39, 0.95] |
| 3.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.57, 1.23] |
| 4 Atopic dermatitis/Eczema (+/‐ sensitisation): medically diagnosed/parental reported Show forest plot | 6 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.1 Up to 12 months | 2 | 203 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.22, 2.62] |
| 4.2 12 to 36 months | 4 | 973 | Risk Ratio (M‐H, Random, 95% CI) | 0.96 [0.69, 1.33] |
| 4.3 Beyond 36 months | 2 | 1237 | Risk Ratio (M‐H, Random, 95% CI) | 0.88 [0.68, 1.13] |
| 5 Allergic rhinitis/Hay fever (with sensitisation): medically diagnosed IgE mediated Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 12 to 36 months | 2 | 825 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.07, 3.06] |
| 5.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.44, 1.54] |
| 6 Allergic rhinitis/Hay fever (+/‐ sensitisation): medically diagnosed/parental reported Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6.2 12 to 36 months | 2 | 805 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.53 [0.25, 1.12] |
| 6.3 Beyond 36 months | 2 | 1169 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.81, 1.30] |
| 7 Asthma/Wheeze (with sensitisation): medically diagnosed IgE mediated Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 7.2 12 to 36 months | 2 | 824 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.21, 3.49] |
| 7.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.34, 3.58] |
| 8 Asthma/Wheeze (+/‐ sensitisation): medically diagnosed/parental reported Show forest plot | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 Up to 12 months | 1 | 83 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.54, 2.94] |
| 8.2 12 to 36 months | 4 | 955 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.73, 1.18] |
| 8.3 Beyond 36 months | 3 | 1697 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.78, 1.13] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Maternal safety Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 Postpartum bleeding | 2 | 2932 | Risk Ratio (M‐H, Random, 95% CI) | 0.73 [0.49, 1.10] |
| 2 Infants safety Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Early childhood infections | 4 | 2280 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.87, 1.12] |
| 2.2 Fever | 1 | 834 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.99 [0.74, 1.31] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Skin prick test results ‐ egg Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Up to 12 months | 2 | 203 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.19, 1.04] |
| 1.2 12 to 36 months | 3 | 893 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.55 [0.39, 0.77] |
| 1.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.63 [0.30, 1.34] |
| 2 Skin prick test results ‐ cows' milk Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 Up to 12 months | 2 | 205 | Risk Ratio (M‐H, Random, 95% CI) | 0.75 [0.24, 2.29] |
| 2.2 12 to 36 months | 3 | 897 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.20, 2.34] |
| 2.3 Beyond 36 months | 0 | 0 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Skin Prick Test results ‐ peanut Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 12 to 36 months | 2 | 778 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.34, 1.08] |
| 3.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.30, 1.18] |
| 4 Skin prick test results ‐ wheat Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Up to 12 months | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.74 [0.16, 89.85] |
| 4.2 12 to 36 months | 2 | 783 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [0.29, 6.84] |
| 4.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.76 [0.56, 13.56] |
| 5 Skin prick test results ‐ fish Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 12 to 36 months | 1 | 666 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.36 [0.33, 122.65] |
| 5.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.84 [0.17, 20.17] |
| 6 Skin prick test results ‐ inhalant allergen (pollens) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6.2 12 to 36 months | 2 | 779 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.44 [0.08, 2.30] |
| 6.3 Beyond 36 months | 1 | 580 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.44, 1.34] |
| 7 Skin prick test results ‐ house dust mite Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 7.1 Up to 12 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 7.2 12 to 36 months | 2 | 738 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.18, 3.28] |
| 7.3 Beyond 36 months | 1 | 580 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.48, 1.46] |
| 8 Skin prick test results ‐ cat Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 8.1 Up to 12 months | 1 | 86 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.05, 12.25] |
| 8.2 12 to 36 months | 2 | 738 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.39, 2.94] |
| 8.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.91 [0.98, 3.75] |
| 9 Skin prick test results ‐ any allergen Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 9.1 Up to 12 months | 2 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.32, 1.09] |
| 9.2 12 to 36 months | 3 | 892 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.53, 0.94] |
| 9.3 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.74, 1.22] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Food allergies: parental reported (non‐validated questionnaires) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Up to 12 months | 1 | 695 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.44 [0.33, 124.23] |
| 1.2 12 to 36 months | 1 | 565 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.36, 1.83] |
| 1.3 Beyond 36 months | 0 | 0 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Eczema: parental reported (non‐validated questionnaires) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Up to 12 months | 1 | 695 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.65, 1.26] |
| 2.2 12 to 36 months | 2 | 1263 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.74, 1.13] |
| 2.3 Beyond 36 months | 2 | 746 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.77, 1.18] |
| 3 Allergic rhinitis/Hay fever: parental reported (non‐validated questionnaires) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.1 Up to 12 months | 1 | 695 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.60 [0.22, 95.48] |
| 3.2 12 to 36 months | 1 | 565 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.26, 1.96] |
| 3.3 Beyond 36 months | 1 | 109 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [0.78, 3.12] |
| 4 Asthma/Wheeze: parental reported (non‐validated questionnaires) Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Up to 12 months | 2 | 1529 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.73, 1.56] |
| 4.2 12 to 36 months | 3 | 2134 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.79, 1.11] |
| 4.3 Beyond 36 months | 2 | 745 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.72, 1.45] |
| 5 Any allergies: parental reported (non‐validated questionnaires) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 Up to 12 months | 1 | 695 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.65, 1.26] |
| 5.2 12 to 36 months | 1 | 565 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.74, 1.21] |
| 5.3 Beyond 36 months | 1 | 110 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.64, 1.30] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Any allergies: last available time (with sensitisation): medically diagnosed IgE mediated Show forest plot | 2 | 823 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.59, 1.13] |
| 1.1 Prenatal | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.61, 1.20] |
| 1.2 Prenatal and postnatal | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.52 [0.17, 1.59] |
| 2 Any allergies: last available time (+/‐ sensitisation): medically diagnosed/parental reported Show forest plot | 4 | 1882 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.83, 1.07] |
| 2.1 Prenatal | 2 | 1234 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.75, 1.07] |
| 2.2 Postnatal | 1 | 531 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.86, 1.28] |
| 2.3 Prenatal and postnatal | 1 | 117 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.44, 1.38] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Any allergy: last available time Show forest plot | 4 | 1882 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.83, 1.07] |
| 1.1 High risk | 2 | 823 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.77, 1.07] |
| 1.2 Unselected risk | 2 | 1059 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.82, 1.21] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Any allergies (with sensitisation): medically diagnosed IgE mediated Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 12 to 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.44, 1.05] |
| 1.2 Beyond 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.61, 1.20] |
| 2 Any allergies (+/‐ sensitisation): medically diagnosed/parental reported Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 12 to 36 months | 1 | 706 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.71, 1.16] |
| 2.2 Beyond 36 months | 2 | 1237 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.86, 1.12] |
