text:
Amazon.com Review
Amy MacDonald's clever rhymes are nicely complemented by Giselle Potter's unusual, naïve-style illustrations (seen also in Kate and the Beanstalk and The Honest-to-Goodness Truth). Quentin Third, with his lacquered hair, pristine white shirt, and prissy face, is the perfect foil to shadowy Quentin Three's sloppy looks and insolent expression. Good kids and bad kids alike will cheer at the happily balanced resolution. (Ages 5 to 8) --Emilie Coulter
From Publishers Weekly
Copyright 2002 Cahners Business Information, Inc.


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I am trying to implement this example here: Reading from and Writing to a Socket
I copied and pasted the code into NetBeans. I changed the port name "taranis" to "localhost" and tried to run the example, but I got the error:
run: Couldn't get I/O for the connection to: localhost. Java Result: 1 BUILD SUCCESSFUL (total time: 1 second)
I also tried to substitute localhost for my actual hostname of my laptop, but it gives the similar error. Can you help pinpoint what I am doing wrong?
Edit: In regards to Mark's recommendation, when I substitute
System.err.println("Couldn't get I/O for " + "the connection to: localhost.");
I get:
java.net.ConnectException: Connection refused: connect
at java.net.PlainSocketImpl.socketConnect(Native Method)
at java.net.PlainSocketImpl.doConnect(PlainSocketImpl.java:351)
at java.net.PlainSocketImpl.connectToAddress(PlainSocketImpl.java:213)
at java.net.PlainSocketImpl.connect(PlainSocketImpl.java:200)
at java.net.SocksSocketImpl.connect(SocksSocketImpl.java:366)
at java.net.Socket.connect(Socket.java:529)
at java.net.Socket.connect(Socket.java:478)
at java.net.Socket.<init>(Socket.java:375)
at java.net.Socket.<init>(Socket.java:189)
at EchoClient.main(EchoClient.java:12)
Java Result: 1
BUILD SUCCESSFUL (total time: 3 seconds)

subset: commoncrawl


text:
Specifications subject to change without notice. Due to differences in screen resolutions, the fabrics and finishes displayed may vary from the actual fabric and finish colors.
Frequently Asked Questions
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Care & Cleaning
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Our History
Social Responsibility
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Contact Us
Join Our Email List
Copyright © 2016. v5.0 Bernhardt Furniture Company. All Rights Reserved.


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:FF: Eyes On Me by AlouetteCosplayWatch
©2012-2016 AlouetteCosplay
such a beautiful photo
looks good
Waaaah! Beautifull photo!!! *o*
This is beautifully done!
When does Rinoa ever wear this?
Well, it is never worn in game. This design comes from 2004-2005 when Square held a contest where the winning "re-design" would be turned into a pixel rendition, and this was the winning design.
WOW. I love this!!
Also, the flour petals and feathers add a nice touch, since they're all over FF VIII's cut scenes X3 Especially the feathers :3
Never play FF VIII, but this looked like a CG screencap and you make an amazing Rinoa!
Oh VIII is my favorite FF! You look wonderful!
if this is final fantasy, it looks kinda like yuffie


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Liege Airport: tailored service in a perfect location Situated in Belgium, at the heart of Western Europe, and located at the crossroad of Belgian's two main uncongested highways, Liege Airport is the biggest cargo airport in Belgium (8th in Europe) and one of the fastest growing in the world. Its succes in cargo relies on the Flexport® concept: tailored services and a true alternative to inefficient "mainports". Liege being the biggest city from the walloon region, the airport also...
Breaking News
VLM Gradually Ends Liege Operation from June 2015
Update at 0600GMT 03JUN15 VLM from June 2015 is gradually ending operations at Liege , as it'll discontinue service to Avignon, Bologna, Nice and Venice. The airline launched these service on...
Breaking News
VLM Begins New Routes from Liege form May 2015
Update at 0440GMT 03MAR15 VLM starting 01MAY15 is expanding operations, with the launch of 4 new routes from Liege , with flights to Avignon, Bologna, Nice and Venice. Avignon and Bologna is...


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Showing 1-1 of 1 Fishing Resorts
Red Pine Wilderness Lodge
Haileybury, Ontario, Canada
Offering 22,000 acres of fishing fun, Lady Evelyn Lake is an angler's paradise, offering a secluded getaway filled with muskie, northern pike, walleye, and bass battles. ... more
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Shares of Columbia Banking System (COLB - Get Report) of Tacoma, Wash., closed at $18.76 Friday, returning 2% year-to-date, following a 7% decline during 2011. Based on a regular quarterly payout of nine cents, the shares have a dividend yield of 1.92%. The shares trade for 1.2 times tangible book value, and for 13 times the consensus 2013 EPS estimate of $1.45. The consensus 2012 EPS estimate is $1.12.
Interested in more on Columbia Banking System? See TheStreet Ratings' report card for this stock.


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$30B ITSSS contract is largest in bureau's history
The FBI has released the names of the 46 vendors that recently qualified to compete for task orders over the next year under the $30 billion Information Technology Supplies and Support Services contract, which also includes seven additional one-year option periods.
The indefinite-delivery, indefinite-quantity ITSSS contract, the largest in the bureau's history, is available for use throughout the Justice Department, the FBI announcement said.
"Per the Federal Acquisition Regulation (FAR), the required guaranteed minimum is $250.00 per vendor over the life of the contract," the announcement states. "The FAR required ceiling amount on the contract is an estimated $30 billion dollars."
The 46 vendors named by the FBI are:
About the Author
David Hubler is the former print managing editor for GCN and senior editor for Washington Technology. He is freelance writer living in Annandale, Va.
If a minority company bid on this it would have had the chance to win like all the other 46 companies (52% SB). Same opprtunity as a WOSB or a VOSB etc (do you care about them?). You only get a chance in govt contracting if you try.
Are any of the companies minorities (real-not fake)?
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In an exclusive for WT Insider members, we are collecting all of the contract awards we cover into a database that you can sort by contractor, agency, value and other parameters. You can also download it into a spreadsheet.
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Editor Nick Wakeman explores the puzzle of why SBA has been so silent on the latest contractor fraud scandal when it has been so quick to act in other cases.
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Summary of findings [Explanations]
Summary of findings 2 Intermittent versus daily use of iron supplements in menstruating women
Description of the condition
Anaemia is a condition in which the oxygen-carrying capacity of the blood is insufficient to meet the physiologic needs of body tissues. It is estimated that the global prevalence of this condition in non-pregnant women of reproductive age is 30.2% (WHO/CDC 2008) and it is more frequent in low income countries or among women who belong to a low socioeconomic strata (Soekarjo 2001; Bodnar 2002; Bentley 2003). Anaemia has multiple causes that very often coexist: it can result from parasitic infections (Kumar 2007; Anah 2008); inflammatory disorders (Yip 1988); inherited disorders of haemoglobin structure, and vitamin and mineral deficiencies, such as that of vitamins A and B12, folate (Herbert 1987; Hercberg 1992; Jimenez 2010), and especially iron, which is responsible for at least half of the cases of anaemia (WHO 2001).
Iron deficiency results from long-term imbalance caused by inadequate dietary iron intake, poor iron absorption or utilisation, increased iron requirements or chronic blood loss (Alleyne 2008). Individual iron requirements vary considerably throughout the human life cycle (Lynch 2007) and both physiological (for example, pregnancy or early postpartum) or pathological (for example, HIV infection) conditions affect iron requirements (WHO 2001). Postmenarchal women are at higher risk of developing iron deficiency because of menstrual losses, and if they do not have an adequate iron intake, this condition can progress to anaemia (known as iron deficiency anaemia or IDA).
There are no official global estimates of iron deficiency, but its prevalence may double that of anaemia, which means that it is the nutritional deficiency that affects most individuals worldwide (WHO 2001). Iron deficiency, even in the absence of anaemia, has significant negative health consequences, including impaired resistance to infections in all age groups (Beard 2005) and reduced physical capacity and work performance of adolescents and adults (WHO 2001; Beard 2001; Clark 2008). Most women throughout the world enter pregnancy with less than desirable iron reserves, which reduces their reproductive performance (Viteri 2005). In addition to iron deficiency, women are frequently deficient in other vitamins and minerals that play important roles in the body (Ramakrishnan 2002; Kontic-Vucinic 2006; Ahmed 2008). An adequate folate intake during the periconceptional period, for example, is crucial to reducing the risk of having a baby with neural tube defects (NTDs) (De-Regil 2010); while vitamin A regulates many critical functions, including vision, epithelial tissue integrity, the expression of several hundred genes, and its deficiency also contributes to nutritional anaemia (WHO 2011). Although these deficiencies may not translate into a comparable prevalence of anaemia, supplementation of these nutrients in women may improve their health throughout life as there is some indication that these deficiencies are of public health concern in certain countries (McLean 2008).
Anaemia in women of reproductive age is diagnosed when the haemoglobin (Hb) concentration in the blood is below 120 g/L, a cut-off that varies with the residential elevation and smoking (WHO 2011a). Iron deficiency anaemia is diagnosed by the combined presence of anaemia and iron deficiency, measured by ferritin (<15 μg/L) or any other indicator of iron status, such as serum transferrin receptors or zinc protoporphyrin (WHO 2011b).
Description of the intervention
Daily iron plus folic acid supplementation remains the standard approach for the prevention and treatment of anaemia among menstruating women because dietary changes alone usually cannot correct this condition as the iron content in diet is relatively constant and difficult to increase (DeMaeyer 1989). The recommended daily supplemental dosage for non-pregnant women of reproductive age living in countries where anaemia is highly prevalent (i.e., above 40%) is 60 mg of elemental iron and 400 µg of folic acid for three months (WHO 2001). The use of folic acid prior to pregnancy aims to improve folate status and this dose has shown to be effective for preventing neural tube defects (NTDs) in women who become pregnant (WHO 2001). Despite its proven efficacy, the main problem of the daily regimen is the lack of compliance due to side effects (for example, diarrhoea, constipation, dark stools, metallic taste, teeth staining or nausea) (Yip 1994).
Intermittent oral iron supplementation (that is one, two or three times a week on non-consecutive days) has been suggested as an effective alternative to daily iron supplementation to prevent anaemia at population level. The efficacy of intermittent iron supplementation for the prevention of iron deficiency and anaemia has been studied over the last 15 years in children, adolescents and pregnant and non-pregnant women of reproductive age. A review of 22 trials performed in all these groups concluded that both daily and once weekly iron supplementation were efficacious under favourable conditions to reduce anaemia (Beaton 1999). Subsequent trials in menstruating women have confirmed these findings (Crape 2005; Khan 2005; Paulino 2005), although some authors have suggested that the weekly intake of supplemental iron may be insufficient to meet women's needs and have proposed the use of iron supplements twice a week (Kianfar 2000; Olsen 2000).
The international recommendation for weekly supplementation for non-pregnant women of reproductive age is that supplements should contain 60 mg of elemental iron in the form of ferrous sulphate and 2800 µg (2.8 mg) of folic acid (WHO 2009). Although evidence for the effective dose of folic acid for intermittent supplementation is very limited, the current recommendation is based on the rationale of providing seven times the recommended daily dose to prevent NTDs and the experimental evidence that high weekly doses can improve red blood cell folate concentrations to levels that have been associated with a reduced risk of NTDs (Martinez-de Villareal 2001; Martinez-de Villareal 2002; Norsworthy 2004; Nguyen 2008). The provision of vitamins and minerals other than iron and folic acid on an intermittent basis may also help to supplement women's diets and therefore improve health and development throughout the life cycle (Allen 2009; Allen 2009a; Dalmiya 2009).
How the intervention might work
Intestinal cells turn over every five to six days in humans. Providing iron on an intermittent basis would hence expose this nutrient only to new mucosal cells, improving the absorption efficiency (Viteri 1995) and reducing the oxidative stress and side effects (Viteri 2005). It may also reduce absorption blockage due to high iron levels in the gut lumen and in the enterocyte (Anderson 2005; Oates 2007). Intermittent regimens may be perceived as more tolerable, increasing adherence to supplementation (Casanueva 2006). In order to improve the success of this intervention, the World Health Organization (WHO) encourages the integration of intermittent iron supplementation programmes with other public health measures, including deworming to prevent hookworm infections, improved bioavailable dietary iron intake and interventions to control other prevalent causes of anaemia, particularly malaria and other infections and vitamin A deficiency (WHO 2009).
The endemicity of malaria in a given region is an important consideration when providing iron supplements at population level. Malaria, which is responsible for more than a million deaths per year (Gajida 2010), causes anaemia through several mechanisms. Provision of iron in malaria-endemic areas, particularly to children, has been a longstanding controversy due to concerns that iron therapy may exacerbate infections, in particular malaria (Oppenheimer 2001; Okabe 2011). Although the mechanisms by which additional iron can benefit the parasite are far from clear (Prentice 2007), intermittent supplementation might be an effective option to prevent anaemia and improve malaria treatment in malaria-endemic areas since less iron is available for the parasite.
Why it is important to do this review
Improving iron and folate nutrition of menstruating women may contribute to adequate mental and physical performance and reproductive health, which may, in turn, enhance maternal and infant health outcomes. Intermittent supplementation is proposed as a viable approach for improving iron and folate status in populations, especially in areas where anaemia is highly prevalent and where mass fortification of staple foods with iron and folic acid is not available and not likely to be available in the near future. Weekly iron supplementation has been implemented in many countries, but there is still a need for the literature to be systematically reviewed so there is updated evidence on the efficacy, effectiveness and safety of this intervention to inform a possible scale up as part of public health programmes.
This systematic review will complement the findings of one ongoing Cochrane systematic review exploring the effects of intermittent regimens among pregnant women (Peña-Rosas 2009), one recently published review of the effects of intermittent iron supplementation in children under 12 years of age (De-Regil 2011) and one review focusing specifically on the effect of oral iron supplementation on preventing and treating anaemia among children in malaria-endemic areas (Okabe 2011).
To assess the effects of intermittent oral iron supplementation, alone or in combination with other nutrients, on anaemia and its associated impairments among menstruating women, compared with no intervention, a placebo or daily supplementation.
Criteria for considering studies for this review
Types of studies
We included randomised and quasi-randomised controlled trials with randomisation at either individual or cluster level. Quasi-randomised trials are trials that use systematic methods to allocate participants to treatment groups such as alternation or assignment based on date of birth or case record number (Higgins 2011). We did not include other study designs (for example, cohort or case-control studies) in this meta-analysis nor they contributed to the results or conclusions, although we considered such evidence in the discussion where relevant.
Types of participants
Menstruating women, that is women beyond menarche and prior to menopause who are not pregnant or lactating or have any condition that impedes the presence of menstrual periods, regardless of their baseline iron status/anaemia status, ethnicity, country of residence or level of endurance.
We did not include studies targeting women with conditions affecting iron metabolism such as intestinal malabsorption conditions, ongoing excessive blood loss (including ongoing blood donations), inflammatory bowel disease, cancer, chronic congestive cardiac failure, chronic renal failure, chronic liver failure, or chronic infectious disease.
Types of interventions
Interventions involving intermittent dosage of iron alone or with other vitamins and minerals versus placebo or no intervention or the same supplements provided on a daily basis.
Oral iron supplementation refers to the delivery of iron compounds directly to the oral cavity, either as a tablet, capsule, dispersible tablet or liquid. For the purpose of this review, intermittent supplementation is defined as the provision of iron supplements one, two or three times a week on non-consecutive days.
We performed the following comparisons:
- intermittent iron supplementation versus no supplementation or placebo;
- intermittent iron supplementation versus daily iron supplementation.
We included studies that combined iron supplementation with other co-interventions, such as education or deworming, only if the other co-interventions were the same in both the intervention and comparison groups.
Studies examining tube feeding, parenteral nutrition or supplementary food-based interventions such as mass fortification of staple or complementary foods, home fortification with micronutrient powders, lipid-based supplements or Foodlets tablets, or biofortification, were excluded.
Types of outcome measures
Primary outcomes
- Anaemia (haemoglobin concentration below a cut-off defined by trialists, adjusted by altitude and smoking as appropriate)*
- Haemoglobin (g/L)*
- Iron deficiency (as defined by trialists by using indicators of iron status such as ferritin or transferrin).
- Ferritin (µg/L)*
- Iron deficiency anaemia (defined by the presence of anaemia plus iron deficiency diagnosed with an indicator of iron status selected by trialists)*
- All-cause morbidity (the most frequent event associated with the intervention independently of the cause, as defined by the trialists)*
* Outcomes included in the 'Summary of Findings' tables.
Secondary outcomes
- Diarrhoea (number of women with at least three liquid stools in one day)
- Respiratory infections (as defined by trialists)
- Any adverse side effects (i.e., nausea, vomit, constipation, gastrointestinal discomfort or others as defined by trialists)
- Work performance and economic productivity (as defined by trialists)
- School performance and cognitive function (for adolescents, as defined by trialists)
- Depression (as defined by trialists)
- Adherence (percentage of participants that consumed 70% or more of the prescribed dose throughout the trial)
We will consider the following outcomes in malaria settings only:
- Malaria incidence (as defined by trialists)
- Malaria severity (as defined by trialists)
All the outcomes were evaluated at the end of the intervention or at the time point closest to the end.
Search methods for identification of studies
Electronic searches
We searched the following electronic databases.
Cochrane Central Register of Controlled Trials 2011 (2), part of the Cochrane Library. Searched 27 May 2011
MEDLINE, 1948 to May Week 2, 2011. Searched 25 May 2011.
EMBASE, 1980 to 2011 Week 20. Searched 25 May 2011.
CINAHL, 1937 to current. Searched 26 May 2011.
ISI SCI, 1970 to 27 May 2011. Searched 27 May 2011.
Conference Proceedings Citation Index - Science, 1990 to 27 May 2011. Searched 27 May 2011.
BIOSIS Previews, 1969 to current. Searched 27 May 2011.
POPLINE. Searched 24 May 2011
SCIELO. Searched 7 July 2011
LILACS. Searched 7 July 2011
IBECS. Searched 7 July 2011
IMBIOMED. Searched 7 July 2011
Networked Digital Library of Theses and Dissertations (http://www.ndltd.org). Searched 7 July 2011
WHO International Clinical Trials Registry Platform (ICTRP). Searched 7 July 2011
metaRegister. Searched 7 July 2011
The search strategies are in Appendix 1
Searches were limited to studies published from 1980 onwards as the first trials on this intervention were published after this year. We did not apply any language restrictions. For those articles written in a language other than English, we commissioned their translation into English to assess them for eligibility according to the prespecified selection criteria.
Searching other resources
On 11 October 2011, for assistance in identifying ongoing or unpublished studies, we contacted authors and known experts to identify any additional or unpublished data. We also contacted, the Departments of Nutrition for Health and Development and regional offices from the World Health Organization (WHO) and the nutrition section of the US Centers for Disease Control and Prevention (CDC), United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the Micronutrient Initiative (MI), Helen Keller International (HKI) and Sight and Life Foundation.
We did not handsearch printed journals but screened previously published reviews in order to identify other possible studies.
Data collection and analysis
Selection of studies
The two review authors independently screened the titles and abstracts resulting from the search strategy and assessed their eligibility against the inclusion criteria. One review author (LMD) searched additional sources.
We obtained the full text of all relevant or potentially relevant studies that seemed to meet the inclusion criteria. Both review authors assessed all full-text papers for inclusion. There were few disagreements due to oversights of either of the review authors but we resolved them through discussion.
Data extraction and management
Both review authors independently extracted the data from eligible studies using a form designed for this review. ACF entered data into Review Manager 5.1 software (RevMan 2011) and LMD carried out checks for accuracy. We resolved any discrepancies through discussion. If the information regarding any of the studies was unclear, we attempted to contact authors of the original reports to provide further details.
We completed the data collection form electronically and recorded information on the study setting and participants (inclusion and exclusion criteria); details of study methods and assessment of risk of bias (see below); a full description of intervention (for example compound, dose, regimen, duration of intervention); outcomes (with details of how and when measured), and results as follows.
(1) Trial methods:
(a) method of allocation and unit of randomisation;
(b) masking of participants and outcomes;
(c) exclusion of participants after randomisation and proportion of losses at follow up.
(2) Participants:
(a) country of origin;
(b) sample size;
(c) age;
(d) sex;
(e) socioeconomic status;
(f) inclusion and exclusion criteria as described in the Criteria for considering studies for this review.
(3) Intervention:
(a) type;
(b) dose;
(c) frequency;
(d) duration and length of time in follow-up;
(e) co-intervention.
(4) Control:
(a) control, placebo or daily supplementation.
(5) Outcomes:
(a) primary and secondary outcomes outlined in the outcome measures section.
Assessment of risk of bias in included studies
Each review author assessed the risk of bias of the included trials using a simple contingency form following the domain-based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion. If there were insufficient information for us to be able to assess the risk of bias, studies were put awaiting assessment until further information is published or made available to us.
We reported this assessment in the 'Description of studies' and risk of bias tables. We explicitly mention when authors provided input on their trials.
(1) Sequence generation (checking for possible selection bias)
We described for each included study the method used to generate the allocation sequence.
We assessed the method as:
- low risk of bias (any truly random process, for example random number table; computer random number generator);
- high risk of bias (any non-random process, for example odd or even date of birth; hospital or clinic record number);
- unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We described for each included study the method used to conceal the allocation sequence (when applicable) and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the method as:
- low risk of bias (for example telephone or central randomisation; consecutively numbered sealed opaque envelopes);
- high risk of bias (open random allocation; unsealed or non-opaque envelopes);
- unclear risk of bias.
(3) Blinding (checking for possible performance and detection bias)
We described for each included study the methods used, if any, to blind: i) study participants, ii) personnel and iii) outcome assessors, from knowledge of which intervention a participant reviewed. Whilst we reported these judgements separately, we combined the results into one judgement of overall risk of bias associated with blinding (low, high or unclear risk of bias) (Higgins 2011).
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We described for each included study the completeness of data including attrition and exclusions from the analysis and noted if for one prespecified outcome or group of outcomes the levels of attrition were higher. We also noted whether missing data were imbalanced across groups, the reasons for attrition or exclusions where reported, or whether data was imputed (and methods used).
We assessed methods as:
- low risk of bias (less than 20% of cases lost to follow up and balanced in numbers across intervention groups);
- high risk of bias (20% or cases lost to follow up or outcome data imbalanced in numbers across intervention groups);
- unclear risk of bias.
(5) Selective reporting bias
We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
- low risk of bias (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);
- high risk of bias (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);
- unclear risk of bias.
(6) Other sources of bias
We described for each included study any important concerns we have about other possible sources of bias and assessed them as:
- low risk of bias;
- high risk of bias;
- unclear risk of bias.
(7) Overall risk of bias
We summarised the risk of bias at two levels: within studies (across domains) and across studies.
For the first, we made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we consider it was likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses - see section on Sensitivity analysis.
For the assessment across studies, the main findings of the review were set out in 'Summary of findings' (SoF) tables prepared using GRADE profiler software (GRADEpro 2008). The primary outcomes for each comparison were listed with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. For each individual outcome, the quality of the evidence was assessed using the GRADE approach (Balshem 2010; Higgins 2011), which involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. The results are expressed as one of four levels of quality (high, moderate, low or very low). This assessment was restricted to the randomised clinical trials included in this review.
Measures of treatment effect
Dichotomous data
For dichotomous data, we present results as average risk ratio with 95% confidence intervals.
Continuous data
We present the results as mean difference (MD) with 95% confidence intervals at the end of the intervention. If trials did not provide this information but reported the mean change, we included these data as suggested by Higgins 2011. There was no need to use the standardised mean difference to combine trials as these outcomes were measured with the same methods.
Unit of analysis issues
Cluster-randomised trials
We included cluster-randomised trials in the analyses along with individually-randomised trials. Cluster-randomised trials are labelled with a (C). We obtained the intra-cluster correlation coefficients from Roschnik 2003 (C) (ICC 0.1123; average cluster size (ACS) 29.0, design effect (DE) 4.35) and Hall 2002 (C) (ICC 0.0698; ACS 18.55; DE 2.22), which was imputed to all cluster trials but Roschnik 2003 (C). We then calculated the ACS from the reports and estimated each trial's effective sample size. Based on other reports (Okabe 2011), we assumed an average cluster size of 32 for classes, when the average cluster size or number of clusters and individuals were not clear (Agarwal 2003 (C); Soekarjo 2004 (C)). In summary, we used the following information to account for the effect clustering in data: Muro 1999 (C) (ACS 43.1; DE 3.94); Jayatissa 1999 (C) (ACS 25.6; DE 2.71); Agarwal 2003 (C) (ACS 32; DE 3.16); Soekarjo 2004 (C) (ACS 32; DE 3.16); Mozaffari 2010 (C) (ACS 25; DE 2.68) .
Additionaly, we conducted a sensitivity analysis taking into a account a design effect of 2 to examine the potential effect of clustering on the confidence intervals of the summary estimates. As the confidence intervals did not change significantly we do not report the results of such analysis.
Studies with more than two treatment groups
For studies with more than two intervention groups (multi-arm studies), we included the directly relevant arms only. When we identified studies with various relevant arms, we combined the groups into a single pair-wise comparison (Higgins 2011) and included the disaggregated data in the corresponding subgroup category. When the control group was shared by two or more study arms, we divided the control group (events and total population) over the number of relevant subgroup categories to avoid double counting the participants. The details are described in the Characteristics of included studies tables.
Cross-over trials
We did not include cross-over trials.
Dealing with missing data
For included studies, we noted the levels of attrition. We did not particularly explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect as the trials with high attrition were in general at high risk of bias and excluded in the sensitivity analysis in which we retained only trials judged at low risk of bias.
We carried out analyses, as far as possible, on an intention-to-treat (ITT) basis, i.e. by attempting to include all participants randomised to each group in the analyses. If it was not possible, we performed an available case analysis in which data are analysed for every participant for whom the outcome was obtained.
Assessment of heterogeneity
We assessed the methodological heterogeneity by examining the methodological characteristics and risk of bias of the studies, and clinical heterogeneity by examining the similarity between the types of participants, the interventions and the outcomes.
For statistical heterogeneity, we examined the forest plots from meta-analyses to look for heterogeneity among studies, and used the I
Assessment of reporting biases
Where we suspected reporting bias (see 'Selective reporting bias' above), we attempted to contact study authors asking them to provide missing outcome data. Where this was not possible, and the missing data was thought to introduce serious bias, we explored the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Very few outcomes had 10 or more studies contributing to the meta-analysis, we investigated reporting biases (such as possible publication bias) using funnel plots. We assessed funnel plot asymmetry visually and it did not find a clear indication of reporting or publication bias.
Data synthesis
We carried out statistical analysis using Review Manager 5.1 software (RevMan 2011). We used random-effects meta-analyses due to possible heterogeneity in the interventions, populations and methods used in different trials.
Subgroup analysis and investigation of heterogeneity
When data were available or appropriate, we carried out the following subgroup analyses on primary outcomes:
- by composition: iron alone, iron + folic acid, iron + multiple micronutrients;
- by anaemia status at baseline (Hb <120 g/L, adjusted by altitude and smoking as appropriate): anaemic, non-anaemic, mixed/unknown ;
- by iron status at baseline (as defined by trialists): iron deficient, not iron deficient, mixed/unknown;
- by dose of elemental iron per week in the intermittent group: 60 mg of iron or less; more than 60 mg of iron;
- by duration of the supplementation: three months or less; more than three months;
- by malaria status of the area at the time of the trial (as reported by authors): yes; no/unknown.
We, pragmatically, decided not to conduct a subgroup analyses in those outcomes with three or less trials. We examined differences between subgroups by visual inspection of the subgroups' confidence intervals; non-overlapping confidence intervals suggesting a statistically significant difference in treatment effect between the subgroups. We also used the Borenstein 2008 approach to formally investigate differences between two or more subgroup categories.
Sensitivity analysis
We carried out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor or unclear sequence generation and allocation concealment and either high levels of attrition or poor blinding) from the analyses.
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Studies awaiting classification.
Results of the search
The search strategy identified 9484 references for possible inclusion, 2706 of which were duplicated references. We assessed 52 articles in full text, two of them were published in languages other than English: Portuguese (Dos Santos 1999) and Spanish (Gonzalez-Rosendo 2002). Figure 1 depicts the process for assessing and selecting the studies. We included 21 trials (26 references), excluded 20 (24 references) and two trials are awaiting classification until we receive additional information from the authors (see Characteristics of studies awaiting classification). We identified two ongoing studies.
|Figure 1. Study flow diagram.
Included studies
We included 21 trials involving 10,258 participants. All the studies were published between 1997 and 2010. Most trials focused on the prevention of anaemia and iron deficiency by improving iron status indicators, and few of the trials reported data on the other pre-specified secondary outcomes.
Trials were conducted in 15 different countries: Bangladesh, Brazil, Guatemala, France, Kenya, India, Iran, Indonesia, Mali, Malawi, Mexico, Nepal, Sri Lanka,Tanzania, and Peru. Four trials were conducted in Latin America (Dos Santos 1999; Zavaleta 2000; Gonzalez-Rosendo 2002; Nguyen 2008); five in Africa (Muro 1999 (C); Beasley 2000; Hall 2002 (C); Roschnik 2003 (C); Leenstra 2009); eleven in Asia (Angeles-Agdeppa 1997; Jayatissa 1999 (C); Kianfar 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Shah 2002; Agarwal 2003 (C); Shobha 2003; Soekarjo 2004 (C); Mozaffari 2010 (C)) and one in Europe (Riuvard 2006).
Most trials were conducted in school settings; however, four studies (Dos Santos 1999; Beasley 2000; Gilgen 2001; Nguyen 2008) implemented the intervention in rural and urban communities and villages, and one trial (Ahmed 2001) was conducted among garment factory workers. Five trials explicitly mentioned that were conducted in areas with some degree of malaria endemicity (Muro 1999 (C); Beasley 2000; Februhartanty 2002; Hall 2002 (C); Leenstra 2009).
Participant age ranged from six to 49 years old. While we did not include studies specifically recruiting premenarchal girls - as these are the subject of a separate review (De-Regil 2011) - two studies recruited young females and separate data was not available only for postmenarchal girls (Hall 2002 (C); Roschnik 2003 (C)). Based on the age range reported in these studies, we assumed that at least half of their participants fulfilled our inclusion criteria and thus we decided to retain them in the review. If the disaggregated data is made available to us, we will include it in future updates of the review.
Most trials involved a mix of anaemic and non-anaemic women with the exception of four trials that included women with mild to moderate anaemia (Dos Santos 1999; Ahmed 2001; Shobha 2003; Leenstra 2009) and one of them (Shobha 2003) only included severely anaemic women; the rest of the trials excluded these women and gave them treatment and/or referred them to health care. Riuvard 2006 specifically included iron-deficient women.
Samples size varied among studies, from 24 (Riuvard 2006) to 2461 (Soekarjo 2004 (C)) participants; however, for cluster-randomised trials the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.
Interventions (intermittent regimens, supplement composition and iron dose)
Most trials provided intermittent iron supplementation once a week except three trials where the supplements were given twice a week (Riuvard 2006; Zavaleta 2000; Shobha 2003) and one trial that compared both weekly and twice weekly supplementation with a placebo (Kianfar 2000). None of the trials gave women iron three times a week on non-consecutive days.
In eleven of the trials women were supplemented for three months or less (Angeles-Agdeppa 1997; Dos Santos 1999; Muro 1999 (C); Kianfar 2000; Ahmed 2001; Hall 2002 (C); Shah 2002; Shobha 2003; Riuvard 2006; Nguyen 2008) and the maximum duration of supplementation was six months (Gilgen 2001).
In nine trials women were supplemented with iron only (Dos Santos 1999; Beasley 2000; Kianfar 2000; Zavaleta 2000; Gonzalez-Rosendo 2002; Shobha 2003; Riuvard 2006; Leenstra 2009; Mozaffari 2010 (C)); in eight trials women received iron + folic acid supplements (Jayatissa 1999 (C); Muro 1999 (C); Gilgen 2001; Februhartanty 2002; Hall 2002 (C); Shah 2002; Agarwal 2003 (C); Roschnik 2003 (C)); in two trials iron + multiple micronutrients supplements (Angeles-Agdeppa 1997; Nguyen 2008), and two trials tested both iron+folic acid and iron+multiple nutrients (Ahmed 2001; Soekarjo 2004 (C)). Most trials supplemented iron as ferrous sulphate except in two trials: Gilgen 2001, who used ferrous fumarate, and Riuvard 2006, who used ferrous chloride; four trials did not specify the form of iron used for supplementing women: Angeles-Agdeppa 1997; Agarwal 2003 (C); Shobha 2003; Nguyen 2008. All trials used supplements as tablets or caplets.
Several supplemental doses of iron were tested in the intermittent group but none of the trials exceeded 120 mg of elemental iron per week. In one trial women were supplemented with 30 mg of elemental iron (Mozaffari 2010 (C)); in two trials trials with 50 mg of iron (Kianfar 2000; Riuvard 2006); in eight trials with 60 mg of iron (Dos Santos 1999; Jayatissa 1999 (C); Zavaleta 2000; Februhartanty 2002; Gonzalez-Rosendo 2002; Shobha 2003; Soekarjo 2004 (C)); in four studies with 65 mg of iron (Muro 1999 (C); Februhartanty 2002; Hall 2002 (C); Roschnik 2003 (C)); in one trial with 70 mg of iron (Shah 2002); in one trial they received 100 mg of iron (Agarwal 2003 (C)), and in three trials they received 120 mg of iron (Beasley 2000; Ahmed 2001; Leenstra 2009). Two trials (Angeles-Agdeppa 1997; Nguyen 2008) examined the effect of two different doses of iron: 60 and 120 mg of elemental iron per week.
Excluded studies
We excluded 20 studies: eleven trials were not randomised controlled trials (Cook 1995; Jackson 2003; Siddiqui 2004; Berger 2005; Crape 2005; Horjus 2005; López de Romaña 2006; Deshmukh 2008; Vir 2008; Casey 2009; Pasricha 2009); two references were reviews (Beaton 1999; Dwividi 2006); one was a commentary on another trial (Perrin 2002); five trials compared interventions out of the scope of this review (Bruner 1996; Tee 1999; Viteri 1999; Ahmed 2005; Ahmed 2010), and one trial excluded post-menarchal girls because the anthelmintic drug given along with the iron supplementation was not safe in case of pregnancy (Taylor 2001).
See Characteristics of excluded studies tables for a detailed description of the studies and the reasons for exclusion.
Risk of bias in included studies
Overall, study methods were not well described in many of the included studies and this meant that assessing risk of bias was difficult. Where we assessed methods of randomisation or allocation concealment as being at high risk of bias (or unclear), and trials were either not blinded or had high or imbalanced attrition rates, we assumed that they were at high risk of bias for the purposes of the sensitivity analysis looking at the impact of study quality. Using these criteria, four studies were assessed as being at low risk of bias (Gilgen 2001; Hall 2002 (C); Nguyen 2008; Leenstra 2009) The remaining studies were either assessed as being at high risk of bias or methods were unclear.
See the 'Risk of bias' tables included in Characteristics of included studies for an assessment of the risk of bias for each included trial and Figure 2 and Figure 3 for an overall summary of the risk of bias of all included trials. In the 'Summary of findings' tables, we present the overall quality of the evidence for each primary outcome, by comparison ( Summary of findings for the main comparison; Summary of findings 2).
|Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
|Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Sequence generation
Six trials adequately randomised the participants to the intervention group (Dos Santos 1999; Gilgen 2001; Gonzalez-Rosendo 2002; Hall 2002 (C); Riuvard 2006; Nguyen 2008); four of them used random number generator (Gilgen 2001; Gonzalez-Rosendo 2002; Hall 2002 (C); Nguyen 2008), one used drawing of lots (Dos Santos 1999) and another used a randomisation table (Riuvard 2006). Thirteen randomised trials did not state the method used to generate the random sequence clearly.
Allocation concealment
Ten trials reported adequate allocation concealment. In three trials the code was kept secure until all data was entered the computer (Ahmed 2001) or after completion of the trial (Leenstra 2009; Nguyen 2008). Seven trials were randomised at cluster level and we considered that the risk of selection bias at the individual level was unlikely (Jayatissa 1999 (C); Zavaleta 2000; Hall 2002 (C); Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Mozaffari 2010 (C)). In ten trials the method used to conceal the allocation was unclear or not mentioned.
Of the 21 included trials, seven were described as being single or double blinded (Angeles-Agdeppa 1997; Zavaleta 2000; Ahmed 2001; Februhartanty 2002; Gilgen 2001; Nguyen 2008; Leenstra 2009), although only four trials specified that the placebos were of identical appearance (Angeles-Agdeppa 1997; Jayatissa 1999 (C); Zavaleta 2000; Nguyen 2008).
Incomplete outcome data
Loss to follow-up varied greatly among trials, from 1% (Agarwal 2003 (C)) to 41% (Roschnik 2003 (C)). Six trials lost more than 20% of the randomised participants and/or had imbalanced losses between study groups (Angeles-Agdeppa 1997; Dos Santos 1999; Beasley 2000; Ahmed 2001; Roschnik 2003 (C); Nguyen 2008). Three trials did not mention the attrition (Gilgen 2001; Gonzalez-Rosendo 2002; Shobha 2003) and it was difficult to judge whether the lack of data was due to no losses to follow-up or to incomplete reporting.
Selective reporting
Assessing selective reporting was difficult because we did not have access to study protocols. Of the 21 included trials, in 19 there was insufficient information to permit judgement as we did not have access to the protocols. One trial was judged at high risk of selective reporting because data for plasma ferritin concentrations were estimated only in some girls and it was unclear how the selection was made (Agarwal 2003 (C)). In Leenstra 2009 data on several outcomes were described as non significant but were not shown (side effects including vomiting and diarrhoea).
Other potential sources of bias
Ten trials (Dos Santos 1999; Jayatissa 1999 (C); Kianfar 2000; Zavaleta 2000; Gilgen 2001; Gonzalez-Rosendo 2002; Hall 2002 (C); Shobha 2003; Nguyen 2008; Riuvard 2006) appeared to be free of other sources of bias. In one trial (Ahmed 2001) there was some variability in the administration of the supplements depending on the factory (that is supplements were given before versus after lunch, with an empty stomach versus having eaten little). In Beasley 2000 the control group was given vitamin B12, which could have potentially impacted anaemia status. In Shah 2002, the daily group were not explicitly supervised while those in the weekly group were supervised. In Februhartanty 2002 there was a higher prevalence of anaemia in the group that received supplements weekly. In Roschnik 2003 (C), the results were affected by a famine in Malawi at the time of the trial.
In two studies (Hall 2002 (C) and Roschnik 2003 (C)) approximately half of the participants were young females (< 12 years of age). We performed a sensitivity analysis ad hoc and found that the exclusion of these studies changed the estimate for anaemia from RR 0.73 (95% CI 0.56 to 0.95) to RR 0.67 (95% CI 0.47 to 0.96) and haemoglobin from MD 4.58 g/L (95% CI 2.56 to 6.59) to MD 5.02 g/L (95% CI 2.80 to 7.24). As the interpretation of our results did not change, we decided to retain these trials in our analyses and thus minimise the risk of publication bias.
Finally, there are two trials awaiting assessment (Olsen 2000; Sharma 2000). We have access to the papers but not to the disaggregated data by sex (Olsen 2000) or the methodological details to correctly assess the trial (Sharma 2000). Based on their abstracts, it is unlikely that their findings would have changed the overall interpretation of our review.
Effects of interventions
See: Summary of findings for the main comparison Intermittent use of iron supplements versus placebo/no intervention in menstruating women; Summary of findings 2 Intermittent versus daily use of iron supplements in menstruating women
The summary of results is organised by comparisons. See the Data and analyses section for detailed results on primary and secondary outcomes.
Comparison 1: Intermittent supplementation of iron (alone or plus any other micronutrients) versus no supplementation or placebo
Sixteen trials (Angeles-Agdeppa 1997; Muro 1999 (C); Jayatissa 1999 (C); Beasley 2000; Kianfar 2000; Zavaleta 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Hall 2002 (C); Shah 2002; Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Leenstra 2009; Mozaffari 2010 (C)) involving 8701 women examined intermittent iron supplementation regimens in comparison with no supplementation or placebo. Three of the trials met the prespecified criteria mentioned above for being at lower risk of bias (Gilgen 2001; Hall 2002 (C); Leenstra 2009) and in sensitivity analyses these trials were retained in the analysis whilst trials at higher risk of bias were temporarily removed to examine whether they had any impact on the overall pattern of results.
Primary outcomes
Ten trials involving 2996 women reported on this outcome (Angeles-Agdeppa 1997; Jayatissa 1999 (C); Muro 1999 (C); Zavaleta 2000; Ahmed 2001; Hall 2002 (C); Agarwal 2003 (C); Roschnik 2003 (C); Soekarjo 2004 (C); Mozaffari 2010 (C)). Women receiving intermittent supplementation were less likely to have anaemia at the end of the intervention than those who received a placebo or no intervention (average risk ratio (RR) 0.73; 95% confidence interval (CI) 0.56 to 0.95) ( Analysis 1.1). There was variation among trials in terms of the size of the treatment effect (T
Haemoglobin (g/L)
Thirteen trials (n = 2599) examined haemoglobin concentrations (Angeles-Agdeppa 1997; Jayatissa 1999 (C); Beasley 2000; Kianfar 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Hall 2002 (C); Roschnik 2003 (C); Agarwal 2003 (C); Soekarjo 2004 (C); Leenstra 2009; Mozaffari 2010 (C)) ( Analysis 1.8). The results were statistically significant the intervention group. Women receiving iron supplements intermittently had 4.58 more grams of haemoglobin per litre (95% CI 2.56 to 6.59) than those who received no intervention or a placebo). There was variation among trials in terms of the size of the treatment effect (T
Iron deficiency
Three trials (Ahmed 2001; Angeles-Agdeppa 1997; Mozaffari 2010 (C)) involving 624 women reported on this outcome ( Analysis 1.15). Results favoured the intervention group but were not statistically significant (RR 0.50; 95% CI 0.24 to 1.04). The heterogeneity was high but the direction of the results was consistent (T
Ferritin (μg/L)
Six trials (Angeles-Agdeppa 1997; Beasley 2000; Ahmed 2001; Gilgen 2001; Februhartanty 2002; Mozaffari 2010 (C)) involving 980 women examined ferritin concentrations, the results were statistically significant in favour of the intervention group (MD 8.32 μg/L; 95% CI 4.97 to 11.66). Heterogeneity was high (T
Iron deficiency anaemia
A single trial (n = 97) (Mozaffari 2010 (C)) reported on this outcome and found no difference between those women receiving iron supplements intermittently and those who did not receive iron (RR 0.07; 95% CI 0.00 to 1.16) ( Analysis 1.23).
All-cause morbidity
A single trial (Beasley 2000) reported on this outcome and found no difference between those women receiving iron supplements intermittently and those who did not receive iron (RR 1.12; 95% 0.82 to 1.52) ( Analysis 1.24).
Secondary outcomes
A single trial (Angeles-Agdeppa 1997) involving 209 women reported diarrhoea and results showed no evidence of a difference between groups (RR 0.28; 95% CI 0.05 to 1.49) ( Analysis 1.25).
Any adverse side effects
Three trials (Angeles-Agdeppa 1997; Gilgen 2001; Leenstra 2009) involving 630 women examined any adverse side effects. Results showed no evidence of a difference between groups (RR 1.98; 95% CI 0.31 to 12.72) ( Analysis 1.26).
Three trials (Zavaleta 2000; Ahmed 2001; Shah 2002) involving 556 women examined adherence. There was no evidence that women receiving iron supplements intermittently adhered better to the intervention than those who did not receive iron (RR 0.99; 95% CI 0.96 to 1.01).
Malaria outcomes
Two trials reported on malaria outcomes and found no difference in the prevalence and incidence of parasitaemia ( Analysis 1.28; Analysis 1.29), prevalence of high density parasitaemia ( Analysis 1.30) and clinical malaria ( Analysis 1.31) between those women who received iron supplements intermittently and those who did not receive iron.
Other secondary outcomes
No studies reported on our other prespecified outcomes: respiratory infections, school performance or depression. Work performance and economic productivity was reported by Gilgen 2001 but data could not be extracted.
Comparison 2: Intermittent iron supplementation versus daily iron supplementation
Eleven trials (Angeles-Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Kianfar 2000; Zavaleta 2000; Gonzalez-Rosendo 2002; Shah 2002; Agarwal 2003 (C); Shobha 2003; Riuvard 2006; Nguyen 2008) involving 5742 women were included in this comparison. Only Nguyen 2008 was considered to be at low risk of bias.
Primary outcomes
Six trials (Angeles-Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Zavaleta 2000; Gonzalez-Rosendo 2002; Agarwal 2003 (C)) with 1492 women reported on this outcome ( Analysis 2.1). Women receiving iron supplements daily were less likely to have anaemia at the end of the intervention than those receiving iron supplements intermittently (RR 1.26; 95% CI 1.04 to 1.51). There was no indication of heterogeneity (T
Haemoglobin (g/L)
Eight trials involving 1676 women reported on this outcome (Angeles-Agdeppa 1997; Dos Santos 1999; Jayatissa 1999 (C); Kianfar 2000; Gonzalez-Rosendo 2002; Agarwal 2003 (C); Shobha 2003; Riuvard 2006). There was no statistical evidence that mean haemoglobin concentrations were different between those women receiving intermittent iron supplementation and those who received daily iron supplementation (MD -0.15; 95% CI -2.20 to 1.91) ( Analysis 2.8). There was high heterogeneity in the size and direction of the effect (T
Iron deficiency
Only Angeles-Agdeppa 1997 (n = 198) reported on this outcome and found no evidence of differences between daily and intermittent groups (RR 4.30; 95% CI 0.56 to 33.20).
Ferritin (μg/L)
Three trials (Angeles-Agdeppa 1997; Agarwal 2003 (C); Riuvard 2006) involving 657 women reported on this outcome ( Analysis 2.16). Women receiving iron supplements daily had higher concentrations of ferritin at the end of the intervention than those women receiving iron supplements intermittently (MD -11.32 μg/L; 95% CI -22.61 to -0.02). The heterogeneity was high (T
Iron deficiency anaemia
None of the included trials reported on this outcome
All-cause morbidity
No trials reported on this outcome.
Secondary outcomes
Only Angeles-Agdeppa 1997 (n=198) reported on this outcome and found no evidence of differences between daily and intermittent groups (RR 2.41; 95% CI 0.12 to 49.43).
Any adverse side effects
Four trials (Angeles-Agdeppa 1997; Jayatissa 1999 (C); Shobha 2003; Nguyen 2008) involving 823 women reported on this outcome ( Analysis 2.18). There was no evidence that the incidence of adverse side effects was different between those women receiving iron supplements daily and those women receiving iron supplements intermittently (RR 0.36; 95% CI 0.10 to 1.31).
Only Nguyen 2008 (n = 198) reported on this outcome and found no evidence of differences between daily and intermittent groups (RR 0.82; 95% CI 0.63 to 1.07).
Four trials (Dos Santos 1999; Gonzalez-Rosendo 2002; Shah 2002; Riuvard 2006) involving 507 women reported on this outcome ( Analysis 2.20). There was no evidence that the adherence to intermittent supplementation was different from that observed among women receiving daily supplements (RR 1.04; 95% CI 0.99 to 1.09).
Other secondary outcomes
No studies reported on our other prespecified outcomes: respiratory infections, work performance and economic productivity, school performance or malaria outcomes.
Non-prespecified outcomes
Nguyen 2008 reported on the incidence of hospitalisation and Riuvard 2006 on oxidative stress post supplementation (expressed as the ferric reducing ability of the plasma, FRAP). There was no evidence that the effects of intermittent supplementation on these indicators were different from that produced by daily supplementation ( Analysis 2.21; Analysis 2.22).
Subgroup comparisons
There was considerable variation among trials in terms of the populations examined and the the way studies were conducted which very likely resulted in the high statistical heterogeneity observed in some outcomes. For primary outcomes, we examined subgroups to look for possible differences between studies in terms of the length of the intervention; women's anaemia and iron status at baseline; higher and lower weekly doses of iron; type of iron compound provided; supplementation regimen, and malaria endemicity.
As very few studies contributed data for most of the outcomes, we limited the subgroup analysis to anaemia and haemoglobin and ferritin concentrations. In the analyses we have provided overall totals along with subtotals for subgroups and the statistics for subgroup differences.
Supplement nutrient composition (iron only, iron plus folic acid, iron plus other micronutrients)
There were no statistical differences between supplements containing iron only, or iron plus folic acid, or iron plus other micronutrients regarding their effect on anaemia, haemoglobin and ferritin ( Analysis 1.2; Analysis 1.9; Analysis 1.17; Analysis 2.2; Analysis 2.9).
Anaemia status at baseline (anaemic, non-anaemic, mixed/unknown)
Intermittent iron supplementation had similar effects on anaemia, haemoglobin and ferritin concentrations in populations with different degrees of anaemia ( Analysis 1.10; Analysis 1.18; Analysis 2.3; Analysis 2.10). Anaemic women tended to have a stronger response ( Analysis 1.3; Analysis 2.10); however, as only one or two trials contributed to this subgroup category the results should be cautiously interpreted.
Iron deficiency at baseline (iron deficient, non-iron deficient, mixed/unknown)
This subgroup analysis was not conducted as only two trials reported the baseline prevalence of iron deficiency (Riuvard 2006; Leenstra 2009).
Dose of elemental iron per week in the intermittent group (60 mg of iron or less, more than 60 mg of iron)
Almost an even number of trials provided more than 60 mg of iron per week or 60 mg or less. In most of the cases there was no difference in haematological outcomes between the effects produced by 60 mg of iron or less per week and those observed with higher doses of iron per week ( Analysis 1.5; Analysis 1.12; Analysis 1.20; Analysis 2.5). In one case, women who received 60 mg or less intermittently showed higher haemoglobin concentrations in comparison to those women who received higher doses ( Analysis 2.12).
Duration of the intervention (three months or less, more than three months)
In most of the cases the duration of the intervention did not affect the effect of intermittent supplementation on haematological outcomes ( Analysis 1.6; Analysis 1.13; Analysis 1.21; Analysis 2.6; Analysis 2.13).
Malaria endemicity (yes, no/unknown)
The endemicity for malaria at the time where the trial was conducted did not affect the effect of intermittent supplementation on haematological outcomes ( Analysis 1.7; Analysis 1.14; Analysis 1.22; Analysis 2.7; Analysis 2.14).
Summary of main results
Available data indicate that, among menstruating women, intermittent oral supplementation with iron (alone or in combination with other nutrients) effectively increases haemoglobin and ferritin concentrations and reduces the prevalence of anaemia compared to a placebo or no intervention. Overall, this positive response does not differ when providing weekly or biweekly iron supplementation; nor with the duration of the intervention, dose used, anaemia status at baseline or malaria endemicity.
Compared with daily supplementation, women receiving intermittent supplementation were more likely to develop anaemia and have lower ferritin concentrations although their haemoglobin concentrations at the end of the intervention were similar.
Information on morbidity (including malaria outcomes), side effects, work performance, economic productivity, depression and adherence to the intervention is scarce, but thus far there is no evidence that intermittent supplementation has any effect on them either when compared with a placebo, no intervention or with daily iron supplementation.
Overall completeness and applicability of evidence
This review includes a total of 21 randomised trials involving 10,258 women; 20 were conducted in countries in Latin America, Africa and Asia where anaemia is a public health problem. The overall quality of the evidence ranged from very low to low and the main limitation of the trials was the lack of blinding and high attrition.
Intermittent iron supplementation regimens have been proposed as an efficacious and efficient approach to the prevention and control of anaemia and at least 100 trials on intermittent iron supplementation regimens in different age groups have been published during the last 15 years. Although the real effect of an intervention is context-specific, the results of this review clearly show that weekly or twice weekly iron supplementation regimens are effective in reducing the prevalence of anaemia and improving haemoglobin and ferritin concentrations in menstruating women in comparison with no supplementation or placebo, even in malaria settings. There is not sufficient information to assess with certainty the effect of this intervention on other health and nutrition outcomes.
The results suggest that the provision of supplements once a week with 60 to 120 mg of iron is enough to produce a positive haematological response in populations with different degrees of anaemia. The efficacy of this intervention to treat anaemia may be deemed as controversial as women receiving daily supplementation were less likely to have anaemia than those receiving intermittent supplements. However in all the trials in which anaemia was an inclusion criterion there was a significant increase in haemoglobin concentrations among women who received supplements intermittently. Folic acid merits a special mention as its consumption did not have a differential effect on anaemia and haemoglobin concentrations; however, its use during the periconceptional period has proven to reduce the risk of having babies with neural tube defects, an outcome that was out of the scope of this review (De-Regil 2010).
Although improved adherence and fewer side effects have been proposed as an advantage of intermittent supplementation over daily supplementation, there is no evidence that in a relatively well controlled environments and for short periods of supplementation women adhere better to the intermittent regimens. However, neither there was a difference when women were compared with those receiving a placebo. Clearly, there are gaps on how the intensity, frequency and duration of side effects indeed affects the short and long term adherence to supplementation.
Quality of the evidence
We summarised the risk of bias at two levels: within studies (across domains) and across studies.
1. Quality of the evidence across within studies. In general, only a few trials were considered to be at low risk of bias after considering the methods for allocating the treatment, the blinding and the attrition rates (see Risk of bias in included studies, Figure 2; Figure 3). In most of the studies, the methods used to randomly assign participants and conceal allocation were not described. Blinding of participants, care providers and outcome assessors was not generally attempted, although in some studies technical staff carrying out laboratory investigations were reported to be unaware of group allocation. This lack of blinding may represent a potentially serious source of bias. Attrition was also a problem in many of these studies.
Variability in participants characteristics, interventions and outcomes studied was likely to be low among included trials. However, differences between studies in terms of methodological factors, specifically blinding and allocation concealment may lead to differences in the observed interventions effects (Higgins 2011). Although this does not necessarily mean that the true intervention effect does vary, results should be interpreted with some caution.
2. Quality of the evidence across studies. We used the GRADE methodology for this assessment and set out the results for primary outcomes in the Summary of findings for the main comparison and the Summary of findings 2. We considered that indirectness or publication bias were unlikely but the quality of the trials and inconsistency (or the lack of studies) were potentially important factors in the overall assessment of the evidence for primary outcomes. The quality of the available evidence ranged between low and very low in our both comparisons.
Potential biases in the review process
There were a number of potential biases in the review process. We attempted to be as inclusive as possible in the search strategy and found publications in different languages in journals from all the continents, although the literature identified was predominantly written in English. We were also able to obtain unpublished information.
We attempted to minimise bias in several ways: both review authors independently assessed eligibility for inclusion and checked data extraction, assessments of risk of bias and data entry. However, carrying out reviews is not an exact science and may require a number of subjective judgements; it is possible that a different review team may have reached different decisions regarding assessments of eligibility and risk of bias. We would encourage readers to examine the Characteristics of included studies tables to assist in the interpretation of results.
Agreements and disagreements with other studies or reviews
To our knowledge, one meta-analysis of randomised controlled trials has been conducted previously on the efficacy of intermittent iron supplementation in the control of iron deficiency anaemia (Beaton 1999). That review included the results of 22 trials completed before 1999 in different age groups. Of the included studies, nine were carried out among adolescents and compared once or twice a week versus daily supplementation; most of them also assessed a control group that did not receive iron. All the trials reported results for haemoglobin and three also measured ferritin. That review did not include adult non-pregnant women and authors pooled the results from school-aged children and adolescents.
Like us, the authors (Beaton 1999) concluded that intermittent supplementation increased haemoglobin and ferritin levels and reduced anaemia when compared with no intervention or a placebo. Intermittent supplementation was also less efficacious than daily supplementation in reducing anaemia (with a stronger effect than in our review: RR 1.44; 95% CI 1.33 to 1.56 versus RR 1.26: 95% CI 1.04 to 1.52) but there were no statistical differences in haemoglobin concentrations between regimens. The authors of Beaton 1999 concluded that weekly supplementation should be considered for school-aged children and adolescents only in situations where there is strong assurance of supervision and high adherence.
A more recent unpublished review included 12 studies evaluating the effects of weekly iron and folic acid supplementation among non-pregnant women of reproductive age (Margetts 2007). The results suggested that the consumption of supplements containing 60 mg of elemental iron with folic acid for at least 12 weeks, with or without deworming treatment, increased iron status, as judged by increased haemoglobin and in some studies serum ferritin levels. The effect of weekly supplementation on Hb concentration was similar to that reported for daily supplementation, except in subsets of women who were severely anaemic at baseline where daily supplementation was more effective.
Overall, the findings of these reviews agree with the findings of this Cochrane review. The 21 trials included in our review, conducted in different age groups, contexts and with different levels of supervision, show that intermittent supplementation may be an effective public health intervention. In contexts where daily supplementation has failed or has not been implemented, the feasibility of delivering intermittent supplementation could make this intervention a viable alternative to consider.
The results of the present review are only applicable to menstruating women. However, another systematic review assessing the benefits and safety of this intervention in preschool-aged and school-aged children (De-Regil 2011) concurs with our findings. From the programme implementation perspective, a recent narrative review reports that weekly iron and folic acid supplementation has been successfully implemented in Cambodia, Egypt, India, Laos, the Philippines and Viet Nam, reaching over half a million menstruating women (WHO-WPRO 2011).
Authors' conclusions
Implications for practice
Intermittent supplementation with iron alone or in combination with other micronutrients is effective for reducing anaemia and improving iron stores among menstruating women in populations with different anaemia and malaria backgrounds. Despite achieving similar haemoglobin concentrations at the end of the intervention, women receiving supplements intermittently were more likely to have anaemia than those who received daily supplements. With the current evidence, there is no indication that this intervention has detrimental effects on women's health and other indicators of nutritional status.
The results suggest that intermittent supplementation in menstruating women is a feasible intervention in settings where daily supplementation is likely to be unsuccessful or not feasible. Most of the trials provided 60 mg of elemental iron or more on a weekly basis and the positive effect on the haematological status seemed not to be affected by the duration of the intervention, although a minimum of three months seems reasonable to trigger the haematological response and start building iron stores. The provision of micronutrients other than iron did not seem to alter the haematological response; however, the use of folic acid in this age group goes beyond improving iron status and it is instrumental in reducing the risk of having babies with neural tube defects if a woman becomes pregnant. Iron and folic acid supplementation, therefore, has the possibility of impacting not only menstruating women, but also of benefiting those women who become pregnant and their babies.
The evidence on the efficacy and effectiveness of this intervention supports its integration with other public health efforts to prevent anaemia and iron deficiency and improve reproductive health. The successful implementation of intermittent supplementation programmes may require motivation, the involvement of multiple stakeholders, the timely supply of good quality supplements and the development of effective behaviour change communication strategies for promoting an adequate use of supplements.
Implications for research
This review has highlighted the need for further research in this area, particularly on:
We would like to thank the trial authors who have contributed additional data for this review. We would like to thank Dr Mona Nasser for her contributions during the protocol stage and to all the staff at the editorial office of the Cochrane Developmental, Psychosocial and Learning Problems Group (CDPLPG) for their support in the preparation of this review.
As part of the pre-publication editorial process, the text has been commented on by three peers (an editor and two referees who are external to the editorial team) and one of the CDPLPG's statisticians. We are grateful for their feedback.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Appendices
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. Search strategy
Cochrane Central Register of Controlled Trials (CENTRAL)
#1MeSH descriptor Iron, this term only
#2MeSH descriptor Iron, Dietary, this term only
#3MeSH descriptor Anemia, Iron-Deficiency, this term only
#4MeSH descriptor Folic Acid, this term only
#5MeSH descriptor Dietary Supplements, this term only
#6MeSH descriptor Trace Elements, this term only
#7folic* or folate* or folvite* or folacin* or pteroylglutamic*
#8diet* NEAR/3 supplement*
#9micro-nutrient* or micronutrient* or multi-nutrient* or multinutrient*
#10MeSH descriptor Ferric Compounds, this term only
#11MeSH descriptor Ferrous Compounds, this term only
#12ferrous* or ferric* or fe
#13MeSH descriptor Micronutrients, this term only
#15MeSH descriptor Drug Administration Schedule, this term only
#16MeSH descriptor Dose-Response Relationship, Drug explode all trees
#17MeSH descriptor Time Factors, this term only
#18week* or biweek* or bi NEXT week* or intermittent* or alternat*
#21(iron NEAR/3 (dose* or dosage or administer* or administration or frequency))
#23MeSH descriptor Adolescent, this term only
#24MeSH descriptor Adult, this term only
#25MeSH descriptor Middle Aged, this term only
#26(teen* or adoles* or pubert* or pubescen*)
#28(girl* or female* or woman* or women*)
#31(#30), from 1980 to 2011
1 Iron/
2 Anemia, Iron-Deficiency/
3 Iron, Dietary/
4 Folic Acid/
5 iron$.tw.
6 (folic$ or folate$ or folvite$ or folacin$ or pteroylglutamic$).tw.
7 Ferric Compounds/
8 Ferrous Compounds/
9 (ferrous$ or ferric$ or fe).tw.
10 micronutrients/
11 (micro-nutrient$ or micronutrient$ or multi-nutrient$ or multinutrient$).tw.
12 Dietary Supplements/
13 (diet$ adj3 supplement$).tw.
14 or/1-13
15 Drug Administration Schedule/
16 Time Factors/
17 (week$ or biweek$ or bi-week$ or intermittent$ or alternat$).tw.
18 or/15-17
19 14 and 18
20 (iron adj3 (dose$ or dosage or administer$ or administration or frequency or regimen$ or supplement$)).tw.
21 19 or 20
22 adolescent/ or adult/ or middle aged/
23 (teen$ or adoles$ or pubert$ or pubescen$).tw.
24 22 or 23
25 Female/
26 (girl$ or female$ or wom#n).tw.
27 or/25-26
28 24 and 27
29 randomized controlled trial.pt.
30 controlled clinical trial.pt.
31 randomi#ed.ab.
32 placebo$.ab.
33 randomly.ab.
34 trial.ab.
35 clinical trials as topic.sh.
36 or/29-35
37 exp animals/ not humans.sh.
38 36 not 37
39 21 and 28 and 38
40 limit 39 to yr="1980 -Current"
1 iron/
2 iron intake/
3 iron deficiency anemia/
4 folic acid/ (32481)
5 diet supplementation/ (
6 trace element/
7 iron$.tw.
8 (folic$ or folate$ or folvite$ or folacin$ or pteroylglutamic$).tw.
9 (diet$ adj3 supplement$).tw.
10 (micro-nutrient$ or micronutrient$ or multi-nutrient$ or multinutrient$).tw.
11 ferric ion/
12 ferrous ion/
13 or/1-12
14 drug administration/
15 drug dose regimen/
16 (week$ or biweek$ or bi-week$ or intermittent$ or alternat$).tw.
17 or/14-16
18 13 and 17
19 (iron adj3 (dose$ or dosage or administer$ or administration or frequency)).tw.
20 18 or 19
21 adult/ or middle aged/ or adolescent/
22 (teen$ or adoles$ or pubert$ or pubescen$).tw.
23 21 or 22
24 female/
25 (girl$ or female$ or wom#n).tw.
26 24 or 25 (
27 23 and 26
28 20 and 27
29 Randomized controlled trial/
30 Randomization/
31 Single blind procedure/
32 Double blind procedure/
33 Crossover procedure/
34 Placebo/ (178428)
35 Randomi#ed.tw.
36 RCT.tw.
37 (random$ adj3 (allocat$ or assign$)).tw.
38 randomly.ab.
39 groups.ab.
40 trial.ab.
41 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
42 Placebo$.tw.
43 Prospective study/
44 (crossover or cross-over).tw.
45 prospective.tw.
46 or/29-45
47 28 and 46
S42 S23 and S41
S41 S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or
S34 or S35 or S36 or S37 or S38 or S39 or S40
S40 (MH "Evaluation Research") OR (MH "Summative Evaluation Research") OR
(MH "Program Evaluation")
S39 (MH "Treatment Outcomes")
S38 (MH "Comparative Studies")
S37 TI (evaluat* study or evaluat* research) or AB (evaluate* study or
evaluat* research) or TI (effectiv* study or effectiv* research) or AB
(effectiv* study or effectiv* research) OR TI (prospectiv* study or
prospectiv* research) or AB(prospectiv* study or prospectiv* research) or
TI (follow-up study or follow-up research) or AB (prospectiv* study or
prospectiv* research)
S36 "cross over*"
S35 crossover*
S34 (MH "Crossover Design")
S33 (tripl* N3 mask*) or (tripl* N3 blind*)
S32 (trebl* N3 mask*) or (trebl* N3 blind*)
S31 (doubl* N3 mask*) or (doubl* N3 blind*)
S30 (singl* N3 mask*) or (singl* N3 blind*)
S29 (clinic* N3 trial*) or (control* N3 trial*)
S28 (random* N3 allocat* ) or (random* N3 assign*)
S27 randomis* or randomiz*
S26 (MH "Meta Analysis")
S25 (MH "Clinical Trials+")
S24 MH random assignment
S23 S17 and S22
S22 S20 or S21
S21 (MH "Women's Health")
S20 18 and 19
S19 CT female or ( woman or women or female* or girl*)
S18 (AG adolescent or AG adult or AG middle aged) OR (adolescen* or
pubert* or pubescen*)
S17 S15 or S16
S16 (iron N3 dose*) or (iron N3 dosage) or (iron N3 administer*) or (iron
N3 administration) or (iron N3 frequency) or (iron N3 supplement*)
S15 S10 and S14
S14 S11 or S12 or S13
S13 (week* or biweek* or bi-week*or bi week* or intermittent* or alternat*
or regimen*)
S12 (MH "Time Factors")
S11 (MH "Drug Administration Schedule")
S10 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9
S9 micro-nutrient* or micronutrient* or micro nutrient* multi-nutrient* or
multinutrient* or multi nutrient*
S8 ferrous* or ferric* or "fe"
S7 diet* N3 supplement*
S6 folic* or folate* or folvite* or folacin* or pteroylglutamic*
S5 iron* 5
S4 (MH "Micronutrients")
S3 (MH "Dietary Supplements")
S2 (MH "Folic Acid")
S1 (MH "Iron") OR (MH "Anemia, Iron Deficiency") OR (MH "Iron Compounds")
OR (MH "Ferric Compounds") OR (MH "Ferrous Compounds")
#6 TS=(random* or RCT or trial* or allocat* or assign* or placebo* or cross-over or crossover or "cross over" or factorial* or "double blind*" or "single blind")
#4 TS=(women or woman or female* or girl*)
#3 #1 same #2
#2 TS=(iron or "folic acid" or ferrous or ferric or micronutrient* or multiutrient* or micro-nutrient* or multi-nutrient* )
#1 TS= (alternate* or week* or intermittent or biweek* or bi-week* or "bi week*" or supplement* )
Science Citation Index (SCI)
#6 TS=(random* or RCT or trial* or allocat* or assign* or placebo* or cross-over or crossover or "cross over" or factorial* or "double blind*" or "single blind")
#4 TS=(women or woman or female* or girl*)
#3 #1 same #2
#2 TS=(iron or "folic acid" or ferrous or ferric or micronutrient* or multiutrient* or micro-nutrient* or multi-nutrient* )
#1 TS= (alternate* or week* or intermittent or biweek* or bi-week* or "bi week*" or supplement* )
Conference Paper Citation Index -Science (CPCI-S)
#6 TS=(random* or RCT or trial* or allocat* or assign* or placebo* or cross-over or crossover or "cross over" or factorial* or "double blind*" or "single blind")
#4 TS=(women or woman or female* or girl*)
#3 #1 same #2
#2 TS=(iron or "folic acid" or ferrous or ferric or micronutrient* or multiutrient* or micro-nutrient* or multi-nutrient* )
#1 TS= (alternate* or week* or intermittent or biweek* or bi-week* or "bi week*" or supplement* )
(iron* /folic* / folate* /supplement*/micronutrient*/micro-nutrient*) & (week* /bi-week* / bi week* / biweek* / intermittent / alternat*) & (women / woman /girl* / female*)
Suplementacion hierro
Suplementacion hierro
Suplementacion hierro
Suplementacion hierro
Iron supplementation AND women
Iron supplementation AND girls
Iron supplementation AND women
Iron supplementation AND girls
Contributions of authors
Both review authors contributed to drafting the text of the review and approved the final manuscript.
Declarations of interest
- Ana Cecilia Fernández-Gaxiola - none known.
- Luz Maria De-Regil - none known.
Disclaimer: Luz Maria De-Regil is currently staff member of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.
Sources of support
Internal sources
- Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.
External sources
- Micronutrient Initiatitive, Canada.WHO acknowledges the Micronutrient Initiative (MI) for their financial support to the Micronutrients Unit for conducting systematic reviews on micronutrient interventions.
- Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.Ana C Fernandez-Gaxiola received partial financial support from the Department of Nutrition for Health and Development for this work.
Differences between protocol and review
In comparison with the protocol, this review has the following differences.
- Types of outcome measures: given that the population of menstruating women includes peri-menarcheal girls and adult women, and each group uses a different anaemia cut-off, we changed our previous definition of anaemia 'haemoglobin concentration <120 g/L, adjusted by altitude where appropriate' to 'haemoglobin concentration below a cut-off defined by trialists, adjusted by altitude where appropriate'. We also changed the name of the outcome 'any other side effects' to 'any adverse side effects' to avoid mixing negative effects such as nausea or vomiting with positive effects such as improved awareness or activity.
- Subgroup analysis: in addition to the visually examination of the forest plots, we also used the Borenstein 2008 approach to formally investigate differences between two or more subgroups. We specified that analyses were conducted in Review Manager version 5.1.1 (RevMan 2011).
Index terms
Medical Subject Headings (MeSH)
*Dietary Supplements; *Menstruation; Anemia, Iron-Deficiency [*prevention & control]; Drug Administration Schedule; Ferrous Compounds [administration & dosage]; Iron [deficiency]; Iron, Dietary [*administration & dosage]; Randomized Controlled Trials as Topic
MeSH check words
Adolescent; Adult; Female; Humans; Young Adult
* Indicates the major publication for the study


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