Amy G. Cantor, MD, MPH; Christina Bougatsos, MPH; Tracy Dana, MLS; Ian Blazina, MPH; Marian McDonagh, PharmD
Disclaimer: The investigators are solely responsible for the content of this article and the decision to submit it for publication. The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of the AHRQ. No statement in this report should be construed as an official position of the AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank the AHRQ Medical Officers Tina Fan, MD, MPH, and Iris Mabry-Hernandex, MD, MPH, as well as the USPSTF Leads: David Grossman, MD, MPH; Glenn Flores, MD; Francisco García, MD, MPH; Alex Kemper, MD, MPH, MS; and Virginia Moyer, MD, MPH.
Financial Support: By the AHRQ under contract no. HHSA290201200015i, task order no. 2, to support the work of the USPSTF.
Disclosures: Ms. Bougatsos reports that this manuscript is based on a larger review funded by the Agency for Healthcare Research and Quality. Ms. Dana reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Mr. Blazina reports support from the Agency for Healthcare Research and Quality for a larger report upon which this manuscript is based. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/Conflict OfInterestForms.do?msNum=M14-2932.
Requests for Single Reprints: Reprints are available from the Pacific Northwest Evidence Based Practice Center, Evidence-based Practice Center, Oregon Health & Science University, Mail Code BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098.
Current Author Addresses: Drs. Cantor and McDonagh, Ms. Bougatsos, Ms. Dana, and Mr. Blazina: Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mail Code BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098.
Author Contributions: Conception and design: A.G. Cantor, C. Bougatsos, M. McDonagh.
Analysis and interpretation of the data: A.G. Cantor, C. Bougatsos, I. Blazina, M. McDonagh.
Drafting of the article: A.G. Cantor, C. Bougatsos, I. Blazina, M. McDonagh.
Critical revision of the article for important intellectual content: A.G. Cantor, I. Blazina, M. McDonagh.
Final approval of the article: A.G. Cantor, C. Bougatsos, I. Blazina, M. McDonagh.
Statistical expertise: A.G. Cantor.
Administrative, technical, or logistic support: A.G. Cantor, C. Bougatsos, T. Dana, I. Blazina.
Collection and assembly of data: A.G. Cantor, C. Bougatsos, I. Blazina.
Cantor AG, Bougatsos C, Dana T, Blazina I, McDonagh M. Routine Iron Supplementation and Screening for Iron Deficiency Anemia in Pregnancy: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:566-576. doi: 10.7326/M14-2932
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Published: Ann Intern Med. 2015;162(8):566-576.
Routine screening and supplementation for iron deficiency anemia (IDA) in asymptomatic, nonanemic pregnant women could improve maternal and infant health outcomes.
Update of a 2006 systematic review by the U.S. Preventive Services Task Force on screening and supplementation for IDA in pregnancy.
MEDLINE and the Cochrane Library (1996 to August 2014) and reference lists of relevant systematic reviews to identify studies published since 1996.
English-language trials and controlled observational studies about effectiveness of screening and routine supplementation for IDA in developed countries.
Data extraction and quality assessment confirmed and dual-rated by a second investigator using prespecified criteria.
No study directly compared clinical outcomes or harms of screening or not screening pregnant women for IDA. Twelve supplementation trials were included, and no controlled observational studies met inclusion criteria. On the basis of 11 trials, routine maternal iron supplementation had inconsistent effects on rates of cesarean delivery, small size for gestational age, and low birthweight and no effect on maternal quality of life, gestational age, Apgar scores, preterm birth, or infant mortality. Twelve trials reported improvements in maternal hematologic indices, although not all were statistically significant. Pooled analysis of 4 trials resulted in a statistically significant difference in IDA incidence at term, favoring supplementation (risk ratio, 0.29 [95% CI, 0.17 to 0.49]; I2 = 0%). Maternal iron supplementation did not affect infant iron status at 6 months. Harms, none of which were serious or had long-term consequences, were inconsistently reported in 10 of the trials, with most finding no difference between groups.
Data from trials in countries with limited generalizability to U.S. populations were included. Studies were methodologically heterogeneous, and some were small and underpowered.
There is inconclusive evidence that routine prenatal supplementation for IDA improves maternal or infant clinical health outcomes, but supplementation may improve maternal hematologic indices.
Agency for Healthcare Research and Quality.
Analytic framework for routine iron supplementation in pregnant women.
KQ = key question.
Analytic framework for screening for iron deficiency anemia in pregnant women.
Appendix Table 1. Search Strategies
Summary of evidence search and selection.
* Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews.
† Prior reports, reference lists of relevant articles, and systematic reviews.
‡ Some studies are included for >1 KQ.
§ Poor-quality studies were excluded because good- and fair-quality evidence was available.
Appendix Table 2. Infant Birth Outcomes*
Meta-analysis: preterm delivery.
M–H = Mantel–Haenszel.
Meta-analysis: low birthweight.
Appendix Table 3. Maternal Hematologic Outcomes*
Meta-analysis: iron deficiency anemia and iron deficiency at term.
* Includes 2 studies that used 20- and 60-mg dosing. Reference 36 was excluded from the analysis because the study used 200-mg dosing. M–H = Mantel–Haenszel.
Appendix Table 4. Maternal Adverse Events
Table. Summary of Evidence
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Robert C Kane
April 23, 2015
Routine iron supplementation in pregnancy
To interpret the results of the trials, we need to know one additional fact. Did the women in fact take their iron pills during their pregnancy? If that fact is not known, the trials cannot be interpreted. I've been told, although I have no first hand experience, that taking iron pills while pregnant is a daunting task. At best, using the ITT population, we could conclude that the trials, as designed and conducted, did not demonstrate a benefit. It does not mean that there is none.
April 24, 2015
Iron supplementation in pregnancy
One more point to make when this same question is evaluated in observational studies, where the concepts of "exposure" and "outcome" are explored. To my knowledge, the "exposure" actually consists of exposure to the drug prescription, not to the drug. It would be great if the researchers, usually non-clinicians, would include that tiny tweak to their reports. The ITT analysis is superb at protecting type 1 errors, but does not intrinsically assure that we know exactly what treatment was received by the subjects.
Amy G. Cantor, MD, MPH; Christina Bougatsos, MPH, Marian McDonagh, PharmD
Pacific Northwest Evidence Based Practice Center, Oregon Health & Science University
June 12, 2015
Routine Iron supplementation in pregnancy
Dr. Kane suggests that we need to further understand adherence to accurately interpret trial results for iron supplementation in pregnant women. We provided data on adherence (or rather non-adherence) in the attached Appendix Table 4 of our manuscript (1). For the supplementation studies, adherence, usually based on pill counts or an equation involving pill counts, was variably reported and ranged from 54% to 98%. Seven of 10 studies reported adherence. While six found no difference in adherence between the groups, the seventh demonstrated significantly greater adherence in the iron supplementation group (97.8% versus 83.9%, p=0.036), (2). This study states that their adherence corresponds to a “range of 19-74 mg/day in women’s average intake of elemental iron during the study period,” which encompasses the 30 mg/day (60-100 mg/day in high risk) often recommended for supplementation. To clarify, the studies in our analysis were randomized controlled trials; no observational studies were included in our results. Therefore, the exposure in the treatment group for the trials was the actual supplements, not the prescription. We agree with Dr. Kane that it is helpful to understand the intention to treat approach to assess the benefit of iron supplementation, but also believe that to fully understand the outcomes of the trials we also need to make a distinction between the efficacy of the intervention and the effectiveness. We were reporting on effectiveness of prenatal iron supplementation, not the efficacy. In evaluating efficacy of an intervention, adherence to the assigned regimen is required as a part of the study concept. However, in evaluating effectiveness, real-world adherence, similar to using the intention to treat analysis, provides the most accurate picture. While adherence may certainly contribute to the effectiveness of iron supplementation, any issues related to lack of adherence is an assumed limitation of supplementation trials in general. References: 1. Cantor AG, Bougatsos C, Dana T, Blazina I, McDonagh M. Routine Iron Supplementation and Screening for Iron Deficiency Anemia in Pregnancy: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:566-576. doi:10.7326/M14-29322. Meier PR, Nickerson HJ, Olson KA, Berg RL, Meyer JA. Prevention of iron deficiency anemia in adolescent and adult pregnancies. Clin Med Res. 2003;1(1):29-36. PMID: 15931282.
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