Iron supplements in pregnant women with normal iron status: A systematic review and meta-analysis.

INTRODUCTION: Effects of daily iron supplementation in iron replete pregnancy are unclear. This systematic review aimed to assess benefits and harms of oral iron supplements in pregnant women without anemia and iron deficiency. MATERIAL AND METHODS: We predefined and registered a protocol in PROSPERO (CRD42020186210) and performed the review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We searched for randomized clinical trials (RCTs) and observational studies comparing daily oral iron supplementation with no iron supplements in non-anemic iron replete pregnant women. Searches were conducted in MEDLINE (by PubMed), EMBASE (by OVID), Cochrane Library, and ClinicalTrials.gov from inception to September 2022 without language restrictions. Two authors independently screened records, extracted data, and assessed risk of bias using the revised Cochrane risk of bias tool (RoB2). One author read full-texts, assessed certainty of evidence by GRADE and conducted meta-analyses using a random-effects model. Primary outcomes included iron deficiency anemia, iron deficiency, hemoglobin >130 g/L, elevated iron status, small for gestational age newborns, low birthweight newborns, preterm birth, and congenital anomalies. RESULTS: Eight RCTs (2822 women) but no observational studies were eligible for inclusion. Daily oral iron supplementation in pregnancy probably reduces iron deficiency anemia at term (risk ratio [RR]: 0.51, 95% confidence interval [CI]: 0.38-0.70; 4 RCTs, 1670 women; I2 = 13%; moderate-certainty evidence) and the incidence of low birthweight babies (RR: 0.30, 95% CI: 0.13-0.68; 2 RCTs, 361 infants; I2 = 0%; moderate-certainty evidence). In addition, it may reduce iron deficiency at term (RR: 0.74, 95% CI: 0.60-0.92; 4 RCTs, 1663 women; I2 = 58%; low-certainty evidence) and the incidence of small for gestational age babies (RR: 0.39, 95% CI: 0.17-0.86; 1 RCT, 213 infants; I2 not estimable; low-certainty evidence). CONCLUSIONS: Daily iron supplementation in iron replete non-anemic pregnant women probably reduces the risk of maternal iron deficiency anemia at term and low birthweight.

Intravenous ferric derisomaltose versus oral iron for persistent iron deficient pregnant women: a randomised controlled trial.

PURPOSE: To compare the efficacy of intravenous (IV) iron (ferric derisomaltose) with oral iron (ferrous fumarate) in women 14-21 weeks pregnant with persistent iron deficiency (ferritin < 30 µg/L). METHODS: In a single-centre, open-label, randomised controlled trial at a Danish hospital, women with persistent iron deficiency after routine oral iron treatment were allocated to receive 1000 mg IV iron (single-dose) or 100 mg elemental oral iron daily. Outcomes were assessed during an 18-week follow-up period. The primary endpoint was the proportion of non-anaemic (haemoglobin [Hb] ≥ 11 g/dL) women throughout follow-up. Other outcomes included changes in haematological parameters, patient-reported fatigue, and quality of life (QoL). Safety was assessed by recording adverse events. RESULTS: From July 2017 to February 2020, 100 women were randomised to IV iron and 101 to oral iron. Throughout follow-up, 91% of women were non-anaemic in the IV iron group compared with 73% in the oral iron group (18% difference [95% confidence interval 0.10-0.25]; p < 0.001). The mean Hb increase was significantly greater with IV iron versus oral iron at Weeks 6 (0.4 versus - 0.2 g/dL; p < 0.001), 12 (0.5 versus 0.1 g/dL; p < 0.001), and 18 (0.8 versus 0.5 g/dL; p = 0.01). Improvements in fatigue and QoL were greater with IV iron versus oral iron at Weeks 3 and 6. The incidence of treatment-related adverse events was comparable between treatment groups. CONCLUSION: IV iron was superior in preventing anaemia compared with oral iron in pregnant women with persistent iron deficiency; biochemical superiority was accompanied by improved fatigue and QoL. CLINICAL TRIAL REGISTRATION: European Clinical Trials Database: EudraCT no.: 2017-000776-29 (3 May 2017); ClinicalTrials.gov: NCT03188445 (13 June 2017). The trial protocol has been published: https://dx.doi.org/10.1186%2Fs13063-020-04637-z .

Maternal first trimester iron status and its association with obstetric and perinatal outcomes.

PURPOSE: To assess the following in singleton pregnant women: (1) associations between first trimester iron deficiency and obstetric and perinatal outcomes, (2) overall first trimester iron status and (3) post-treatment iron status after intensified iron supplementation. METHODS: A prospective cohort study was conducted with linkage of first trimester hemoglobin and plasma ferritin with obstetric and perinatal data from a hospital database. Blood sample data were obtained from a Danish University Hospital. The cohort was divided into groups according to ferritin and hemoglobin: (1) iron-deficient anemic (ferritin < 30 ng/mL and Hb < 110 g/L), (2) iron-deficient non-anemic (ferritin < 30 ng/mL and Hb ≥ 110 g/L), and (3) iron-replete non-anemic (ferritin 30-200 ng/mL and Hb ≥ 110 g/L). Obstetric and perinatal outcomes in each iron-deficient group were compared to the iron-replete non-anemic group using multivariable logistic regression. The effect of 4 weeks intensified iron supplementation on hemoglobin and ferritin was assessed by groupwise comparisons. RESULTS: The cohort comprised 5763 singleton pregnant women, of which 14.2% had non-anemic iron deficiency, and 1.2% had iron-deficiency anemia. Compared to iron-replete non-anemic women, iron-deficient anemic women had a higher risk of gestational diabetes (aOR 3.8, 95% CI 1.4-9.0), and iron-deficient non-anemic women had a higher risk of stillbirth (aOR 4.0, 95% CI 1.0-14.3). In group 1 and 2, 81.5% and 67.7% remained iron-deficient after intensified iron supplementation. CONCLUSION: Iron-deficiency anemia was associated with gestational diabetes, and non-anemic iron deficiency with stillbirth, although risk estimates were imprecise due to few events. Iron deficiency was present in 15.4% and often persisted despite 4 weeks intensified iron supplementation.

Intravenous iron isomaltoside versus oral iron supplementation for treatment of iron deficiency in pregnancy: protocol for a randomised, comparative, open-label trial.

BACKGROUND: Iron deficiency is common in pregnancy. If left untreated, iron deficiency can lead to iron deficiency anaemia, which is a condition related to maternal and neonatal morbidity. The prevalence of iron deficiency increases through the trimesters, which means that women with iron deficiency in the beginning of pregnancy also have a great risk of developing iron deficiency anaemia during pregnancy. Standard treatment is oral iron in individualised intensified doses based on screening values in 1st trimester. Maternal symptoms of iron deficiency and iron deficiency anaemia include fatigue, reduced physical performance, and restless legs syndrome (RLS). Severe anaemia may cause dizziness, dyspnea, palpitation, orthostatism, and syncope, and it decreases the woman's ability to cope with blood loss during delivery. The anaemia may also compromise contractility in the uterine musculature increasing the risk for prolonged labour, caesarean section, and postpartum haemorrhage. Foetal iron deficiency may cause low birthweight and adversely affect foetal and early childhood brain development with long-term deficits. METHODS: In this randomised comparative, open-label, single-centre, phase IV trial, 200 pregnant women between 14 and 21 weeks of gestation who have iron deficiency after 4 weeks of standard treatment will be randomised 1:1 to either a single 1000 mg dose of intravenously administered ferric derisomaltose/iron isomaltoside 1000 or a fixed dose of 100 mg oral ferrous fumarate containing 60 mg ascorbic acid. The primary endpoint is to prevent iron deficiency anaemia defined by a low level of haemoglobin throughout the trial. Other endpoints include other haematological indices of iron deficiency and anaemia, clinical outcomes by questionnaires, and collection of adverse events. Explorative endpoints by medical record follow-up include complications up to 7 days after delivery. DISCUSSION: This trial will provide evidence on how to prevent iron deficiency anaemia. The trial population represents a clinical reality where pregnant women often have sustained iron deficiency despite an increased oral iron dose. Thus, this evidence can be used to consider the optimal 2nd line of treatment in iron-deficient pregnant women. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database 2017-000776-29. Registered on 3 May 2017. ClinicalTrials.gov NCT03188445 . Registered on 15 June 2017.