Iron deficiency in infants and children <12 years: Treatment

INTRODUCTION — 

Anemia affects one-fourth of the world's population, predominantly in women and children, and has important consequences for health and development. Iron deficiency is the most common cause of anemia [1]. Anemia is particularly common in Asian and sub-Saharan African nations [2,3] but is also a common condition in resource-abundant settings including the United States. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Prevalence'.)

The treatment of iron deficiency in infants and young children will be reviewed here. Related material can be found in the following topic reviews:

●(See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

●(See "Iron requirements and iron deficiency in adolescents".)

●(See "Approach to the child with anemia".)

DIAGNOSIS — 

A clinical diagnosis of iron deficiency anemia (IDA) is made by the combination of positive clinical risk factors and laboratory findings of microcytic anemia. The diagnosis is confirmed if a trial of oral iron supplementation (3 mg/kg elemental iron per day) produces a hemoglobin (Hgb) rise of ≥1 g/dL within four weeks for children with mild anemia [4] or ≥2 g/dL for those with moderate to severe anemia. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Evaluation for suspected iron deficiency anemia'.)

Prior to embarking on the empiric trial of iron supplementation, every child should have a detailed dietary history, including an assessment of milk intake and of iron-rich foods (all age groups). For young children, particularly those with a history of pica, we also suggest reviewing risk factors for lead exposure, followed by laboratory evaluation of blood lead levels, if risk factors are identified. In some cases, including for children between three years of age and adolescence, and/or children with severe anemia (<7 g/dL), additional laboratory testing beyond a complete blood count (CBC) is appropriate to ensure that the correct diagnosis has been made prior to initiating a trial of iron therapy. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Laboratory testing'.)

ORAL IRON THERAPY — 

Three steps are essential for successful treatment of iron deficiency anemia (IDA) in infants and young children:

●Appropriate dose and scheduling of oral iron therapy

●Addressing the underlying etiology of the iron deficiency, which, in young children, is most commonly nutritional and requires appropriate dietary modifications

●Follow-up assessment for response

Dose and scheduling — For infants and children with proven or suspected IDA, we suggest initiating treatment with oral ferrous sulfate, 3 mg/kg elemental iron, administered once daily. For optimal absorption, the iron should be given in the morning or between meals and with water or juice. Milk and/or dairy products should be avoided for approximately one hour before and two hours after each dose because such products limit iron absorption [5].

Standard recommended dosing is 3 to 6 mg/kg elemental iron per day. We suggest ferrous sulfate and the 3 mg/kg dose because it was effective in a randomized clinical trial of 80 young children (ages 9 to 48 months) with nutritional IDA (NCT01904864) [6]. Children who cannot tolerate ferrous sulfate due to taste may be more willing to accept a polysaccharide-iron complex formulation, resulting in better adherence. Other oral iron products are also available (table 1). Side effects are generally similar among different preparations. Some preparations such as ferrous bisglycinate may have fewer gastrointestinal side effects but are costly.

Studies in adults with nonanemic iron deficiency have demonstrated that oral iron therapy at relatively low doses or given on alternate days is effective and is better tolerated and has higher fractional absorption compared with higher doses [7,8]. Alternate-day therapy has not been evaluated in children. A few studies suggest that weekly iron-folic acid supplementation and intermittent iron supplementation may increase hemoglobin (Hgb) levels in school-age children, but optimal dosing guidelines have not been developed for these strategies [9,10].

We do not recommend the use of transdermal iron delivery systems (patch). This modality is being studied in animal models and is commercially available, but there is no clinical evidence in humans that the transdermal route is effective or safe. A study in adult athletes found that an iron patch had no effect on serum ferritin [11]. (See "Treatment of iron deficiency anemia in adults", section on 'Routes we do not use (IM, transdermal)'.)

Side effects — Side effects commonly attributed to oral iron therapy include abdominal pain, constipation, and diarrhea. However, placebo-controlled trials have demonstrated that low-dose iron supplementation (eg, 3 mg/kg) and iron-fortified formulas rarely cause gastrointestinal symptoms [12-17]. Larger doses rarely are necessary and may produce some degree of intolerance.

Oral iron is best absorbed on an empty stomach when taken with water or juice. It should not be taken with milk or other dairy and calcium-containing products, as this will lessen its absorption. Data are limited on whether taking oral iron with meals lessens gastrointestinal side effects, but it is known that taking oral iron with food will decrease absorption, thus rendering the therapy less effective.

Liquid preparations of iron occasionally cause gray or brown staining of the teeth or gums. These effects are temporary and can be avoided or minimized by administering the iron with a syringe directed toward the back of the mouth and/or brushing the child's teeth or rinsing the mouth with water after administration of the drops. Liquid iron may also stain fingernails if the child places his or her hand in the mouth after iron administration.

Iron therapy appears to have mixed effects on immune function and susceptibility to infection. There is no evidence that iron supplementation increases the risk for infection, with the possible exception of special populations in which malaria is endemic if initiated during high-transmission seasons. Studies in a cohort of Kenyan infants found that iron deficiency at the time of vaccination predicted decreased response, as measured by vaccine antibody titers, and that iron supplementation at the time of vaccination may improve the primary immune response [18]. These findings suggest that improved iron status allows for optimal immunologic response to vaccines. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Associated disorders and effects of treatment'.)

Dietary changes — For children with proven or suspected IDA, in addition to therapeutic iron supplementation, we suggest the following dietary changes, which are also used to prevent iron deficiency (table 2). (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Dietary recommendations'.)

●All infants (<12 months of age) should either be breastfed or receive iron-fortified formula. Infants should not be given low-iron formula or cow's milk. Infants consuming cow's milk (rather than formula or breastfeeding) may have increased risk for cow's milk protein-induced colitis with associated intestinal blood loss. The resulting iron deficiency is exacerbated by lack of iron fortification in cow's milk. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Dietary factors'.)

●Infants six months and older, especially breastfed infants, require iron-rich complementary foods including iron-fortified infant cereals and pureed meats. Plant-based food sources rich in nonheme iron include legumes (eg, lentils, black beans, chickpeas) and dark, leafy vegetables such as spinach (table 3). Iron absorption is enhanced by including foods rich in vitamin C.

●For all children 12 months of age and older, intake of cow's milk (or plant-based milk such as almond or soy) should be limited to less than 20 oz per day. Higher intake of cow's milk in toddlers is associated with increased risk for iron deficiency [19,20]. When iron deficiency is first detected or suspected, the toddler's diet should be promptly evaluated and steps taken to reduce milk intake to below this threshold. If the child is still bottle-fed, discontinuation of the bottle will help to limit milk intake and encourage intake of other foods [21]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Dietary factors'.)

For those with persistent or refractory IDA despite dietary changes and an appropriate period on therapeutic iron supplementation, assessment for gastrointestinal blood loss is warranted.

Follow-up assessment for response — All children should have follow-up laboratory testing to determine their response to therapeutic iron. This is important to monitor for adherence to therapy and to identify children who fail to demonstrate an appropriate response to therapy. Children who do not respond to oral iron therapy should be provided additional support to optimize adherence, further evaluation to determine the cause of the anemia, and consideration of parenteral therapy [22]. Laboratory testing should be performed when the child is healthy, without signs of an acute or recent illness, because infection may cause a transient decrease in Hgb.

The timing of follow-up testing depends on the severity of the IDA:

●Mild anemia (Hgb ≥10 g/dL) – Reevaluate approximately four weeks after treatment initiation by checking Hgb or complete blood count (CBC).

●Moderate (Hgb ≥7 to <10 g/dL) or severe anemia (Hgb <7 g/dL) – Reevaluate 7 to 10 days after treatment initiation to assess initial response to therapy by checking CBC and reticulocyte count. An appropriate response is demonstrated by reticulocytosis and increment in Hgb.

Children presenting with moderate to severe IDA in acute care settings are at higher risk for being lost to follow-up. Thus, early follow-up should be arranged to confirm that treatment has been started and assess tolerance and adherence.

Responders — An adequate initial response to therapeutic iron is reflected by the following results:

●Mild anemia (Hgb ≥10 g/dL) – The Hgb should improve to within the normal range within four weeks of treatment initiation [4].

●Moderate (Hgb ≥7 to <10 g/dL) or severe anemia (Hgb <7 g/dL) – The Hgb should rise at least 1 g/dL within the first two weeks of treatment initiation and >2 g/dL within four weeks. If testing is performed earlier, a reticulocyte response peaks at seven days but may be seen as soon as 72 hours after treatment initiation.

For patients who respond to treatment as described above, therapeutic iron should be continued for at least three months. Additional testing should be performed approximately three months after initiation of iron therapy, including a CBC, paying particular attention to the Hgb, mean corpuscular volume (MCV), and red blood cell distribution width (RDW). Measurement of serum ferritin concentration also may be helpful to determine the need for further iron therapy to replenish iron stores. Many children require longer treatment courses to replenish iron stores.

In general, we suggest continuing iron therapy for approximately one month after all CBC parameters have normalized (Hgb, MCV, and RDW) or upon achieving a serum ferritin value of >20 ng/mL, provided that the appropriate dietary changes have been made. Early discontinuation of iron therapy and/or lack of improvement in the diet frequently lead to recurrent IDA.

Nonresponders — Patients who do not demonstrate an adequate rise in Hgb as described above should be reevaluated. Potential causes of recurrent or refractory IDA include ineffective treatment (nonadherence or incorrect dosing), persistent low-iron diet (eg, ongoing excessive milk intake), an incorrect diagnosis, or ongoing blood loss or malabsorption (table 4) [22]. The clinician should interview the parent or caregiver to determine whether the supplement has been given at the appropriate dose and timing, whether the appropriate diet modifications have been made, and if there has been any significant intercurrent illness (which might cause a transient decrease in Hgb).

If the patient has indeed been taking an appropriate dose of iron and has not had an intercurrent illness, we suggest the following additional evaluation:

●Evaluation for other causes of anemia – The three most common causes of microcytic anemia in children are IDA, alpha or beta thalassemia trait, and anemia of chronic inflammation (also known as anemia of chronic disease) (table 5). These conditions can be assessed by measuring serum ferritin, Hgb analysis (to assess for beta thalassemia trait), and C-reactive protein (CRP), respectively. Newborn screening results should be reviewed to determine whether any abnormal Hgb were present. Elevated levels of Hgb Barts (on newborn screening) or Hgb H suggest the possibility of a form of alpha thalassemia. Alpha thalassemia trait (also known as alpha thalassemia minima) cannot be detected by Hgb analysis after the newborn period. Less common causes of mild microcytic anemia include Hgb C and Hgb E, which will be detected on Hgb analysis. (See "Diagnosis of thalassemia (adults and children)".)

In children with both thalassemia trait (alpha or beta) and iron deficiency, sufficient treatment of the iron deficiency is necessary to ensure accurate Hgb analysis results.

●Evaluate for gastrointestinal blood loss – Patients with persistent IDA despite appropriate dietary changes and iron therapy for at least three months should be evaluated with a careful clinical history to assess for potential disorders that may cause gastrointestinal blood loss. Further testing depends on the suspected disorder and can be done before or after referral to a pediatric gastroenterologist (where available). Some clinicians initiate the evaluation by testing three stool samples for occult blood. However, it is also reasonable to skip this step and base testing decisions on the clinical history and symptoms. Oral iron supplements cause false-positive results for some traditional kits for occult blood testing. However, this is not the case for contemporary test kits (eg, Hemoccult II, Hemoccult Sensa, HemoQuant), so there is no need to suspend oral iron supplements during testing if these kits are used [23-25].

The following disorders should be considered, depending on the patient's age and characteristics (see "Lower gastrointestinal bleeding in children: Causes and diagnostic approach"):

•Cow's milk protein-induced colitis – This disorder may cause occult blood loss in infants whose diet is primarily cow's milk. It can also occur in breastfed infants whose mother's diet includes cow's milk or in infants fed cow's milk-based formulas. The colitis generally responds to elimination of all milk protein from the diet of the infant and/or from the mother's diet if the infant is breastfed. (See "Food protein-induced allergic proctocolitis of infancy".)

•Celiac disease – Celiac disease may be a cause of refractory IDA in children and is more common in older children compared with toddlers. Screening for celiac disease is performed using tissue transglutaminase antibodies (tTG). Other steps in the diagnosis of celiac disease, including upper endoscopy, are discussed separately. (See "Diagnosis of celiac disease in children", section on 'Pretesting diet'.)

•Inflammatory bowel disease – Anemia is a common complication of active inflammatory bowel disease. Patients may present initially with IDA or a combination of IDA and anemia of chronic inflammation, usually in association with other symptoms such as loose stools (with or without gross blood) and/or growth failure. Most children with inflammatory bowel disease are diagnosed in late childhood or adolescence, but a few present in early childhood or even infancy. Measurement of a CBC, iron panel, erythrocyte sedimentation rate (ESR), CRP, and serum albumin, as well as fecal occult blood and calprotectin, serve as an initial screen. However, a more detailed evaluation including endoscopy is warranted in children with clinical features suggesting inflammatory bowel disease. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

●Consider rare causes of anemia – Extremely rare genetic mutations that interfere with iron transport result in a moderate to severe anemia that has hematologic parameters identical to IDA but is refractory to iron supplementation; this condition is termed iron-refractory iron deficiency anemia (IRIDA) [26] (see "Determining the cause of iron deficiency in adolescents and adults", section on 'Inherited disorders/IRIDA'). IRIDA is unlikely in children with a history of a normal CBC and iron parameters prior to the onset of iron deficiency. We recommend performing an oral iron absorption test prior to consideration of genetic testing for IRIDA. The iron regulatory hormone hepcidin, which is elevated in patients with IRIDA, is now also a clinically available laboratory test. (See "Approach to the child with anemia".)

INTRAVENOUS IRON THERAPY — 

During the past three decades, new forms of intravenous (IV) iron therapy with good safety profiles have become available. Nonetheless, IV iron is generally considered second-line therapy for the majority of patients with iron deficiency anemia (IDA) due to its high cost, as well as potential for adverse effects, though rare [27]. Indications for IV iron therapy include persistent anemia with oral iron intolerance, malabsorption, or nonadherence to oral iron therapy despite attempts at family/caregiver education and support. Children with ongoing or poorly controlled blood loss such as dysfunctional uterine bleeding may benefit from IV iron therapy. Those with underlying gastrointestinal disease, including conditions causing intestinal failure (eg, short bowel syndrome) or inflammatory bowel disease, may have particular difficulty tolerating oral iron and require early initiation of IV iron therapy. IV iron therapy may also benefit patients with other chronic conditions such as heart failure.

The following four IV iron preparations are approved by the US Food and Drug Administration for use in pediatrics. Selection among these options may depend on relative costs/insurance coverage and availability, time required for administration, and maximum permissible dose per infusion.

●Iron sucrose – Iron sucrose (Venofer) is a common form of IV iron utilized in children [28]. Rates of adverse events including anaphylaxis are very low in this formulation when given in low doses. No test dose or routine premedications are required. Dosing depends on weight (maximum dose of 100 to 300 mg, depending on the size of the child). As a result, most patients require multiple infusions to complete replacement of their calculated iron deficit.

●Iron dextran – Low-molecular weight (LMW) iron dextran (INFeD) is commonly given off label as a single replacement dose (eg, up to 1000 mg elemental iron in adults) [29]. A protocol for a test dose and replacement dose in pediatric patients is outlined in the related drug monograph (see "Iron dextran: Pediatric drug information"). Routine premedication with corticosteroids may be considered. Minor self-limiting infusion reactions occur in less than 1 percent of patients. Serious adverse events such as anaphylaxis are extremely rare [29]. (See "Treatment of iron deficiency anemia in adults", section on 'LMW iron dextran'.)

High molecular weight iron dextran (Dexferrum) should not be used, because of higher rates of adverse events such as anaphylaxis; it is no longer available in the United States.

●Ferric carboxymaltose – Ferric carboxymaltose (Injectafer) is approved for patients who are intolerant to oral iron therapy and also permits administration of the full replacement dose in a single infusion (maximum 750 mg) in many patients [30]. Two doses may be required in some individuals (eg, hemoglobin [Hgb] 2 g/dL or more below the normal threshold for age) [31]. Studies have demonstrated a good hematologic response and low rates of adverse effects in children with IDA due to a variety of causes and who failed oral iron therapy including inflammatory bowel disease, intestinal failure, and other gastrointestinal conditions [31-33].

Hypophosphatemia is a common complication in adults treated with ferric carboxymaltose; it was reported in more than one-half of treated adults from two large trials [34]. In a retrospective study of 225 children treated with ferric carboxymaltose, 40 (18 percent) developed hypophosphatemia within six weeks after the infusion [35]. Among the 40 children who developed hypophosphatemia, all were asymptomatic; eight (4 percent) received supplemental phosphorus. In the majority of patients, hypophosphatemia is transient. (See "Treatment of iron deficiency anemia in adults", section on 'Ferric carboxymaltose'.)

●Ferric gluconate – Ferric gluconate (Ferrlecit) is another form of IV iron with a similar profile to iron sucrose including low rates of adverse events. No test dose or routine premedications are indicated. It is approved for children with chronic kidney disease on dialysis and erythropoietic-stimulating agents. The maximum dose is 125 mg elemental iron per infusion.

Ferumoxytol and ferric derisomaltose are also approved in the United States for use in adult patients. Both of these formulations allow for larger doses to be administered per infusion. Data on the use in children are limited. (See "Treatment of iron deficiency anemia in adults".)

Response to treatment with IV iron may be assessed in the same manner as that of oral iron therapy (complete blood count [CBC], reticulocyte count). Repeat iron studies should be assessed no earlier than six weeks after IV iron infusion because some iron parameters, specifically serum ferritin, may be elevated initially after IV iron infusion as the iron is utilized for erythropoiesis and incorporated into iron storage sites. (See 'Follow-up assessment for response' above.)

BLOOD TRANSFUSION — 

Transfusion therapy may be indicated for children with very severe iron deficiency anemia (IDA; hemoglobin [Hgb] concentration is <5 g/dL). These patients are at risk for serious short-term morbidity and mortality, such as cardiac failure, stroke, and even death [36], which could be prevented by stabilization with transfusion. Children with complicated comorbid conditions may benefit from transfusion at a higher Hgb threshold. In this setting, transfusions should be administered with caution to avoid fluid overload and heart failure, giving transfusion volumes in small aliquots. As examples, give 4 mL/kg in a child with an Hgb 4 g/dL or 5 mL/kg in a child with Hgb 5 g/dL, over three to four hours. (See "Red blood cell transfusion in infants and children: Indications" and "Red blood cell transfusion in infants and children: Administration and complications".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric iron deficiency".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Low iron in children – Discharge instructions (The Basics)" and "Patient education: Good food sources of iron (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Empiric trial of iron therapy

•For children with presumed iron deficiency anemia (IDA; on the basis of history and initial laboratory testing), we suggest an empiric trial of oral iron therapy and dietary changes rather than either intervention alone (Grade 2C):

-To initiate oral iron therapy, we suggest a dose of 3 mg/kg of elemental iron once daily (table 1), rather than higher doses (Grade 2C). A 3 mg/kg dose of ferrous sulfate is generally effective and is tolerated by most children. For optimal absorption, the iron should be given in the morning or between meals and with water or juice. Milk and/or dairy products should be avoided for approximately one hour before and two hours after each dose. (See 'Dose and scheduling' above.)

●Dietary changes – Meanwhile, the following dietary goals should be implemented to prevent recurrence (table 2) (see 'Dietary changes' above):

•Infants (<12 months of age) should be fed with breast milk or iron-fortified formula. Infants should not be given low-iron formula or cow's milk.

•For patients six months and older, especially breastfed infants, ensure adequate consumption of iron in complementary foods. These include infant cereals, which are fortified with iron, foods rich in vitamin C, and pureed meats.

•For children older than 12 months of age, intake of milk (cow, almond, or soy) should be limited to less than 20 oz per day and bottle feeding should be discontinued to limit milk intake. Excessive milk intake is the primary reason for the development of IDA in this age group and can be associated with occult intestinal blood loss.

●Follow-up and monitoring – After beginning therapeutic iron, perform follow-up testing to determine the response, consisting of a complete blood count (CBC) or hemoglobin (Hgb) and reticulocyte count. The testing should be performed when the child is healthy, approximately four weeks after beginning iron therapy for children with mild anemia or one to two weeks after beginning iron therapy in those with moderate to severe anemia. Follow-up is essential to confirm that the anemia was due to iron deficiency and to ensure that it is adequately treated. (See 'Follow-up assessment for response' above.)

●Management of responders – If the Hgb has increased by 1 g/dL within four weeks (or 2 g/dL in moderate to severe anemia), therapy is continued for at least three months, at which time, the CBC is retested. Iron therapy should be given for at least three months, and many children require longer treatment courses to replenish iron stores. In general, iron therapy should be continued for at least one month after the Hgb reaches the age-adjusted normal range. If possible, a serum ferritin concentration should be measured to check iron stores prior to discontinuation of iron therapy, with a goal of raising serum ferritin to ≥20 ng/mL. (See 'Responders' above.)

●Further evaluation for nonresponders – Patients who do not demonstrate an adequate response within four weeks of initiating iron therapy should be reevaluated. Potential causes of recurrent or refractory IDA include ineffective treatment (nonadherence or incorrect dosing), ongoing low-iron diet (eg, excessive milk intake), an incorrect diagnosis, or ongoing blood loss or malabsorption (table 4). Our approach is as follows:

•Interview the parent or caregiver to determine whether the iron therapy has been given at the appropriate dose and timing, whether the appropriate diet modifications have been made, and if there has been any significant intercurrent illness (which might cause a transient decrease in Hgb). The most common reason for failure is that the treatment plan was not correctly followed. (See 'Nonresponders' above.)

•If the patient has indeed been taking an appropriate dose of iron and has not had an intercurrent illness, assess detailed dietary history and/or perform additional laboratory tests to confirm the diagnosis (eg, iron testing, if not previously performed) and rule out conditions that might simulate or complicate IDA (eg, thalassemia trait or anemia of chronic disease) (table 5). In addition, children with persistent or recurrent IDA despite appropriate dietary changes and iron therapy should be evaluated for gastrointestinal blood loss; key considerations are cow's milk protein-induced colitis in infants and celiac disease or inflammatory bowel disease in older children. (See 'Nonresponders' above.)

●Intravenous (IV) iron therapy – IV iron therapy may be warranted for patients with severe or persistent anemia who have proven oral iron intolerance, malabsorption, or nonadherence despite family/caregiver education and support to optimize oral therapy. Several forms of IV iron therapy with good safety profiles are available for use in pediatrics. Selection among these options may depend on relative costs and availability, time required for administration, and maximum permissible dose per infusion. (See 'Intravenous iron therapy' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Donald H Mahoney, Jr, MD, who contributed to earlier versions of this topic review.