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Anemia in pregnancy

Anemia in pregnancy
Literature review current through: Jan 2024.
This topic last updated: Nov 22, 2023.

INTRODUCTION — Anemia in pregnancy is a global health problem. While some degree of dilutional anemia is part of normal pregnancy physiology, anemia can have serious adverse health consequences for the mother and child. Thus, it is critical to distinguish iron deficiency anemia from physiologic anemia, as well as to identify other less common causes of anemia that may require treatment.

This topic discusses an approach to evaluating and treating anemia during pregnancy. The general approach to anemia in adults and children and the diagnosis of iron deficiency in other populations are discussed in separate topic reviews:

General approach to anemia – (See "Diagnostic approach to anemia in adults" and "Approach to the child with anemia".)

Diagnosis of iron deficiency in children and adolescents – (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents".)

Diagnosis of iron deficiency in adults – (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

DEFINITION OF ANEMIA — Definitions of anemia are different during pregnancy compared with nonpregnant individuals, and the lower limit of normal for the hemoglobin concentration may vary in different populations. However, it is helpful to have a threshold for determining the presence and severity of anemia. We do not use different thresholds for different racial or ethnic groups, as discussed separately. (See "Diagnostic approach to anemia in adults", section on 'Anemia definitions'.)

Anemia in pregnancy can be defined as follows, based mostly on data in nonpregnant individuals [1-3]:

First trimester – Hemoglobin <11 g/dL (approximately equivalent to a hematocrit <33 percent)

Second trimester – Hemoglobin <10.5 g/dL (approximate hematocrit <32 percent)

Third trimester – Hemoglobin <11 g/dL (approximate hematocrit <33 percent)

Postpartum – Hemoglobin <10 g/dL (approximate hematocrit <30 percent)

The definition of postpartum anemia as hemoglobin <10 g/dL is based on a guideline from the United Kingdom, as proposed by the World Health Organization (WHO) and is largely consistent with other guidelines [4].

Some individuals may have a significant decrease from baseline without crossing these thresholds, and clinical judgment is required to determine the reason(s) for the decrease and the need for (and aggressiveness of) further evaluation. As examples:

For an individual with a baseline hemoglobin of 14 g/dL that decreases to 11 g/dL associated with macrocytosis, it is reasonable to check a reticulocyte count and test for vitamin B12 and folate deficiencies.

For an individual with a baseline hemoglobin of 14 g/dL that decreases to 11 g/dL without macrocytosis, it is reasonable to test for iron deficiency and vitamin B12 and folate deficiencies.

For a postpartum individual, iron parameters may be more meaningful than hemoglobin concentration. (See 'Postpartum' below.)

EPIDEMIOLOGY AND HEALTH CARE DISPARITIES

Prevalence of anemia — An estimated 30 percent of reproductive-age females are anemic [5,6]. Among those who are pregnant, the prevalence is even higher; the World Health Organization (WHO) estimates that over 40 percent of pregnancies are complicated by anemia [7].

Variations in regional and global prevalence of anemia during pregnancy reflect socioeconomic status and associated nutritional deficiencies [8].

Data from the WHO provide estimates of pregnancy-associated anemia in various global regions over time [9]. Data from 2019 included the following rates of anemia during pregnancy:

Southeast Asia – 48 percent

Africa – 46 percent

Eastern Mediterranean – 37 percent

Europe – 24 percent

Americas – 19 percent

The overwhelming majority of anemia in reproductive-age females is due to low or absent iron stores, making iron deficiency anemia the world's most common anemia. The incidence of iron deficiency anemia in the United States, Western Europe, and other high-resource regions of the world, while substantial, is lower than in low-resource regions. Iron deficiency anemia remains a formidable problem worldwide. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Epidemiology'.)

In addition to iron deficiency anemia, a large number of gravidas have iron deficiency without anemia (low iron stores that have not yet caused anemia). (See 'Supporting evidence for risk of iron deficiency and recommendations of others' below.)

Racial disparities — Racial disparities in the prevalence of anemia are largely due to higher rates of iron deficiency in Black individuals with less access to healthy foods, education, and safe environments; increased exposure to infectious diseases, poverty, and stress; and reduced health care access, especially screening for heavy menstrual bleeding [10].

A 2023 cohort study of nearly 4 million births in the state of California during the period from 2011 through 2020 documented that antepartum anemia was most common in Black individuals (22 percent), followed by Pacific Islanders (18 percent), Native American and Alaska Native peoples (14 percent), multiracial individuals (14 percent), Hispanic individuals (13 percent), Asian individuals (11 percent) and White individuals (10 percent) [11]. During the study period, the prevalence of anemia in Black individuals doubled. Antepartum anemia was associated with an approximately threefold increase in the risk of severe maternal morbidity (SMM) across all groups and contributed to approximately 20 percent of SMM in Black individuals.

A 2022 report from the United States Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) documented a twofold higher prevalence of pregnancy-associated anemia in Black females than non-Hispanic White females. The prevalence in Black gravidas was >15 percent in the first trimester, approximately 20 percent in the second trimester, and nearly 50 percent in the third trimester [12]. This study also documented an increasing prevalence of pregnancy-associated anemia over the course of the study, from 10.1 percent in 2008 to 11.4 percent in 2018.

A 2021 study found that Black patients were nearly twice as likely to have hemoglobin <11 g/dL at admission for delivery, compared with non-Black patients, and a trend toward increased transfusions in Black patients over non-Black patients that did not reach statistical significance [13].

A 2012 study found pregnancy-associated anemia in 27 percent of African American females, versus 7 percent of non-Hispanic White females [14].

The association of anemia with SMM and other SMM risk factors are discussed separately. (See "Severe maternal morbidity", section on 'Risk factors'.)

CAUSES OF ANEMIA — Physiologic anemia of pregnancy and iron deficiency are the two most common causes of anemia during pregnancy; these two conditions account for the vast majority of low hemoglobin concentrations during pregnancy. However, other potential causes of anemia should not be overlooked [3].

Physiologic (dilutional) — Physiologic changes during pregnancy result in dilutional anemia despite an overall increase in red blood cell (RBC) mass. Plasma volume increases by 10 to 15 percent at 6 to 12 weeks of gestation, expands rapidly until 30 to 34 weeks, and then plateaus or decreases slightly to term. The total gain at term averages 1100 to 1600 mL and results in a total plasma volume of 4700 to 5200 mL, which is 40 to 50 percent above that prior to pregnancy [3]. The RBC mass also increases, but to a lesser extent (approximately 15 to 25 percent). Typically, these changes result in mild anemia (hemoglobin 10 to 11 g/dL), but there is no specific hemoglobin value that can be used to distinguish physiologic dilutional anemia from other causes of anemia. Additional details of the mechanisms and timing of physiologic anemia of pregnancy are discussed separately. (See "Maternal adaptations to pregnancy: Hematologic changes", section on 'Dilutional or physiologic anemia'.)

Our approach to distinguishing between physiologic anemia and other causes of anemia is discussed below. (See 'Screening during pregnancy' below.)

Iron deficiency — Physiologic anemia is the most common cause of anemia in pregnancy, but iron deficiency is the most common pathologic cause of anemia in pregnancy. (See 'Physiologic (dilutional)' above.)

Iron deficiency is very common in reproductive-age females, even if never pregnant. Results of case series in a number of countries dating back several decades continue to show that iron deficiency is a widespread phenomenon. As examples:

In a 2018 series in which iron status was assessed in 299 healthy young females in the general population in Australia, 87 (29 percent) had iron deficiency [15]. Of these, only 16 (representing 18 percent of those who were iron deficient; 5 percent of the total cohort) were anemic; the remainder would not have been identified by hemoglobin alone.

In a 2017 review of micronutrient deficiencies in the Middle East, the prevalence of iron deficiency in young healthy females ranged from 27 to 47 percent depending on the country [16].

In a 2008 series of healthy young females in Italy, the prevalence of iron deficiency was 27 and 30 percent in athletes and non-athletes, respectively [17].

In a 1967 series of 114 healthy college-age females in the United States who had not been pregnant and had testing of bone marrow iron, 58 percent had absent hemosiderin, consistent with very low iron stores [18]. This type of analysis has not been repeated; we believe it remains highly relevant.

The prevalence of iron deficiency during pregnancy is as high or higher, depending on the gestational age and ferritin cutoff used for assessing iron deficiency. Several factors contribute to iron deficiency in this population:

Individuals in some parts of the world, especially in resource-limited settings, may have insufficient dietary iron.

Blood loss from previous pregnancies and/or menstruation, as well as a short interpartum interval, may lead to iron deficiency or borderline iron stores. Physiologic iron loss is approximately 1 mg per day in adults; females of childbearing age require additional daily iron to compensate for menstruation (approximately 0.8 mg/day) [19,20]. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Blood loss'.)

Iron requirements increase dramatically through pregnancy due to the expanding blood volume of the mother and the iron requirements for fetal RBC production and fetoplacental growth, as illustrated in the figure (figure 1).

Cumulative total requirements for expansion of the maternal RBC mass and fetal RBC production/fetoplacental growth are approximately 500 mg and 300 to 350 mg, respectively.

-In the first trimester, approximately 1 to 2 mg/day of iron is needed due to normal gastrointestinal sloughing and the early pregnancy-related increase in RBC mass [20]. This amount is similar to normal requirements in the non-gravid state.

-By the second trimester, the demand for iron increases to 4 to 5 mg/day due to requirements for increased maternal RBC production as well as fetal RBC production and fetoplacental growth.

-In the third trimester, the demand for iron increases to approximately 6 mg/day due to ongoing maternal and fetal RBC production and fetoplacental growth.

Delivery results in the loss of approximately 250 mg of elemental iron.

Certain underlying conditions that preclude adequate iron intake or impair iron absorption can increase the risk of iron deficiency during pregnancy, especially if the woman has not received adequate supplementation. Examples include nausea and vomiting of pregnancy, inflammatory bowel disease, bariatric surgery (eg, gastric bypass), and other conditions. These are discussed in more detail separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Reduced iron absorption'.)

Mouse models and in vitro studies suggest that iron regulation favors iron delivery to the placenta over the fetus [21].

Other causes — Other causes of anemia besides physiologic anemia and iron deficiency are much less common in pregnancy. Some inherited and acquired causes of anemia (table 1), especially those that are mild, may only come to medical attention because of routine prenatal laboratory testing or exacerbation related to pregnancy. Examples include:

Hemoglobinopathies

Thalassemia (see "Diagnosis of thalassemia (adults and children)", section on 'Anemia')

Sickle cell disease (see "Diagnosis of sickle cell disorders")

RBC membrane disorders (see "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders")

Acquired anemias

Folate deficiency – Folate deficiency is the most common cause of megaloblastic anemia during pregnancy, often associated with diets low in animal proteins, fresh leafy vegetables, and legumes [22]. Recommended daily folate intake is 400 to 800 mcg beginning at least one month prior to attempting conception and continuing throughout pregnancy for all individuals planning to or becoming pregnant [23]. This dose is consistent with the general population recommendation to prevent maternal folate deficiency and neural tube defects.

In individuals with documented folate deficiency, supplemental folic acid (1 mg/day) is advised prior to conception. This dose is more than sufficient for prevention of folate deficiency and fetal neural tube defects associated with folate deficiency in the vast majority of individuals. Exceptions are discussed separately (eg, for a previous pregnancy affected by fetal neural tube defects, the recommended dose of preconception folic acid is 4 mg/day). (See "Preconception and prenatal folic acid supplementation".)

Vitamin B12 deficiencyVitamin B12 deficiency is a cause of macrocytic anemia in pregnancy in some individuals, particularly those who have had partial or total gastrectomies or those with Crohn disease. In a 2017 bariatric surgery guideline, vitamin B12 deficiency was reported in 2 to 18 percent of individuals with obesity and in 6 to 30 percent of those taking proton pump inhibitors [24]. Almost one-half of pregnant individuals who previously underwent bariatric surgery (Roux-en-Y gastric bypass in 75 percent) had vitamin B12 deficiency requiring supplementation [25]. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies" and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Treatment of vitamin B12 and folate deficiencies".)

Other vitamin deficiencies – Vitamin A deficiency and/or chronic infections (eg, helminthic infections) can cause anemia, particularly in resource-poor settings [26]. Of note, excessive intake of vitamin A can be teratogenic. (See "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Supplements and dietary intake that can be harmful'.)

Autoimmune hemolytic anemia – Autoimmune hemolytic anemia can occur initially during pregnancy or may be exacerbated during pregnancy, although it is very uncommon [27]. It may occur as a primary condition or secondary to another disorder such as systemic lupus erythematosus (SLE) or an acute viral infection. (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)

Hypothyroidism – (See "Clinical manifestations of hypothyroidism", section on 'Anemia'.)

Chronic kidney disease – (See "Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)

SCREENING DURING PREGNANCY

Screening for anemia and iron deficiency — Screening for anemia during pregnancy is universally accepted (algorithm 1).

We screen all pregnant individuals for anemia at the first prenatal visit with a complete blood count (CBC), along with other appropriate prenatal testing, in agreement with several guidelines [2,3,28]. Individuals with anemia should be evaluated for the cause. Of possible causes, iron deficiency is the most common (algorithm 1). (See 'Supporting evidence for risk of iron deficiency and recommendations of others' below.)

It is also reasonable to screen all pregnant individuals for iron deficiency, even if not anemic, as discussed in a 2023 International Federation of Gynecology and Obstetrics (FIGO) statement [29]. (See 'Supporting evidence for risk of iron deficiency and recommendations of others' below and 'How to screen for iron deficiency' below.)

Individuals with iron deficiency should be treated. (See 'Treatment of iron deficiency' below.)

We perform repeat screening with a CBC at week 24 to 28. Anemia is evaluated and treated according to standard guidelines. (See 'Evaluation of anemia' below.)

For those who do not perform routine screening for iron deficiency at the initial prenatal visit, screening may be stratified by risk for iron deficiency.

Individuals at high risk – Both authors agree that it is worthwhile to screen all gravidas at high risk of iron deficiency. This includes individuals with one or more of the following:

Previous diagnosis of iron deficiency

Diabetes

Smoking

HIV infection

Inflammatory bowel disease

Multiparas, especially those with an interpregnancy interval <6 months

History of abnormal uterine bleeding

Body mass index (BMI) above or below the normal range

Vegetarian or vegan diet

Symptoms such as restless legs syndrome or pica, especially pagophagia (ice craving)

Decreased access to health care, which may correlate with decreased screening for heavy menstrual bleeding and infections and reduced access to healthy foods

Individuals who are not high risk Available guidelines are mixed in their recommendations for routine screening for iron deficiency in non-anemic pregnant individuals at average risk of iron deficiency. However, there is a concern that limiting testing to those with anemia has the potential to miss a substantial percentage of iron-deficient gravidas and deprive them of a straightforward therapy (iron replacement) that is potentially beneficial to both the mother and the child and is not harmful [30,31].

Supporting evidence for risk of iron deficiency and recommendations of others

Risk of iron deficiency – Data from studies using iron studies (ferritin, transferrin saturation [TSAT], or both) suggest that approximately 50 percent of pregnant individuals have iron deficiency.

In a 2021 retrospective study of 44,552 pregnant individuals who underwent prenatal testing over a five-year period, ferritin was checked in 59 percent, most during the first trimester [32]. Ferritin was low (<30 ng/mL) in approximately 53 percent, borderline (30 to 44 ng/mL) in approximately 25 percent, normal in approximately 45 percent, and above the reference range in approximately 4 percent. Severe iron deficiency (ferritin <15 ng/mL) was seen in 24 percent. A baseline CBC was only done in three-fourths of the patients. Of those who had hemoglobin tested, 8 percent had anemia (defined as hemoglobin <10.5 g/dL), and only one-fourth of those with anemia had a ferritin test. Individuals of lower household income were less likely to be screened for iron deficiency than those with higher household income, suggesting disparities in health care delivery.

Disparities in maternal iron deficiency rates are likely to translate to higher rates of iron deficiency in infants from high-risk maternal groups [10]. (See 'Epidemiology and health care disparities' above.)

In a 2021 study of 102 non-anemic, first trimester gravidas who had iron parameters (ferritin and TSAT) added to routine laboratory testing, 42 percent were iron deficient [33]. Another study of 54 non-anemic gravidas who were screened with inflammation-adjusted ferritin found probable iron deficiency in 28 percent at baseline and 81 percent at week 24 to 38, although other parameters including hemoglobin, mean corpuscular volume (MCV), and reticulocyte hemoglobin did not change from baseline to the end of the study [34]. The inflammation-adjusted ferritin uses a calculation that adjusts for acute-phase proteins [35]. Management that followed the USPSTF recommendations would have missed all of these pregnant individuals, many of whom may have benefited from iron repletion. (See 'Epidemiology and health care disparities' above.)

An analysis from the United States from 1999 to 2006 reported that iron deficiency (defined as serum ferritin <12 ng/mL [<12 mcg/L]) was present in 25 percent of pregnant individuals [36]. The prevalence of iron deficiency increased from 7 percent in the first trimester to 24 and 39 percent in the second and third trimesters, respectively. The prevalence of anemia based on WHO definitions was (see 'Definition of anemia' above):

-First trimester – 3 percent

-Second trimester – 2 percent

-Third trimester – 11 percent

Using this very low ferritin cutoff may miss many patients with iron deficiency. We use a higher cutoff of 30 ng/mL, which is consistent with studies correlating serum ferritin with the absence of bone marrow iron stores [37]. (See 'Iron deficiency anemia' below.)

Studies from 2019 to 2022 suggest the incidence of iron deficiency without anemia may be even higher (depending on the gestational age at sampling and the criteria for iron deficiency used, from 53 to 81 percent) [32-34].

Individuals with iron deficiency may be at risk for progressing to iron deficiency anemia during pregnancy, when the demand for iron increases. Treatment of iron deficiency that is initiated after diagnosis of iron deficiency anemia may be too late to prevent some adverse outcomes. Correction of iron deficiency before the third trimester is ideal, as iron-dependent neurogenesis is maximal during the third trimester and early neonatal life, and iron deficiency during this period has been associated with deficits in neurocognitive development [38]. Infants born of iron-deficient mothers are at high risk for having iron deficiency at birth [39]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Perinatal risk factors'.)

Recommendations of others – Professional organizations are increasingly moving to suggest a more proactive approach to identifying and treating iron deficiency before anemia develops.

A 2023 International Federation of Gynecology and Obstetrics (FIGO) statement emphasized the high prevalence of iron deficiency and anemia in females and reinforced the concepts that anemia is a late-stage finding in iron deficiency and both iron deficiency and anemia are associated with adverse fetal and maternal outcomes [29]. They support the adoption of routine screening for heavy menstrual bleeding, iron deficiency, and anemia throughout the life course and specifically recommend assessing iron status and hemoglobin before planned pregnancy and as early as possible during pregnancy.

A 2021 American College of Obstetricians and Gynecologists practice bulletin recommends low dose iron supplementation during pregnancy to reduce anemia, and screening for anemia during pregnancy, but it does not address screening for iron deficiency [3]. (See 'Screening for anemia and iron deficiency' above.)

A 2019 United Kingdom guideline recommended using the history to identify increased risk of iron deficiency and then either starting prophylactic iron empirically or checking serum ferritin and then treating if the level is low [2]. Individuals at high risk for iron deficiency include those with a high risk of bleeding during pregnancy or delivery, those who would decline transfusions (eg, Jehovah Witnesses), those for whom finding compatible blood would be challenging (eg, rare blood type), and those with a previous history of anemia, current multiple gestation, short interpregnancy interval, low-iron diet, or teenage pregnancy. Unselected routine screening with serum ferritin level is not recommended outside the context of a research study.

A 2015 United States Preventive Services Task Force (USPSTF) guideline concluded that available evidence was insufficient to assess the balance of benefits and harms of screening for iron deficiency anemia in pregnant individuals living in the United States who do not have symptoms of iron deficiency anemia [40-42]. (See "Prenatal care: Initial assessment", section on 'Laboratory tests'.)

How to screen for iron deficiency — A ferritin level is generally sufficient for screening for iron deficiency. However, some individuals with iron deficiency may have a serum ferritin in the normal range and may require testing of the transferrin saturation (TSAT) to diagnose iron deficiency. Based on data from a study in which healthy females in the general population were screened, it may be prudent to add a TSAT to the serum ferritin test [33]. This is especially true for patients with active inflammation, which can increase ferritin since it is an acute phase reactant, and for those in whom adding a TSAT later would require a second blood draw.

Interpretation of levels is the same as in individuals undergoing testing for iron deficiency anemia. (See 'Iron deficiency anemia' below.)

Supporting evidence for adverse outcomes associated with anemia — Routine screening for anemia and/or iron deficiency (and treatment if identified) is supported by the following observations of adverse outcomes associated with anemia:

Maternal outcomes

A study evaluating >18 million pregnancies found associations between anemia and several adverse maternal outcomes [43]. The authors stated that individuals in the study population (females in China) are not routinely advised to take iron supplements, and anemia is due to iron deficiency in approximately 70 percent of pregnant females in China. The likelihood of adverse outcomes correlated with the severity of anemia. As examples:

-Placental abruption (adjusted odds ratio [aOR] 1.36 with mild anemia, 1.98 with moderate anemia, 3.35 with severe anemia)

-Preterm birth (aOR 1.08 with mild anemia, 1.18 with moderate anemia, 1.36 with severe anemia)

-Severe postpartum hemorrhage (aOR 1.45 with mild anemia, 3.53 with moderate anemia, 15.65 with severe anemia)

-Maternal shock (aOR 1.50 for moderate anemia, 14.98 for severe anemia)

-Maternal intensive care unit (ICU) admission (aOR 1.08 with moderate anemia, 2.88 for severe anemia)

A study that extracted information from over 160,000 pregnancies in the United States documented antepartum maternal anemia, as defined above (see 'Definition of anemia' above), in 6.1 percent [44]. Compared with non-anemic individuals, those with anemia had an approximately twofold increase in severe maternal morbidity (SMM), defined as maternal death, eclampsia, transfusion, hysterectomy, or intensive care unit admission at delivery (adjusted odds ratio [OR] 2.04, 95% CI 1.86-2.23).

Anemic individuals also experienced additional complications (postpartum hemorrhage, preeclampsia, cesarean delivery, infections). Neonates born to anemic mothers had higher rates of fetal distress and admission to the neonatal intensive care unit. Rates of preterm delivery and birth weight <2500 grams and small-for-gestational-age infants were not increased. It could not be determined whether antepartum anemia was the major contributor to SMM or whether these patients had additional unidentified risk factors leading to SMM. Regardless, this study emphasizes the importance of diagnosing antepartum maternal anemia as a means of identifying pregnancies at greater risk of severe maternal outcomes.

A study by the World Health Organization (WHO) documented that severe antenatal or postnatal maternal anemia (of any type) was associated with an increased risk of maternal death (adjusted OR 2.36, 95% CI 1.60-3.48) [45].

Other studies have observed that maternal anemia was associated with these and several other adverse outcomes such as low birth weight, small for gestational age birthweight, maternal transfusion, antenatal/postnatal maternal sepsis, cesarean delivery, and future maternal cardiovascular disease [43,46-54].

Outcomes in the child

A cohort study from Sweden involving >500,000 children born between 2010 and 2016 found that maternal anemia was associated with increased risks of autism spectrum disorder, attention deficit hyperactivity disorder, and intellectual disability in pregnancies when the anemia was identified in the first 30 weeks of pregnancy as compared with maternal anemia identified after 30 weeks or no maternal anemia (odds ratios [ORs], 1.4 to 2.2) [55]. The cause of anemia was likely to be iron deficiency in the majority of cases, but this was not verified in the study, and other potential cofounders were not evaluated.

A longitudinal study of 185 individuals who were followed from infancy to the age of 19 years found that those who had iron deficiency or iron deficiency anemia as infants for three or more months had impaired cognitive functioning compared with those who did not have iron deficiency [56]. The gap in cognitive functioning was greatest in those of low socioeconomic status but persisted even in those with high socioeconomic status. Other studies have documented correlations of maternal anemia with later cognitive defects [57]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Associated disorders and effects of treatment'.)

Animal studies have demonstrated a clear role for iron in normal brain development, dendritic growth, and synapse formation, as well as behaviors such as grooming, tasks requiring executive function, timidity, and poor spatial learning [58-60]. Animal studies also suggest that iron is not preferentially transferred to the fetus if the mother is iron deficient [61,62].

Correlations between maternal and cord-blood ferritin levels have been observed [63].

These data do not definitively demonstrate a cause-and-effect relationship between iron deficiency and adverse outcomes or between iron supplementation and improved outcomes (see 'Prevention of iron deficiency' below). Studies are needed to evaluate neonatal and childhood outcomes following iron supplementation to iron-deficient gravidas during pregnancy or to their infants.

There are a number of confounding factors in these observational studies, and several outcomes are not mutually exclusive [55]. Iron deficiency is often seen in those with other nutrient deficiencies and/or with socioeconomic disadvantages, making it difficult to sort out what cognitive deficits are attributable to iron deficiency. Whether developmental deficits in children are independently related to ferritin levels at birth and whether they would persist if iron deficiency is corrected in infancy have not been definitively established.

The implications of these findings, as well as the role of iron supplementation in infants, are discussed in more detail in society guidelines, review articles, and a separate UpToDate topic review [2,38,64]. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Associated disorders and effects of treatment'.)

EVALUATION OF ANEMIA — Gravidas with anemia are tested for likely causes. The details of the evaluation will depend on the clinical history, red blood cell (RBC) indices, and other findings on the complete blood count (CBC). Physiologic anemia of pregnancy is a diagnosis of exclusion; thus, other causes of anemia must be eliminated before anemia is attributed to normal pregnancy physiology. (See 'Physiologic (dilutional)' above.)

Iron deficiency anemia — All gravidas with anemia or symptoms of anemia (restless legs syndrome, pica) should have prompt testing for iron deficiency because iron deficiency can progress to anemia; iron deficiency is the most common pathologic cause of anemia in pregnancy. Microcytosis may be present, but microcytosis is a late finding of iron deficiency (table 2) and may also be caused by thalassemia; the absence of microcytosis does not eliminate the possibility of iron deficiency and the presence of microcytosis does not confirm it. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Stages of iron deficiency' and "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis'.)

When testing for iron deficiency, most gravidas without comorbidities can be tested with a serum ferritin alone [65].

If low (eg, <30 ng/mL [<30 mcg/L]), this is sufficient to confirm the diagnosis of iron deficiency.

Levels ≥30 ng/mL are sufficient to eliminate the possibility of iron deficiency in the majority of cases.

A 2019 United Kingdom guideline suggests immediate treatment and assessment of response in two to three weeks (a therapeutic trial), which has the potential advantage of avoiding the costs of other testing and additional visits [2,66].

Borderline serum ferritin (30 to 40 ng/mL) can occur with active inflammation from chronic illnesses such as diabetes, or up to 100 ng/mL with chronic kidney disease or from collagen vascular diseases such as systemic lupus erythematosus or rheumatoid arthritis. This occurs because ferritin is an acute phase reactant. Some pregnancies have evidence of an acute phase response even in the absence of one of these chronic illnesses [67,68]. Thus, borderline ferritin levels should prompt testing of a full set of iron studies including ferritin, serum iron, total iron binding capacity (TIBC), and calculation of transferrin saturation (TSAT). We consider a TSAT below 20 percent to be evidence of iron deficiency whether the ferritin level is low or normal; this practice is consistent with other sources, which cite values below 16 percent without inflammation and below 20 percent with inflammation [65,69,70]. The rationale is that a normal ferritin level may represent elevation due to inflammation.

Iron supplements can falsely elevate the TSAT (appearing to be normal when it is actually low) by raising the serum iron level, an effect that peaks at approximately four hours after an oral dose. To avoid this test interference, iron parameters should be drawn after an overnight fast, or the woman should simply be advised to avoid iron-containing foods or supplements to mitigate otherwise falsely elevated TSAT values. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Test interference'.)

The United States Preventive Services Task Force (USPSTF) noted that serum ferritin may have limited use during late pregnancy because its concentration often decreases with advancing gestational age as maternal iron stores are used to supply iron to the placental and fetal circulations (figure 1), but using hemoglobin or hematocrit measurement alone to determine iron deficiency status is indirect and imprecise [41]. Other than iron deficiency, no other causes of a low serum ferritin have been identified.

Iron studies as well as other tests for iron deficiency and their interpretation are discussed in more detail separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)

Other anemias — We promptly evaluate for other causes of anemia if there are any features of the anemia that suggest another condition or if testing for iron deficiency is negative (ie, if iron stores are adequate). Examples of features that suggest another cause include:

Extreme microcytosis (eg, mean corpuscular volume [MCV] <80 fL), suggestive of thalassemia

Macrocytosis (MCV >100 fL), suggestive of vitamin B12 or folate deficiency or reticulocytosis due to hemolysis

Other cytopenias such as thrombocytopenia or neutropenia

Abnormally high white blood cell (WBC) count or platelet count

Abnormal RBC or WBC morphologies

Failure of the anemia to correct with iron supplementation

The details of the evaluation depend on the specific abnormalities found. Of note, macrocytosis due to vitamin B12 or folate deficiency can be masked by concomitant iron deficiency [65]. Thus, absence of macrocytosis should not be considered sufficient to eliminate the possibility of these deficiencies if there are other reasons to suspect them. A general approach to the evaluation of anemia is also presented separately. (See "Diagnostic approach to anemia in adults".)

Screening for hemoglobinopathy is important to identify and counsel individuals whose offspring may be at risk of an inherited hemoglobinopathy. (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

MANAGEMENT — The health of both the mother and the child can be affected by anemia during pregnancy. Thus, identifying, preventing, and treating anemia in pregnancy is likely beneficial, although not established by high-quality studies.

Prevention of iron deficiency — We provide supplemental oral iron 27 to 30 mg daily throughout pregnancy to all pregnant individuals to compensate for the increased iron demands during pregnancy; this is considered "low dose" supplementation and corresponds to the amount of iron in most iron-containing prenatal vitamins. This practice is in agreement with guidance from the Centers for Disease Control and Prevention (CDC) in the United States and the American College of Obstetricians and Gynecologists (ACOG) [3,19]. This allows most gravidas to receive iron from iron-containing prenatal vitamins.

For those who are intolerant of the iron in prenatal vitamins, it may be possible to take prenatal vitamins without iron and to supplement with oral iron supplements on an every-other-day basis (typical dose, 60 mg once every other day or 60 mg once daily on Monday, Wednesday, and Friday). The rationale for alternate-day dosing (improved absorption due to effects on hepcidin and reduced gastrointestinal adverse effects) is discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

A 55 kg female requires approximately one gram of additional iron from conception to delivery (figure 1), which includes 300 to 350 mg for the fetus and placenta, 500 mg for the expansion of the maternal red blood cell (RBC) mass, and 250 mg associated with blood loss during labor and delivery [65]. Supplementation exceeds this one gram requirement because only a small portion of ingested iron is absorbed, and the increase in the portion absorbed does not match the increase in iron requirements [20].

Despite the increase in iron requirements during pregnancy, high-quality evidence that routine iron supplementation improves health outcomes and quality of life has been challenging to obtain. The 2015 review of evidence dating back to 1996 from the United States Preventive Services Task Force (USPSTF) concluded that "there is insufficient evidence that routine prenatal supplementation for iron deficiency anemia improves maternal or infant clinical health outcomes, but supplementation may improve maternal hematologic indices" [41]. A 2015 Cochrane review came to similar conclusions, stating that "supplementation reduces the risk of maternal anaemia and iron deficiency in pregnancy, but the positive effect on other maternal and infant outcomes is less clear" [71]. This lack of high-quality evidence is largely due to the challenges of performing prospective randomized trials in gravidas as well as the limited outcomes reported for iron supplementation in gravidas or neonates.

Treatment of iron deficiency — The standard treatment for uncomplicated iron deficiency (regardless of hemoglobin level) is administration of iron at doses higher than found in prenatal vitamins. The choice between oral and intravenous iron depends on a number of factors, as discussed below. (See 'Oral versus IV iron' below.)

Antenatal maternal treatment with iron results in an increase in the hemoglobin level in approximately two weeks (the time it takes to create new RBCs in the bone marrow). (See 'Assessing response to treatment' below.)

For gravidas with severe anemia for whom this two-week delay would be expected to result in significant morbidity, transfusion and/or referral to a specialist (eg, hematologist) may be appropriate [2]. We reserve transfusion for those who have significant symptoms associated with severe anemia or those for whom transfusion is indicated for other reasons, such as those mentioned below. (See 'Management of other anemias' below.)

Transfusion is not required for mild symptoms of anemia, which may be difficult to distinguish from other symptoms related to the hormonal or anatomic changes of pregnancy. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Overview of our approach'.)

Oral versus IV iron — Oral and intravenous iron are both effective for replenishing iron stores. Each route carries different advantages and disadvantages as outlined in the table (table 3). We generally use oral iron for most gravidas with iron deficiency who can tolerate it, and for all individuals being treated during the first trimester. We give intravenous iron to gravidas beyond the first trimester who cannot tolerate oral iron; those who have severe anemia, especially later in the pregnancy; and those for whom oral iron does not effectively increase the hemoglobin and/or ferritin levels. This practice is consistent with a 2019 United Kingdom guideline [2].

Three meta-analyses published in 2018 to 2019 evaluated the benefits and risks of oral versus intravenous iron based on data from randomized trials in pregnant or postpartum females with iron deficiency [72-74]. These analyses found that iron supplementation by either route (oral or intravenous) increased the hemoglobin and ferritin levels; compared with oral iron, intravenous iron was associated with a higher hemoglobin level following therapy (at four weeks, upon admission to the labor and delivery service, or at the six-week postpartum check). (See 'Postpartum' below.)

In one of the meta-analyses, the magnitude of the antepartum hemoglobin increase was modest (weighted mean difference [WMD] at admission to labor and delivery, 0.66 g/dL, 95% CI 0.31-1.02) [73]. Maternal and neonatal outcomes were not significantly different (rates of maternal blood transfusion or cesarean delivery), but intravenous iron was associated with higher neonatal birth weight (WMD 69 grams, 95% CI 12-127 grams) and higher neonatal ferritin levels (WMD, 21 ng/mL, 95% CI 6-37 ng/mL) [73]. All of the analyses found that adverse effects were less frequent with intravenous iron.

In a 2023 open-label randomized trial including 862 pregnant individuals in Malawi with hemoglobin <10 g/dL, intravenous iron (single dose ferric carboxymaltose, 20 mg/kg up to 1000 mg) at a median gestational age of 22 weeks modestly reduced the prevalence of anemia at four weeks post-treatment (77 versus 84 percent), 36 weeks of gestation (52 versus 57 percent), at delivery (27 versus 31 percent), and at four weeks postpartum (46 versus 54 percent) compared with standard care with oral iron (ferrous sulfate, 60 mg twice daily for 90 days), although the differences in prevalence were not statistically significant at all time points [75]. Rates of iron deficiency based on serum ferritin were substantially lower in the intravenous iron group at all time points (at four weeks after treatment, <1 percent versus 26 percent; at 36 weeks, 18 versus 42 percent; at four weeks postpartum, 12 versus 29 percent). Infant weights and rates of premature birth and pregnancy loss were not different between groups. Many participants did not have iron deficiency at baseline and many remained anemic after treatment, highlighting the multifactorial causes of anemia in pregnancy. (See 'Other causes' above.)

A protocol for screening and management may help in the decision to start with oral or intravenous iron. One such protocol screened for iron deficiency in the second and third trimesters and treated with oral iron for hemoglobin 9.5 to 11 g/dL or intravenous iron for hemoglobin <9.5 g/dL [76]. Use of the protocol resulted in higher hemoglobin at delivery but did not produce a statistically significant reduction blood product use.

Oral iron — For most individuals with iron deficiency, especially those diagnosed in the first trimester, we treat with oral iron. Oral iron is safe, inexpensive, readily available, and, when tolerated, effective. Ferrous sulfate (FS) is the most commonly prescribed oral formulation. Up to 70 percent of those to whom it is prescribed report significant gastrointestinal perturbation, and two meta-analyses of oral iron therapy in pregnancy report that the incidence of gastrointestinal side effects is unacceptably high [77-79]. Some experts use intravenous iron in the second half of the pregnancy due to concerns that oral iron will not provide sufficient iron to the developing fetus [63,65].

Dosing – Recommended doses of oral iron range from 40 to 200 mg elemental iron per day [2,80]. There has been a trend towards using doses on the lower end of this range as well as alternate day dosing due to recognition that higher and more frequent doses may increase adverse effects without improving iron uptake [2]. We agree with this dose range and often administer 60 mg of elemental iron. Standard oral iron formulations and their elemental iron content are listed in the table (table 4). However, we provide the dose every other day (or, on Monday, Wednesday, and Friday) rather than daily, based on evidence that alternate-day dosing results in improved absorption of oral iron as well as improved tolerability. Compared with more frequent dosing (such as once daily or three times per day), alternate-day dosing improves iron absorption and reduces gastrointestinal adverse effects in nonpregnant individuals [81]; supporting evidence is presented separately. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

Absorption may be improved by avoiding coffee, tea, and milk at the time the iron supplement is taken. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diet'.)

Adverse effects – While oral iron is inexpensive, available, and easy to use when tolerated, it may be associated with gastrointestinal side effects including metallic taste, gastric irritation, nausea, diarrhea, and/or constipation; the latter is exacerbated by high progesterone levels, which slow bowel transit, and the enlarging gravid uterus pressing posteriorly on the rectum. A meta-analysis of 43 randomized trials comparing oral iron with intravenous iron or placebo in adults reported that as many as 70 percent of those to whom oral iron was prescribed experienced significant gastrointestinal perturbation with resultant decreased adherence to therapy [77]. A subgroup analysis of seven trials in pregnant individuals showed a statistically significant increase in gastrointestinal side effects with oral iron (odds ratio [OR] 3.3, 95% CI 1.2-9.2). Two additional studies of adherence and side effects with oral iron concluded the incidence of adverse events was unacceptably high [78,79].

Options to improve tolerability include extending the interval between doses, switching to a liquid that can be more easily titrated, or switching to intravenous iron (if in the second or third trimester) [2]. Changing the oral iron formulation is unlikely to be helpful as standard oral iron formulations have similar efficacy and similar rates of adverse events, with a few exceptions.

We do not use enteric-coated or timed-release formulations (Ferro-Sequels, Slow-Fe). While some of these formulations may be better tolerated, modifications to the iron or coatings intended to result in timed release or protect against gastric irritation have the potential to reduce absorption in the distal duodenum and proximal jejunum, impairing treatment benefit. As a result, these formulations should be avoided [82,83]. Formulations with a polysaccharide-iron complex (PIC) or heme iron polypeptide (HIP) have also been tried. However, a randomized trial in children found PIC to be slightly less effective than ferrous sulfate, and a randomized trial in individuals with chronic kidney disease found HIP to have similar effects on iron absorption as ferrous sulfate [84,85]. Additional details are discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Oral iron'.)

Oral iron is likely to be ineffective in individuals with inflammatory bowel disease (IBD; Crohn disease, ulcerative colitis) due to worsening of gastrointestinal symptoms, reduced absorption, and a possible effect on bowel flora. For those who have undergone bariatric surgery (with either Roux-en-Y bypass or biliopancreatic procedures), oral iron cannot be exposed to gastric acid from the stomach, which is required to protect it from alkaline pancreatic secretions; as a result, the iron will be converted to ferric hydroxide (rust), which cannot be absorbed (see "Treatment of iron deficiency anemia in adults", section on 'Following gastrointestinal/bariatric surgery'). Thus, we use intravenous iron in these populations. Some patients, especially those having undergone minimally invasive procedures such as gastric banding, may tolerate oral iron. However, multiple gastrointestinal perturbations are often present in this population, and intravenous iron may simplify care. (See 'Intravenous iron' below.)

Intravenous iron — We use intravenous iron if there is intolerance of oral iron; severe anemia, especially later in the pregnancy; and if oral iron is not effective in raising the hemoglobin and/or ferritin level [31,66].

Intravenous iron is not used during the first trimester, as there are no safety data for first-trimester use. However, we consider it to be safe and effective during the second and third trimesters of pregnancy, with a much lower frequency of adverse effects than oral iron and a negligibly low frequency of serious adverse effects (SAEs). As described above, meta-analyses report better efficacy and fewer adverse effects with intravenous compared with oral iron. (See 'Oral versus IV iron' above.)

Indications – For individuals with iron deficiency and/or iron deficiency anemia (especially if severe or symptomatic) who do not tolerate oral iron (or those who do not have the expected increase in hemoglobin level with oral iron, which suggests impaired absorption and/or impaired adherence with therapy), intravenous iron is the optimal route of administration, as it can fully correct the deficiency in a single administration (table 5).

Intravenous iron is not given during the first trimester but can be started after 13 to 14 weeks [65]. For those for whom intravenous iron is not available, additional strategies for improving absorption and tolerability are discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Strategies to improve tolerability'.)

Intravenous iron may also be appropriate for individuals in the second or third trimester for whom there would be insufficient time to replete iron orally (after week 30), as well as those with anatomic abnormalities such as history of bariatric surgery or other conditions that interfere with oral iron absorption (eg, IBD) [82]. Gastric surgeries most likely to impair iron absorption include gastric resection, Roux-en-Y, biliopancreatic diversion, or similar procedures. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Reduced iron absorption' and "Treatment of iron deficiency anemia in adults", section on 'Following gastrointestinal/bariatric surgery'.)

Intravenous iron is likely to be superior to oral iron in promoting rapid correction of anemia and iron deficiency, which may become more important as the pregnancy progresses, and to ensure iron sufficiency in the developing fetus. In a study of gravidas treated with intravenous iron, none of the newborns were diagnosed with iron deficiency anemia [86].

We have a low threshold for switching from oral iron to intravenous iron (or for using intravenous iron as initial treatment) for iron deficiency in the second or third trimester of pregnancy [66]. We believe the reluctance of many clinicians to use intravenous iron is based on fears of serious hypersensitivity reactions leading to anaphylaxis that were reported with formulations that are no longer clinically available, as well as a lack of clear guidance across different countries; the concerns about anaphylaxis are not supported by evidence that reflects use of intravenous iron after HMWID was removed from markets. (See "Treatment of iron deficiency anemia in adults", section on 'Choice of IV formulation' and "Treatment of iron deficiency anemia in adults", section on 'Dosing/administration of specific IV iron preparations'.)

Our approach is consistent with a 2019 United Kingdom guideline, which states that intravenous iron may be appropriate in the second trimester onwards into the postpartum period for individuals with iron deficiency who cannot tolerate oral iron or for whom oral iron is ineffective [2].

Choice of formulation – All intravenous iron products appear to have equivalent safety and efficacy, as illustrated by various studies, including single-agent studies and direct comparisons between different products in pregnant and nonpregnant populations [72,87-91]. (See "Treatment of iron deficiency anemia in adults", section on 'Allergic and infusion reactions'.)

Thus, the choice of products is based on the costs and burdens of administration (table 5).

One exception is formulations that contain benzyl alcohol as a preservative (eg, the ferric gluconate preparation Ferrlecit), especially since multiple vials are required; we avoid these formulations due to the potential risk to the fetus [92,93].

We also avoid iron sucrose due to the administration schedule, which requires four to five separate infusions, in contrast to other formulations for which a single replacement dose can be administered in a single visit with a single infusion.

Ferric carboxymaltose (FCM), low molecular weight iron dextran (LMWID), ferumoxytol, ferric derisomaltose (iron isomaltoside) and iron polymaltose (IPM) are least burdensome as they can each be administered in a single infusion of the entire dose; IPM is not available in the United States [66]. Single dose infusion reduces costs, which include costs of the product as well as its administration. Costs and burdens associated with oral iron administration may include more office visits and laboratory testing if medication adherence becomes an issue. However, there are concerns with hypophosphatemia with FCM that may limit its use; FCM has been reported to cause hypophosphatemia in as many as one-half of patients, the clinical significance of which is under investigation. Clinically significant hypophosphatemia has not been reported in gravidas. (See "Treatment of iron deficiency anemia in adults", section on 'Choice of IV formulation'.)

Ferric derisomaltose (iron isomaltoside) has not been prospectively studied in pregnancy, but a retrospective review of 213 pregnant females who received this formulation reported similar safety and efficacy to that typically observed with other parenteral iron formulations [87]. As noted above, there is no theoretical or pharmacologic reason to believe this formulation is less safe or less effective than any other intravenous iron.

Dosing – Dosing is listed in the table (table 5). Additional considerations for dosing are discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing/administration of specific IV iron preparations'.)

Administration – Intravenous iron is administered in a monitored setting without premedications (we do not give acetaminophen or diphenhydramine as premedications). Selected patients with a history of inflammatory arthritis or IBD or those with multiple (more than one) drug allergies may be given a dose of a glucocorticoid and a histamine receptor blocker such as ranitidine or famotidine, prior to the iron infusion to reduce the likelihood of the minor infusion reactions that occur in 1 to 3 percent of administrations. The dosing and administration of specific products and additional details regarding the prevention and treatment of infusion reactions are discussed in more detail separately. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron'.)

Safety and efficacy – As noted above, we believe the reluctance of many clinicians to use intravenous iron is based on experience with a product (HMWID) that is no longer available. Evidence for products that are currently available includes the following:

A 2022 trial that randomly assigned 278 pregnant individuals to receive FCM at a dose of 500 mg or 1000 mg found that the 500 mg dose led to greater likelihood of needing a repeat infusion (36 percent, versus 8 percent in the 1000 mg group at four weeks) due to inadequate increase in iron stores [94]. These results confirm the importance of adhering to recommended doses, which can be administered as a single infusion. Considerations for FCM dosing are discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Ferric carboxymaltose'.)

A 2018 open-label trial randomly assigned 246 pregnant individuals with iron deficiency anemia, mostly in the third trimester of pregnancy, to be treated with intravenous iron (FCM or iron polymaltose [IPM], given as a single-dose infusion) or oral iron (ferrous sulfate [FS]) [95]. The mean increase in hemoglobin level was greater in both intravenous iron groups than the oral iron group at four weeks (approximately 0.9 g/dL for intravenous iron versus approximately 0.5 g/dL for oral iron) and at predelivery (1.5 g/dL for intravenous iron versus 1 g/dL for oral iron). There were no serious adverse events. No transfusions were used in the intravenous iron groups; two participants in the oral iron group received transfusions (not statistically significant). One-half of the oral iron recipients reported gastrointestinal side effects, and one-third did not adhere to oral iron therapy. Including all costs, intravenous iron was reported to be less expensive than oral iron. As noted above, FCM has been reported to cause hypophosphatemia in nonpregnant individuals; phosphate levels were not measured in the trial.

In a 2017 trial, 252 pregnant individuals with iron deficiency anemia in gestational weeks 16 to 33 were randomly assigned to receive intravenous iron or oral iron (FCM, 1000 to 1500 mg intravenously in one or two doses, or FS, 100 mg orally twice daily for 12 weeks) [88]. Those in the FCM group were more likely to have correction of anemia (84 versus 70 percent; OR 2.06, 95% CI 1.07-3.97) and to have a faster correction of anemia (median 3.4 versus 4.3 weeks). Most adverse events were mild. One serious treatment-associated adverse event (bronchospasm) occurred in the FCM group, which resolved without sequelae. Oral iron was discontinued in seven of the participants in the FS arm. All newborns were healthy (Apgar score of 10 by 10 minutes). Other randomized trials comparing intravenous and oral iron, trials comparing different intravenous iron products, or studies reporting on administration of other intravenous iron products, have reported similar findings, leading us to conclude that intravenous iron is effective and safe during pregnancy, with virtually no serious adverse events [86,89,90,96-106].

FCM has been reported to cause hypophosphatemia. Phosphate levels were not routinely measured in these trials, but no clinical sequelae of hypophosphatemia were reported. (See "Treatment of iron deficiency anemia in adults", section on 'Ferric carboxymaltose'.)

Data from a 2015 meta-analysis that included over 10,000 patients (not restricted to pregnancy) also suggested that intravenous iron is safe (relative risk [RR] of SAEs versus other comparators [placebo, oral iron, intramuscular iron [which should be avoided], or no iron] 1.04, 95% CI 0.93-1.17) [107]. In a subset analysis of trials in pregnant individuals, there was a slight increased risk of SAEs, but the quality of the data was poor, with 8 of 12 trials lacking safety data.

A case report described rhabdomyolysis with intravenous iron sucrose in a patient with a prior infusion reaction to its administration [108]. The mechanism is unclear, rhabdomyolysis resolved with supportive care, and the pregnancy was otherwise unaffected, with delivery of a healthy newborn.

A 2023 observational study erroneously concluded that intravenous iron was associated with worse outcomes; however, as suggested by the authors, use of intravenous iron was likely a marker for greater baseline risk rather than a causative relationship [109]. Many of the patients receiving intravenous iron did not receive the prescribed dose; when stratified by adequate treatment, there was no adverse impact on outcomes. Such observational results demonstrate the pitfalls of using retrospective, inadequately stratified data.

Assessing response to treatment — The expected response to iron repletion is improvement in RBC production, which typically begins with reticulocytosis after approximately one week, an increase in the hemoglobin level of at least 1 g/dL within two to three weeks, and an increase in serum ferritin into the normal range, typically within three weeks [90,105]. The response is similar with oral or intravenous administration and mostly depends on the time it takes to incorporate iron into RBC precursors and their maturation to mature, circulating RBCs. Potential reasons for a lack of response include non-adherence, reduced absorption, ongoing bleeding, or a cause of anemia other than iron deficiency [3]. (See "Treatment of iron deficiency anemia in adults", section on 'Approaches to lack of response'.)

For antepartum patients receiving oral iron, we typically check the hemoglobin level and reticulocyte count two to three weeks after starting therapy and review tolerability of the oral iron. If the expected response has occurred and the oral iron is well tolerated, it is continued throughout the pregnancy and into the postpartum period (see 'Postpartum' below). If the oral iron is not well tolerated and/or the expected increase in hemoglobin level has not occurred, options include making changes to improve tolerability (appropriate if anemia is mild) or changing to intravenous iron beginning in the second trimester. (See 'Intravenous iron' above.)

For antepartum patients receiving intravenous iron, we generally obtain repeat iron parameters four to eight weeks after the iron has been administered. We wait a minimum of four weeks because intravenous iron interferes with most assays of iron status [110]. As noted in the 2019 United Kingdom Guideline, it may be reasonable to monitor an increase in hemoglobin level without rechecking iron parameters [2].

Patients also undergo repeat complete blood count (CBC) testing at 24 to 28 weeks.

Once the hemoglobin has reached the normal range, oral iron replacement should continue for three months and until at least six weeks postpartum [2]. Postpartum assessment is discussed below. (See 'Postpartum' below.)

Prevention of other causes of anemia — The following interventions may apply to selected individuals:

Folic acid – Folic acid supplementation is routinely recommended to prevent neural tube defects. Optimal doses for various populations based on risk are presented separately; doses used to prevent neural tube defects are sufficient to prevent maternal folate deficiency. (See "Preconception and prenatal folic acid supplementation".)

Vitamin B12 – For individuals who consume a strict vegetarian/vegan diet or those with anatomic reasons to develop vitamin B12 deficiency (eg, Roux-en-Y or biliopancreatic bariatric surgery), the importance of supplemental oral vitamin B12 should be emphasized. Some groups recommend a slightly higher daily allowance of vitamin B12 in pregnancy than in nonpregnant adults [65]. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Overview of intake and metabolism'.)

Oxidant drug avoidance – Gravidas with glucose-6-phosphate dehydrogenase (G6PD) deficiency should be reminded to avoid oxidant medications, foods, and other substances. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Management'.)

Management of other anemias — Inherited and acquired anemias may worsen during pregnancy; however, individuals with baseline anemia may tolerate these reductions without the need to alter management.

Specific aspects of management are discussed in separate topic reviews and include the following:

Sickle cell disease (SCD) – Transfusion in individuals with SCD; genetic counseling for those with SCD or sickle cell trait. (See "Sickle cell disease: Obstetric considerations", section on 'Transfusion therapy' and "Sickle cell trait", section on 'Reproductive issues'.)

Thalassemia – Transfusion in certain individuals; genetic counseling; prenatal testing for thalassemia A, which manifests before birth. (See "Management of thalassemia", section on 'Pregnancy' and "Management of thalassemia", section on 'Reproductive testing and genetic counseling'.)

Hereditary hemorrhagic telangiectasia (HHT) – Intravenous iron is the preferred route and can usually eliminate the need for transfusion in individuals with significant blood loss from HHT (also called Osler-Weber-Rendu syndrome). Oral supplementation cannot keep up with losses and should not be used. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Pregnancy'.)

Autoimmune hemolytic anemia (AIHA) – Transfusions, glucocorticoids, or intravenous immune globulin if needed; attention to possible anemia in the neonate due to autoantibodies that cross the placenta [27]. (See "Management of non-RhD red blood cell alloantibodies during pregnancy", section on 'Warm autoimmune hemolytic anemia' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management'.)

Rarely, microangiopathic hemolytic anemia (MAHA) with thrombocytopenia can develop during pregnancy due to a thrombotic microangiopathy. (See "Thrombocytopenia in pregnancy", section on 'Thrombotic microangiopathy (TMA)'.)

POSTPARTUM — Postpartum management is largely based on expert opinion and clinical experience; there are few major randomized trials to guide screening for anemia or iron deficiency after delivery. It is not routine practice to obtain a complete blood count (CBC) or ferritin level at a four- to six-week postpartum visit, but there may be circumstances in which one or both of these tests are appropriate.

Iron repletion is effective by either the oral or the intravenous route, with intravenous iron (administered as a total dose infusion in one hour) producing higher hemoglobin concentration postpartum compared with oral iron. In a small randomized trial (40 patients), intravenous and oral iron both increased the hemoglobin and ferritin postpartum; the improvement at six weeks was greater in the intravenous arm [111]. Intravenous iron has also been used following postpartum hemorrhage. (See 'Oral versus IV iron' above and "Postpartum hemorrhage: Medical and minimally invasive management".)

Studies evaluating the prevalence of postpartum anemia have found it to be common (range, 22 to 29 percent; as high as 35 to 60 percent in some populations, such as those with instrumental delivery, manual removal of the placenta, or third- or fourth-degree vaginal tear) [112,113]. These patient and delivery characteristics do not have a high predictive value for anemia; however, they may be useful if present. If anemia is caused by hemodilution due to pregnancy physiology or by blood loss without iron deficiency, it is likely to resolve within a few weeks.

We advise most individuals to continue their prenatal vitamin and/or supplemental iron for six to eight weeks following delivery, to increase iron stores following blood loss after delivery.

Routine testing for anemia after delivery has been suggested because anemia is prevalent and iron deficiency (the most common cause) is readily treatable [113]. It seems reasonable that a person should be iron replete following pregnancy so that they do not develop iron deficiency anemia in the future; however, high-quality data or guidelines on this subject are lacking. (See 'Screening for anemia and iron deficiency' above.)

Following postpartum discharge from the hospital, anemia may be suspected based on symptoms such as fatigue, depressed mood, or exercise intolerance, although these symptoms may have other causes associated with delivery and/or caring for a newborn. Anemia also may be suspected because of uncorrected anemia during the antenatal period, significant blood loss during delivery (eg, >500 mL), pallor, or ongoing lochia (vaginal bleeding after the birth). Laboratory testing such as a CBC to evaluate for anemia is pursued on a case-by-case basis. Anemia, if present, should be further evaluated with testing for iron deficiency and/or other causes, depending on the patient history, red blood cell (RBC) indices, and other findings on the CBC. (See "Diagnostic approach to anemia in adults".)

Those with iron deficiency anemia postpartum are treated with iron; choice of iron product, route of administration, and dosing are the same as in the antepartum period. (See 'Treatment of iron deficiency' above.)

For individuals who begin iron therapy before hospital discharge because of postpartum anemia, it is reasonable to check the ferritin level and percent transferrin saturation (TSAT) after two to three weeks to confirm that treatment has been successful and that iron stores have been repleted [2,66,114]. This may be done at the postpartum visit or primary care visit. With intravenous iron, the serum ferritin will be abnormal for approximately four weeks, and ferritin testing should be delayed for four weeks. If the ferritin level remains low following treatment, the potential causes must be evaluated. These may include nonadherence, reduced absorption, or ongoing blood loss. The approach to correcting the persistent deficiency depends on the cause. (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)

Individuals with persistent, unexplained anemia should be reevaluated for iron deficiency and/or other causes of anemia. The evaluation is determined by the characteristics of the anemia (eg, RBC indices, reticulocyte count) and the patient's clinical status (eg, blood loss, dietary practices, presence of other chronic conditions). (See "Diagnostic approach to anemia in adults", section on 'Premenopausal females'.)

The evaluation and treatment of iron deficiency in neonates are presented in detail separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Recommendations for iron supplementation' and "Approach to the child with anemia", section on 'Age of patient'.)

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: Anemia in adults".)

SUMMARY AND RECOMMENDATIONS

Definition – The World Health Organization (WHO) defines anemia as a hemoglobin level <11 g/dL (approximately equivalent to a hematocrit <33 percent) in the first trimester, <10.5 g/dL in the second trimester, <10.5 to 11 g/dL in the third trimester, or <10 g/dL postpartum. (See 'Definition of anemia' above.)

Prevalence – Anemia affects approximately 30 percent of reproductive-age females and 40 percent of pregnant individuals, mostly due to iron deficiency. A large number of individuals have iron deficiency without anemia that may progress during pregnancy. Anemia and iron deficiency are more common in Black individuals and contribute substantially to severe maternal morbidity. (See 'Epidemiology and health care disparities' above.)

Causes – Physiologic anemia of pregnancy and iron deficiency are the two most common causes of anemia in pregnancy. Other causes of anemia should not be overlooked. (See 'Causes of anemia' above.)

Screening and evaluation – The algorithm summarizes our approach (algorithm 1).

We screen all pregnant individuals for anemia with a complete blood count (CBC). (See 'Screening for anemia and iron deficiency' above.)

We evaluate all anemic individuals for iron deficiency, consistent with several guidelines. Evaluation for other causes of anemia may also be appropriate for those with an atypical clinical picture and other abnormal CBC findings (eg, signs of hemolysis, abnormal white blood cell [WBC] or platelet count). (See 'Evaluation of anemia' above.)

We screen all pregnant individuals for iron deficiency, especially those with symptoms of iron deficiency (restless legs syndrome, pica) and those at high risk for iron deficiency. (See 'How to screen for iron deficiency' above.)

Our approach is based on evidence that approximately 50 percent of pregnant individuals have iron deficiency. While guidelines remain mixed, a newer statement from the International Federation of Gynecology and Obstetrics (FIGO) and evidence of adverse maternal and fetal outcomes associated with anemia support this approach. (See 'Supporting evidence for risk of iron deficiency and recommendations of others' above and 'Supporting evidence for adverse outcomes associated with anemia' above.)

Iron deficiency can usually be assessed with a ferritin level; selected individuals may require transferrin saturation (TSAT) or other testing. Ferritin <30 ng/mL (<30 mcg/L) or TSAT <20 percent is sufficient to diagnose iron deficiency. Ferritin ≥30 ng/mL is sufficient to exclude iron deficiency if there are no comorbidities. (See 'How to screen for iron deficiency' above and 'Evaluation of anemia' above.)

Prevention of iron deficiency – Prenatal vitamins with iron are appropriate. (See 'Prevention of iron deficiency' above.)

Treatment of iron deficiency – Iron deficiency is treated with oral or intravenous iron; these have different advantages and disadvantages (table 3). (See 'Treatment of iron deficiency' above.)

First trimester – We use oral iron (typical dose, one tablet containing 60 mg of elemental iron every other day or Monday, Wednesday, and Friday (table 4). Every-other-day dosing improves absorption and tolerability. Safety data for intravenous iron in the first trimester are lacking.

Second and third trimesters – Intravenous iron may be appropriate or preferred in some cases (intolerance of oral iron, impaired absorption, severe iron deficiency anemia, significant symptoms), and for those initiating iron after week 30, when there is insufficient time to replete iron stores orally. Several intravenous iron formulations are available with similar efficacy (table 5).

Transfusions – Used only for severe, symptomatic anemia when iron would not be sufficient.

Prevention/treatment of other anemias – Other interventions may be appropriate to prevent or manage other anemias (table 1). (See 'Prevention of other causes of anemia' above and 'Management of other anemias' above.)

Postpartum testing – CBC and ferritin may be checked postpartum but this is not routine. Postpartum anemia should be evaluated. It is reasonable to check ferritin and TSAT after treatment of iron deficiency. (See 'Postpartum' above.)

Evaluation and treatment of infants – (See "Approach to the child with anemia" and "Iron deficiency in infants and children <12 years: Treatment".)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

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Topic 115637 Version 49.0

References

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