Iron deficiency and anemia can often occur during pregnancy, and prevention is critical for the health of both mother and unborn baby. Iron supplementation may seem a simple and practical solution, but it is not recommended for everyone as there are risks involved. In this article, we explain in detail the most important considerations.

Why is iron deficiency and anemia more frequent in women?

We produce millions of red blood cells every second, which ensure the transport of oxygen in our blood. This process requires a lot of iron, and our body covers ~90% of its iron needs by recycling older red blood cells. (1) Our biggest store of iron is none other than the red blood cells in our blood, or more specifically the iron-containing hemoglobin they contain.

We have no easy pathway of getting rid of the excess iron; we can only regulate the absorption of incoming iron to some extent. Excessive iron intake can therefore lead to poisoning over time. (2) However, if intake is insufficient and blood loss is high, deficiency can easily develop.

Because young women lose a lot of blood during menstruation and thus a significant amount of iron on a monthly basis, they are much more likely to be iron deficient than men of a similar age. (3) To compensate for this, they need more than twice as much iron, but few people pay it mind.

Pregnancy further increases the need for iron, as the unborn child needs to be sufficiently provided as well, which is about 1,000 mg of extra iron in total. (4) A significant proportion of fertile women do not have iron stores of this magnitude, so it is not surprising that iron deficiency and anemia are common during pregnancy. (5)

Physiological anemia associated with pregnancy

During pregnancy, a kind of physiological anemia occurs, which is thought to facilitate the flow of oxygen and nutrients to the placenta and the fetus, but is not yet a real problem. (6)

From about the sixth week of pregnancy onwards, the volume of blood plasma increases and reaches a maximum value in the 24th week of pregnancy. Plasma volume can be up to 45% higher than in early pregnancy. (6)

Reduced hemoglobin, also known as anemia, is therefore to some extent a natural reaction during pregnancy, which occurs in almost everyone and is beneficial for the development of the fetus.

Excessive hemoglobin levels, which may be due to a lack of this natural physiological response or to excessive iron intake, can lead to problems similar to anemia, as it makes it difficult for nutrients to reach the placenta. (7)

The occurrence of iron-deficiency anemia

Iron deficiency is the most common micronutrient deficiency in the world, affecting billions of people. Fortunately, it is less common in more developed countries due to a more nutrient-dense diet, but for the reasons already mentioned, it can affect up to 25-50% of pregnant women, depending on the population studied. (5,8,9,10)

According to the WHO definition, anemia in pregnancy is defined as hemoglobin levels below 11 g/dl, moderate anemia as between 7-9.9 g/dl and severe anemia as below 7 g/dl. (11) It is important to note that anemia may be caused not only by iron deficiency but also by other micronutrient deficiencies such as vitamin B9 or vitamin B12. (12) Several markers need to be tested for an accurate diagnosis. 

Iron deficiency and anemia during pregnancy have serious consequences for both the mother and the unborn child, so prevention and proper treatment are of paramount importance. (13)

Surveys suggest that in European countries, 40-55% of menstruating women have low iron stores (where serum ferritin <30 mcg/L), the prevalence of iron deficiency is 10-32% (ferritin <12-15 mcg/L), while the prevalence of iron deficiency anemia is 2-5% depending on the cut-off values used. (5)

Controlled trials have shown that 28-85% of women who did not supplement iron during pregnancy had iron deficiency by the end of the third trimester, and the prevalence of iron-deficiency anemia increased to 21-35%. (5) This indicates that iron stores are completely depleted in many women by the end of pregnancy.

Diagnosing iron deficiency and anemia

Various markers are used to detect iron deficiency. The more tests a person does, the more accurate a picture they can get of their iron status. 

Hemoglobin

A general blood count and hemoglobin level are often used to diagnose iron deficiency, but these only show anemia. The test has the advantage of being cheap and easily available, but unfortunately it does not reveal iron deficiency per se.

The incorporation of iron into hemoglobin is a crucial process, so anemia is the final stage of iron deficiency, when the problem is very severe. The hemoglobin level does not indicate mild iron deficiency, but at this stage negative effects can already be seen at the tissue level and the development of the unborn child may be impaired. (14)

In addition to iron deficiency, many other things can also cause low hemoglobin, such as other diseases or the nutrient deficiencies mentioned earlier. (12,15)

Ferritin

Ferritin is a stored form of iron, and it is the level of ferritin that is the most accurate way to determine the body's iron stores. If ferritin levels are low, it indicates that there is not enough stored iron, which can lead to iron deficiency over time.

Measuring ferritin levels is not perfect either, as chronic inflammatory conditions or infections can cause the body to try to lock up iron, which can cause ferritin levels to rise significantly. To detect this, it is necessary to test in combination with an inflammation marker such as CRP. (16)

The combined hemoglobin and ferritin levels are a relatively good indicator of iron deficiency and anemia. To avoid iron deficiency during pregnancy, more than 500 mg of stored iron is required, which corresponds to a ferritin level of about ~70 mcg/L. (17)

Transferrin and total iron-binding capacity

Transferrin is responsible for iron transport: when there is too little iron available, the body produces more transferrin, so higher levels indicate iron deficiency. (18)

Transferrin levels can be measured directly, but alternatively, total iron-binding capacity can be determined, which shows how much iron can be bound by the transferrin present in the serum. (19)

In iron deficiency, total iron-binding capacity and transferrin levels are both elevated, while certain inflammatory diseases or nutrient deficiencies may reduce their levels. 

Serum iron

This refers to the amount of free iron in the blood that is transported by transferrin. Too low a level may indicate iron deficiency, but it is significantly affected by recent iron consumption and should not be relied upon as a predictor of iron deficiency. (20)

Transferrin saturation

It shows the percentage of transferrin proteins that are saturated with iron. It is calculated as the ratio of serum iron to total iron binding capacity, which is normally around 30%. (21) 

Serum iron concentration decreases in the early stages of iron deficiency, resulting in lower transferrin saturation. In the later stages of iron deficiency, transferrin concentrations increase to optimize the iron-binding capacity for transport, but this results in even lower transferrin saturation.

Low transferrin saturation is therefore also a useful value to help identify iron deficiency.

Consequences of iron deficiency during pregnancy

It is clear that iron deficiency in pregnancy, and especially iron deficiency anemia, is associated with many health problems. The mother may become ill more easily, the baby may be born with low birth weight and there may be an increased risk of premature birth. (22)

Fortunately, in mild iron deficiency, the body favors the fetus, so the unborn child is usually protected from the harmful consequences of iron deficiency. (23) 

In severe iron depletion, however, a deficiency may even present itself in the placenta, with negative short- and long-term consequences for the fetus and the child's later development. Other risk factors can also cause reduced iron delivery to the fetus, such as high blood pressure, diabetes, smoking or twin pregnancy. (24,25,26)

Since iron is very important for energy production and is necessary for proper neurodevelopment, severe iron deficiency in the mother can affect the brain and neurodevelopment of the unborn child. Cognitive abilities such as memory may be impaired by severe iron deficiency. (27,28,29)

Children who have not received enough iron as fetuses are much more likely to develop iron deficiency. As the iron content of breast milk is very low, they can only rely on the iron stores accumulated during gestation. (30)

Iron deficiency in early childhood may also be associated with impaired development of many cognitive skills and increased social dysfunction, and may increase the development of anxiety and depression in later life. (31,32,33)

How can we prevent iron deficiency through diet?

To prevent iron deficiency during pregnancy, iron stores need to be replenished well in advance. We can do this mainly through our diet and by avoiding frequent blood donations.

The absorption of heme iron in meat and fish is much better than that of iron in plants, (34) and even the iron in plants is better utilized when consumed with animal protein. (35,36) Those not following a vegetarian or vegan diet and considering having children should eat these foods regularly to improve their iron intake.

Absorption of plant iron is not very high, but citrus fruits and vitamin C significantly increase it. (37) In contrast, calcium-rich foods, (38) polyphenols and "anti-nutrients" found in whole grains, legumes, seeds, tea, coffee and vegetables can significantly reduce absorption. (39,40)

Certain drugs, such as proton pump inhibitors used for reflux, also interfere with iron utilization. (41)

Tea, coffee and calcium-rich foods should therefore be separated from iron-rich sources in good time, and vitamin C-rich foods or vitamin C supplements should be eaten alongside plant foods. Soaking, sprouting, fermenting and thoroughly heating grains and pulses significantly reduce phytic acid and other anti-nutrients, so that more iron is utilized. (42)

For vegetarians and vegans, it is particularly important diet to pay attention to iron intake and to adopt these strategies, as they are more likely to have iron deficiency. (43,44)

Since our nutrition as a whole provides only a few mg of iron per day, it can take several months to replenish depleted iron stores, so it is not recommended to rely on this alone for severe iron deficiency, especially during pregnancy. 

Supplementing lactoferrin

Pregnancy lactoferrin supplementation has been studied on several counts and has been successful in boosting hemoglobin and iron levels, often better than iron supplementation itself. (45)

An additional advantage over iron supplementation is that it causes no digestive complaints or other unpleasant side effects. Another in-depth article is already available on the subject, presenting the results of lactoferrin in detail, so we will not go into this in detail here. (46) It is important to note, however, that lactoferrin does not contain iron by itself, so it is important to follow dietary strategies alongside it.

Supplementing iron during pregnancy

With so many women affected by iron deficiency in pregnancy, iron supplementation may seem like an obvious solution for everyone. However, iron supplementation has well-known side effects and too high an intake can cause many problems.

High doses of iron supplementation are usually associated with constipation and other intestinal side effects, including nausea, vomiting and diarrhea, the frequency and severity of which depend on the amount of elemental iron released. (47,48)

Gastrointestinal complaints are a well-known side effect, but iron supplementation may also increase inflammation, potentially lead to oxidative damage to cells or DNA, or even provide nutrients for certain pathogens, promoting their proliferation and negatively affecting gut flora. (49)

Although severe iron deficiency can impair children's cognitive development, the evidence is not clear whether iron supplementation helps to correct this: several reviews have found it to be ineffective. (27,28)

According to a 2015 summary, iron supplementation in pregnancy helps prevent iron deficiency, anemia, and iron deficiency anemia in mothers at delivery, but has no significant effect on the risk of preterm birth and birth defects, or on children's weight. (50)

In a recent summary, iron supplementation in pregnancy had a similar effect in women with normal iron levels, helped prevent the development of iron deficiency and, based on the studies included here, reduced the risk of low birth weight, although relatively few studies reported in detail on the risks and side effects. (51)

For both iron intake and hemoglobin levels in pregnancy, a U-shaped curve, typical of most micronutrients, is observed in terms of risk factors, with both too low and too high levels being problematic. (52,53) For iron, it is particularly important to find this healthy range, as it is much narrower than for other micronutrients; when supplementing, it is therefore advisable to monitor levels regularly.

A randomized trial in 2007 showed that, in the presence of higher hemoglobin levels, iron supplementation during pregnancy had no benefit, but increased high blood pressure and resulted in a greater number of low birth weight babies. (54) 

Because of the potential dangers of iron supplementation and the mixed results, most European and American health and gynecological organizations do not recommend it for all women during pregnancy, (55,56,57) unless there is a proven iron deficiency. However, it is considered important to screen for iron deficiency, and if iron deficiency is confirmed, it is agreed that iron supplementation has more benefits than potential harms.

Studies on iron supplementation

Patients with iron deficiency anemia should be treated to replenish iron stores and normalize hemoglobin levels. This improves quality of life, reduces the risk of chronic disease and mortality, and improves pregnancy outcomes. (58)

Iron sulphate is used primarily to treat iron deficiency because it is inexpensive, has good bioavailability and effectively replenishes iron stores, which helps to eliminate anemia. The problem is that it causes very frequent gastrointestinal complaints, mainly constipation, but also nausea and diarrhea. Many people are forced to stop the therapy because of the unpleasant side effects, sometimes before their iron deficiency has resolved. (47)

There is not complete agreement on how much iron sulphate should be used to treat iron deficiency, but as the body can only utilize a limited amount of iron, overly high doses provide no benefit, but can significantly increase side effects.

A 2020 study found that if women with iron deficiency supplemented only every other day, they would utilize nearly twice as much iron as if they supplemented the same dose every day. (59)

The presumed reason for this is that the body senses the arrival of large amounts of iron and reduces its absorption for 24 hours, even in iron deficiency. 

In a randomized trial in elderly subjects, supplementation with 15 mg, 50 mg, and 150 mg of elemental iron per day increased hemoglobin levels to the same extent, but higher and higher doses caused increasing side effects. (60)

In one summary, intermittent iron supplementation (1, 2 or 3 times a week) was as effective as daily iron supplementation in raising hemoglobin levels and caused far fewer side effects in pregnant women. (61)

It may therefore be worth avoiding too high doses and trying intermittent supplementation.

There are several new generations of iron preparations that have the advantage of better utilization and/or fewer side effects than iron sulphate. A few active ingredients in brief:

As is true for other minerals, iron has a much better utilization in organic forms such as iron bisglycinate. In a randomized trial, 25 mg of iron bisglycinate was as effective in preventing iron deficiency as 50 mg of ferrous sulfate and caused fewer gastrointestinal side effects. (62)

Sucrosomial® iron, is a proprietary carrier material that locks the iron in a membrane so that the free iron does not come into contact with the digestive tract wall. The advantage is also better utilization and fewer digestive side effects. It has also been more effective than conventional iron sulphate in boosting hemoglobin levels at much lower doses. (63) In other studies, it has been shown to boost hemoglobin levels in some chronic patients in a similar way to intravenous iron supplementation.(64)

Ferric maltol is an iron supplement in which the iron is linked to a sugar derivative. This facilitates its absorption as less free iron is produced, thus reducing free radical formation, and a lower dose is sufficient for better utilization. It has been tested in people with inflammatory bowel disease and was effective in increasing hemoglobin levels compared to placebo. (65)

Sodium ferro-cedetate is a water-soluble iron preparation that in a clinical trial was more effective than ferrous sulphate in increasing hemoglobin levels, with far fewer side effects. (66)

Intravenous iron supplementation

Another alternative to traditional iron supplementation is intravenous supplementation. It has the advantage that hemoglobin levels normalize much faster and, because it bypasses the digestive tract, it does not cause digestive complaints. The old formulations had several side effects, which are much less common with the newer formulations. (67,68) However, intravenous iron supplementation may increase the risk of infections even compared to oral iron supplementation.(69)

Finally, for very serious cases, we ought to mention blood transfusions, which can be risky and are usually used as a last resort. (70,71)

Summary

• Iron deficiency and iron-deficiency anemia affect a significant proportion of pregnant women and it is important to treat it.
• Anemia may have other causes, it does not necessarily mean iron deficiency.
•  Physiological anemia during pregnancy is natural  to some extent and beneficial for the development of the fetus.
• If you are planning to have a baby, you should take extra care with your iron intake to ensure that you stock up your iron stores in good time. A number of dietary strategies can help with this.
• Lactoferrin supplementation is an effective and safe way to increase hemoglobin and iron levels, even during pregnancy.
• Iron supplementation should only be started if iron deficiency or iron deficiency anemia is confirmed. Intermittent or alternative daily supplementation is more effective and may also help reduce side effects.
• High doses are not necessarily more effective but may have many more side effects.