Taking ferrous sulfate: How and when to take ferrous sulfate
How and when to take ferrous sulfate
If you or your child are prescribed ferrous sulfate, follow a doctor’s instructions about how and when to take it.
If you buy ferrous sulfate from a pharmacy, follow the instructions that come with the packet.
Dosage and strength
Ferrous sulfate comes as 200mg tablets, or as drops containing 125mg of ferrous sulfate in 1ml.
Your dose of ferrous sulfate depends on why you’re taking it and whether you take tablets or drops.
Dose to treat anaemia
The usual dose for adults is:
- tablets – one 200mg tablet usually once a day, but it may be 2 to 3 times a day. If you get side effects your doctor may advise you to take it on alternate days
- drops – 4ml, taken once or twice a day
For children aged 12 to 17 years, the doctor will use your child’s age and blood results to work out the right dose of ferrous sulfate. For children under 12 years old, the doctor will also use your child’s weight to work out the right dose.
Dose to prevent anaemia
The usual dose for adults is:
- tablets – one 200mg tablet, taken once a day
- drops – 2.4ml to 4.8ml, taken once a day
For children aged 12 to 17 years, the doctor will use your child’s age and blood results to work out the right dose of ferrous sulfate. For children under 12 years, the doctor will also use your child’s weight to work out the right dose.
How to take it
Ferrous sulfate works best when you take it on an empty stomach. If you can, take it 30 minutes before eating, or 2 hours after eating. But if it upsets your stomach, you can take it with or after food.
A doctor (or a pharmacist) may recommend taking ferrous sulfate with orange juice or a vitamin C supplement. Vitamin C is believed to increase the amount of iron absorbed by the body.
Swallow the tablet whole with a drink of water. Do not suck, chew or keep the tablet in your mouth as this can cause mouth ulcers or stain your teeth.
Do not take it with tea, coffee, eggs or dairy products, as they can reduce the amount of iron that gets into your system. When you take ferrous sulfate (or when you eat foods that are high in iron), leave a 2-hour gap before having these foods or drinks.
If you have difficulty swallowing the tablets tell your doctor or pharmacist.
The drops may be easier for children and people who find it difficult to swallow tablets.
If you’re taking ferrous sulfate as drops, it will come with a plastic syringe or dropper to help you measure out the right dose. If you do not have one, ask a pharmacist for one. Do not use a kitchen teaspoon as it will not measure the right amount of medicine.
Keep ferrous sulfate out of sight and reach of children, as an overdose may be fatal.
Ferrous sulfate is not harmful if it’s been prescribed for your child and you follow your doctor’s instructions, or the instructions on the packet.
How long to take it for
To prevent iron deficiency anaemia, you’ll need to take ferrous sulfate for as long as you’re at risk of getting this condition.
To treat iron deficiency anaemia, you’ll need to take it for several months. Your doctor will usually advise you to keep taking it for 3 to 6 months after your condition has improved to help build up your body’s iron supply.
If you forget to take it
If you forget a dose, take it as soon as you remember, unless it’s almost time to take the next dose. In this case, skip the missed dose and take your next dose at the usual time.
Do not take 2 doses to make up for a forgotten dose.
If you often forget doses, it may help to set an alarm to remind you. You could also ask your pharmacist for advice on other ways to remember to take your medicine.
If you take too much
Taking more than the recommended dose of ferrous sulfate can cause vomiting, stomach pain or diarrhoea.
In serious cases you may vomit blood, have a seizure or fit, or become unconscious.
Urgent advice: Contact 111 for advice now if:
- you or your child takes more than the recommended dose of ferrous sulfate
Go to 111.nhs.uk or call 111
If you go to A&E do not drive yourself. Get someone else to drive you, or call an ambulance.
Take the ferrous sulfate packet or the leaflet inside it and any remaining medicine with you.
Page last reviewed: 9 February 2023
Next review due: 9 February 2026
Side effects of ferrous sulfate
Like all medicines, ferrous sulfate can cause side effects in some people, but many people have no side effects or only minor ones.
Common side effects
There are things you can do to cope with these common side effects of ferrous sulfate:
Feeling or being sick (nausea or vomiting)
Try taking ferrous sulfate with, or just after, a meal or snack. Stick to simple meals and do not eat rich or spicy food. If you’re being sick, try small frequent sips of water to avoid dehydration. Signs of dehydration include peeing less than usual or having dark, strong-smelling pee.
If you take contraceptive pills and you’re being sick, your contraception may not protect you from pregnancy. Check the pill packet for advice.
Stomach discomfort or heartburn
Try taking ferrous sulfate with, or just after, a meal or snack. It can help to eat and drink slowly and have smaller and more frequent meals.
Losing your appetite
Eat when you would usually expect to be hungry. If it helps, eat smaller meals more often than usual. Snack when you’re hungry. Have nutritious snacks that are high in calories and protein, such as dried fruit and nuts.
To help with constipation, get more fibre into your diet by eating fresh fruit, vegetables and cereals, and drink plenty of water. Try to exercise more regularly, for example, by going for a daily walk or run.
Drink lots of fluids, such as water or squash, to avoid dehydration. Signs of dehydration include peeing less than usual or having dark, strong-smelling pee. Do not take any other medicines to treat diarrhoea without speaking to a pharmacist or doctor.
If you take contraceptive pills and you have severe diarrhoea for more than 24 hours, your contraception may not protect you from pregnancy. Check the pill packet for advice.
Dark or black poo
This is common when taking iron and is nothing to worry about.
Talk to a doctor or contact 111 straight away if your poo is black and sticky looking, or has red streaks in it, or if you also feel unwell in any other way.
Black stained teeth
Rinse your mouth with water after taking the drops. Do not suck or chew the tablet, or keep it in your mouth.
Speak to a doctor or pharmacist if the advice on how to cope does not help and a side effect is still bothering you or does not go away.
Serious allergic reaction
In rare cases it’s possible to have a serious allergic reaction (anaphylaxis) to ferrous sulfate.
Immediate action required: Call 999 or go to A&E now if:
- you get a skin rash that may include itchy, red, swollen, blistered or peeling skin
- you’re wheezing
- you get tightness in the chest or throat
- you have trouble breathing or talking
- your mouth, face, lips, tongue or throat start swelling
You could be having a serious allergic reaction and may need immediate treatment in hospital.
Other side effects
These are not all the side effects of ferrous sulfate. For a full list, see the leaflet inside your medicines packet.
You can report any suspected side effect using the Yellow Card safety scheme.
Visit Yellow Card for further information.
Page last reviewed: 9 February 2023
Next review due: 9 February 2026
Ferrous sulfate in the treatment of iron deficiency anemia: position maintained
CI – confidence interval
duodenum – duodenum
IDA – iron deficiency anemia
FBC – iron in blood serum
MDA – malondialdehyde
RR – relative risk
OS – oxidative stress
OSH – odds ratio
Pancreas – iron preparations
PE – side effects
SF – ferrous sulfate
GM – gastric mucosa
SRP – free radical processes
The use of iron compounds for therapeutic purposes goes deep into the history of medicine, when these compounds were not yet positioned as a pharmacological class under the heading “iron preparations” (I) and did not have a clear justification for the appointment. Iron compounds began to be prescribed to patients with anemia around 1660 with the aim of “strengthening strength”, not even suspecting that iron was part of hemoglobin, the oxygen carrier. For this purpose, even ordinary iron filings were used. In the 18th century, Count A.P. Bestuzhev-Ryumin (1693-1766) proposed drops containing iron as a tonic and aphrodisiac. These drops, called “Bestuzhevsky”, were a solution of ferric chloride in a mixture of ethanol and ethyl ether. Over time, the arsenal of pancreas was gradually replenished, and doctors, together with their patients, went through a difficult and long way to assess the clinical efficacy and tolerability of various pancreas that filled the pharmaceutical market and competed with each other due to their chemical and pharmacological innovations.
Currently, in clinical practice, there are 2 groups of pancreas, which differ depending on the valence of iron (bivalent or trivalent) included in the preparation. The degree of absorption of ferrous salts is several times higher than that of ferric salts, since they passively diffuse through protein channels, which provides a faster increase in serum iron (HBC) and hemoglobin levels. Preparations containing iron in the ferric state should be used for a longer time, and in case of copper deficiency in the body, they may be ineffective. The degree of absorption is also reflected in the incidence of side effects (PE).
Clinical experience with the use of pancreas, the results of a study of their comparative efficacy and tolerability, data from meta-analyses formed the basis for the creation of national practical recommendations, as well as WHO recommendations for the management of patients with iron deficiency anemia (IDA) [1, 2]. A rich arsenal of oral pancreas produced by various pharmaceutical companies poses the problem of choosing the optimal pancreas in a particular clinical situation for the doctor. At the same time, along with an orientation on the properties of the pancreas (the amount of elemental iron, the presence of additional substances that improve the absorption of iron, valence, dosage form, etc.), the doctor is under constant pressure from publications about the effectiveness and safety of various pancreas. These publications do not always meet the requirements of evidence-based medicine and are sometimes not devoid of some bias. The main target of “attacks” among oral pancreas was ferrous sulfate (SF), the most common dosage form of pancreas prescribed for people with IDA (children, adults, the elderly, pregnant women). As the main negative properties of ferrous iron preparations, in particular SF, discrediting the supposedly given dosage form, the following are given:
– insufficient bioavailability and effectiveness,
– the presence of PE elevated to the rank of toxic action,
– oxidative stress (OS).
Comparative efficacy of oral pancreas. Currently, the first-line drugs for the treatment of IDA are PG for oral administration, among which SF continues to occupy the main place . More than 10 years ago, we conducted a study on the comparative evaluation of the effectiveness of SF preparations (sorbifer durules, ferrofoil gamma) and the preparation of the iron-polymaltose complex ferrumlek in the form of chewable tablets . In all patients, while taking pancreas, a favorable clinical effect was obtained (a significant decrease or disappearance of signs of anemia and sideropenia) and an increase or normalization of hemoglobin levels. However, the most important in this study were the magnitude and rate of increase in hemoglobin levels with the use of these pancreas.
From the 2nd week of treatment, there was a statistically significant difference in the increase in hemoglobin levels between the group of patients who received sorbifer durules and ferrum lek (2.2 g and 1.1 g / l, respectively; p <0.05), and on 3rd week — between the group treated with ferrum lek and two other SG preparations ( p <0.05). On average, the daily increase in hemoglobin level in the groups of patients treated with sorbifer durules, ferro-foil gamma and ferrum lek was 1.8±0.6, 1.4±0.6 and 0.9±0.7 g/l, respectively. The difference in the mean value was statistically significant in all 3 groups: sorbifer durules — ferro-foil gamma ( р <0. 005), sorbifer durules — ferrum lek ( р <0.001) and ferro-foil gamma — ferrum lek ( р <0 .05). The more pronounced effectiveness of iron salt preparations in comparison with iron-containing complexes preparations, apparently, is due to the different bioavailability of these pancreas.
Thus, the increase in hemoglobin level was most pronounced in the drug sorbifer durules. It should be noted that these data actually confirmed our previous results on assessing the magnitude and rate of increase in hemoglobin levels during treatment of patients with IDA with sorbifer durules . In a later study, when comparing the effectiveness of 5 different SF preparations at a daily dose of 70-200 mg of elemental iron, the magnitude and rate of increase in hemoglobin levels were almost the same and were 2.5 and 2.2 for the group of patients treated with ferro-foil and sorbifer durules. g/l/day, respectively , which practically corresponded to our results. According to another study evaluating the effectiveness of SF preparations, in the treatment of women with oncogynecological pathology and diseases of the gastrointestinal tract with sorbifer durules, the increase in hemoglobin levels during the 1st month ranged from 10 to 50 g/l with a median increase of 30 g/l, i. e., about 1 g/l/day . The lower rate of daily increase in hemoglobin level in this study could be due to a heterogeneous contingent of patients (patients with IDA and anemia of chronic diseases) who had different ferrokinetics and sensitivity to the pancreas.
The clinical significance of the high bioavailability of SF can be evidenced by the effectiveness of one of the preparations of SF, sorbifer durules, when administered to patients after bariatric surgery (biliopancreatic shunting) for morbid obesity. According to long-term monitoring data (5 years), in patients who did not take pancreas, significantly lower levels of hemoglobin and iron in blood serum (HBC) were recorded, starting from 4 and 3 years after surgery, respectively . It is noteworthy that similar results were achieved when taking oral pancreas in conditions of a significant decrease in the “intestinal area” of iron absorption, i.e. in situations that would seem to be an indication for the use of pancreas parenterally. However, the high bioavailability of the drug sorbifer durules allows, under conditions of a significant reduction in the area of iron absorption, to achieve absorption adequate to maintain its homeostasis in patients of this category. The presence of ascorbic acid in its composition may contribute to the improvement of the bioavailability of the drug sorbifer durules.
The revealed pattern of increase in hemoglobin level, which was registered already by the end of the 1st week, made it possible to regard this trend as a predictor of effectiveness and an orientation towards continuing treatment with P.Zh. Much later, it was possible to confirm the prognostic value of the rate and magnitude of the increase in hemoglobin levels for predicting the effect of P.Zh. Important results of a meta-analysis of 5 clinical randomized trials evaluating the effectiveness of SF preparations in patients with IDA due to various causes (menorrhagia, postpartum period, inflammatory bowel disease, etc. ) have been obtained. In 73% of cases, there was an increase of 1 mg / dl in hemoglobin levels by day 14 (group 1 – responders to treatment), while in 27% of cases, the hemoglobin level increased by less than 1 g / dl by this time ( Group 2 – non-responders). Subsequently, patients of the 1st group continued to receive long-term therapy with oral pancreas with an effect, and patients of the 2nd group were prescribed pancreas intravenously (iron-polymaltose complexes). The results obtained allowed the authors to evaluate the amount of hemoglobin increase after two weeks of treatment as a predictor of the effectiveness of treatment in the future, and, depending on the dynamics of the hemoglobin level, make a decision on further tactics – to continue taking oral pancreas or prescribing pancreas intravenously . Special calculations showed that the sensitivity and specificity of the “two-week increase in hemoglobin test” were 90.1 and 79.3%, and the predictive value of positive and negative test results was 92. 9 and 72.7%, respectively.
OS and PZh. As is known, preparations of iron salts contain divalent iron, which, after entering the blood, turns into ferric iron for its subsequent inclusion in the hemoglobin molecule. The transformation of ferrous to ferric iron due to the loss of one electron can be accompanied by the formation of free radicals and the activation of free radical processes (FRP) – OS, theoretically capable of negatively affecting physiological processes in various organs and tissues. At the same time, there is an opinion that preparations of iron-containing complexes, which include trivalent iron, are devoid of prooxidant action. This difference between the two groups of iron preparations has been postulated as a disadvantage of iron salt preparations and an advantage of iron complexes. Meanwhile, the ability of iron salt preparations to cause OS has been shown only in experiments and under conditions in vitro . Reality O.S. in the treatment of iron salts in the clinical setting remained unproven [10, 11].
In our study of CRP activity in patients with IDA during treatment with iron salts (sorbifer durules, ferro-foilgamma) and iron-containing complexes (ferrum lek), we failed to identify differences in the dynamics of CRP indicators (basal and stimulated chemiluminescence, malondialdehyde – MDA) and antiperoxide activity of plasma, depending on the prostate taken . Moreover, during treatment with sorbifer durules, there was a statistically significant decrease in plasma MDA levels compared with baseline, and a positive correlation was found between MDA and FSC levels. The obtained results indicate that, contrary to the existing opinion, not only OS does not develop during the treatment of GS, but there is a decrease in PRP activity. Perhaps this is the result of a decrease in the severity of anemia during treatment with sorbifer durules, as well as the presence of ascorbic acid in its composition, which has antioxidant properties. In later works, ambiguous results were obtained regarding the development of OS in the treatment with iron salt preparations. Thus, when studying the effect of SF and the iron polymaltose complex on the processes of peroxidation in pregnant women with IDA, a decrease in the level of MDA, the main indicator of peroxidation activity, and an increase in the total antiperoxide activity of plasma were observed. These changes were expressed to the same extent with the use of bi- and ferric iron preparations . Another study revealed an increase in lipid peroxidation  and a decrease in antioxidant activity in women with IDA who received S.Zh. In any case, the clinical significance of such a “laboratory phenomenon” as changes in PRP parameters against the background of SF use remains unclear and needs further study.
Fluid tolerance. The results of a meta-analysis of placebo-controlled studies assessing the tolerability of oral and parenteral pancreas with the inclusion of 6831 patients  showed that PE in the form of gastrointestinal dysfunction in the treatment of oral SF drugs occurred more often than against the background of placebo (relative risk – RR 2. 32 at 95% confidence interval – CI from 1.74 to 3.08) and RV for intravenous administration (RR 3.05 at 95% CI from 2.07 to 4.48). The frequency and severity of PE in groups of patients with inflammatory bowel diseases and in pregnant women was the same. There was no relationship between PE and daily dose of pancreas in the range of 100–400 mg of elemental iron. In a number of publications, special attention is paid to PE with the use of SF and the obvious clinical effect, the magnitude and rate of increase in hemoglobin levels, the availability and economic benefits of SF are ignored. In the absence of studies of a high methodological level on the safety of SF, for persuasiveness, there are single reports on the toxic effects of SF (damage to the esophagus, stomach, intestines, etc.)  in patients of various ages, without analyzing the specific situation, comorbidity, taking other drugs and etc. Moreover, in an attempt to convince of the toxicity of SG in this work, even a reference is made to the case of poisoning of a child who took 30 (!) Tablets of this drug . The absurdity of this case as an illustration of the toxicity of SF drugs is obvious, since in such situations, in the absence of parental control, any pharmacological drug can be discredited. As an additional argument against SF, the results of an experimental study evaluating the effect of bivalent and trivalent prostate on the function of the liver and kidneys in rats are presented . The results, supported by photographs of iron deposition in the organs, indicate, according to the authors, the toxic effect of ferrous iron preparations compared to ferric. True, it was not taken into account that the study was conducted on rats without signs of iron deficiency, and this could determine the features of ferrokinetics. Therefore, these data from experimental studies cannot be unconditionally transferred to clinical practice. In addition, toxic doses (LD 50 ) sulfate and iron gluconate for white mice are almost the same (11 and 13 mg/kg, respectively), which does not give grounds to speak of a greater “toxicity” of SF . In the last few years, descriptions of cases of iron deposition in the gastric mucosa (GM) and duodenum (DU) in patients with IDA during treatment with P.Zh. have been published. According to researchers , cases of iron deposition in the gastric mucosa and duodenum are not uncommon in the treatment of iron salt preparations and usually disappear after P.Zh. In addition, the deposition of iron in the coolant can occur in various pathological conditions (hemochromatosis, alcoholism, varicose veins of the esophagus with portal hypertension, transfusion of red blood cells, with erosive and ulcerative gastric bleeding). The presence of a local inflammatory process, bleeding, comorbidity, concomitant drug therapy contribute to the deposition of iron in the mucosa in patients treated with oral pancreas . The description of individual cases of erosive processes in the upper gastrointestinal tract with the use of SF does not go beyond spontaneous reports regarding both the number and nature of PE, which were not previously indicated in the characteristics of the drug. These reports of PE only illustrate the class-specific manifestations that are inherent in both PG and other pharmacological drugs and cannot be the basis for excluding or limiting the use of SF drugs in clinical practice. After all, such well-known class-specific manifestations as erosive and ulcerative lesions of the gastrointestinal tract, even with bleeding in non-steroidal anti-inflammatory drugs and glucocorticosteroids, hemorrhages in anticoagulants, allergic reactions, including anaphylactic shock in antibiotics, have never served as a reason for recalling these groups of drugs. from the pharmaceutical market. At the mention of the PE of any pharmacological drug, including SG, the statement of the well-known domestic internist B.E. Votchala: “If a drug has no side effects, it’s worth considering whether it has any effects at all.”
Already in the early attempts to assess the tolerability of the pancreas in a randomized double-blind study, which seemed to anticipate the current lively discussions about the tolerability of various oral pancreas, it was shown that adverse reactions of the gastrointestinal tract were observed equally often when using equivalent doses of preparations of iron salts of three groups – sulfate , fumarate, gluconate . More than half a century later, these results were confirmed by a large clinical material. A comprehensive systematic review, which included electronic databases, Cochrane reviews, as well as clinical trial results and spontaneous reports of PE, analyzed the tolerability of various oral pancreas in patients with IDA. At the same time, 111 studies were analyzed, including 10,695 patients . The lowest frequency of PE was observed with the use of SF containing mucoprotease (general 4.1%, gastrointestinal dysfunction 3.7%). In further analysis of PE, this RV was used as a reference in the regression model. Frequency of P.E. when using other pancreas, the following was found: iron protein succinylate – 7.3% (GI-PE – 7%; odds ratio – OR compared with the reference drug 1.96), iron glycine sulfate – 23.5% (GI-PE – 18, 5%; OR 5.90), ferrous gluconate — 30.9% (GIT-PE — 29.9%; OR 11.06), SF without mucoprotease — 32.3% (GIT-PE — 30.2%; OR 11.21), ferrous fumarate — 47% (GIT-PE — 43.4%; OR 19. 87).
The difference in the incidence of PE in the use of SF with mucoprotease (a drug with a delayed form of iron release) and other PG is statistically significant ( p <0.001). These data not only confirm the well-known fact of PE with the use of oral pancreas, but also clarify the incidence of these PEs in various pancreas. At the same time, the incidence of PE with the use of SF slightly exceeds that for ferrous gluconate and is inferior to ferrous fumarate. The most important in the tolerability of oral pancreas should be considered not so much the belonging of the drug to a specific iron salt (gluconate, sulfate, fumarate, etc.), but the dosage form of pancreas containing products that provide sustained release of iron (SF with mucoprotease). A significant difference in the incidence of PE when using different dosage forms of SF allows critical evaluation of the results of studies on drug tolerability, including reports of various PE in the form of impaired gastrointestinal function without taking into account the dosage form used (regular or sustained release). In this regard, it is appropriate to point out the peculiarity of one of the preparations based on SF with a delayed release of iron – sorbifer durules. Durules technology is based on the presence of an active substance in a biologically inert plastic substance. The release of this active substance occurs gradually – first from the surface, and then from the deeper layers. After complete release, the empty carrier is destroyed and excreted from the intestine. Uniform and gradual release of iron in small amounts contributes to less irritation of the intestinal mucosa and better tolerability of the drug, which is important in long-term therapy P.Zh. The available data on the tolerability and, moreover, the danger of conventional SF dosage forms cannot be automatically transferred to the forms with a sustained release of iron, which are generally better tolerated . As early as the 1970s, three randomized trials showed better tolerability of sustained-release iron preparations compared to conventional pancreatic formulations [25-27]. A systematic review of 106 studies, including more than 10,000 patients treated with various oral prostates , showed a statistically significantly lower incidence of gastrointestinal dysfunction when taking prostate with a sustained release of iron (3.7%) compared with other dosage forms of SF (31.6%), including ferrous fumarate (44.8%).
When making a decision on the appointment of PZh, it is necessary to take into account the balance of benefits and risks, i.e., the question inevitably arises, voiced in the title of one of the articles on the treatment of IDA, “What is more important, efficacy or tolerability?” . Thus, the benefit of SF preparations in ensuring the quality of life in menstruating women with IDA may justify the appointment of PG in this group, despite the reality of emerging PE .
Ways to prevent and reduce the incidence of PE when using SF preparations. To reduce the incidence of PE during treatment with oral pancreas, the following is recommended :
– reduced daily dose,
– increasing the intervals between taking the drug,
– the use of prostate with a sustained release of iron (for example, the “durules” technology),
– taking pancreas with food or milk (in this case, a decrease in iron absorption is possible),
– switching to a pancreas with a lower content of elemental iron (there is a risk of using an insufficient dosage of iron),
– transition to liquid dosage forms (easier dose selection),
– when selecting a dose, it is possible to gradually increase the dose to a tolerable one.
Recent studies of iron absorption and the factors affecting it in iron deficiency may serve as a reason for revising the traditional regimens of P.Zh. Iron absorption is known to be regulated by the hepcidin protein produced in the liver. One study  assessed the absorption of radiolabeled iron in women with iron deficiency (ferritin <20 ng/mL) without anemia while receiving oral pancreatitis at various dosages (from 40 to 80 mg of elemental iron). It has been shown that at a higher dose and frequent intake of pancreas, the level of hepcidin increases, and this leads to inhibition of iron absorption. The elevated level of hepcidin persists for about 48 hours after a single dose of the pancreas, and therefore the absorption of iron after taking the next dose of the drug decreases in a day under the influence of the still remaining elevated level of hepcidin.
The data obtained require confirmation and clarification, since the study was conducted in women with iron deficiency without anemia, who may respond differently to the pancreas than patients with clinically manifested IDA. Nevertheless, these results are fundamentally important, since they can change the paradigm of the PZh dosing regimen (daily dose and frequency of administration) in patients with IDA, which will prevent PE or reduce the frequency of their development.
There is reason to believe that prescribing pancreas with a lower content of elemental iron may provide optimal bioavailability of the drug and a lower risk of developing PE . This assumption can be confirmed by the results of a randomized trial involving 90 IDA patients older than 80 years. After taking oral pancreas containing 15, 50 and 150 mg of elemental iron in the preparation for 2 months, the rates of increase in hemoglobin and ferritin levels were approximately the same and did not depend on the dose . At the same time, the incidence of PE was significantly less when prescribing pancreas with a lower content of elemental iron.
The undesirable effect on the gastrointestinal tract of iron salt preparations can be reduced by taking them with meals or with milk, although iron absorption may be reduced . The appointment of liquid forms of pancreas allows you to change the dosage, but it turns out to be less comfortable for patients, as well as taking other drugs in the form of liquid dosage forms, which can become one of the factors reducing the accuracy of patient compliance with the prescribed treatment regimen. In addition, taking liquid formulations of pancreas can cause staining of the teeth.
One of the ways to prevent PE and reduce the frequency of their development is the use of prostate with a sustained release of iron (for example, the “durules” technology), which provides a gradual and prolonged release of the active ingredient (iron ions). It is noteworthy that the sales volume of one of the preparations of SF with a sustained release of iron (Sorbifer durules) exceeds that of all other oral SFs and remains stable for several years .
The use of sustained-release SF preparations is positioned as the clinical standard for the treatment of IDA, regardless of indication [37, 38].
SG retains its position and continues to be the optimal oral PG in terms of efficacy, tolerability, availability, economy and demand by patients. The available single publications on lesions of the upper and lower gastrointestinal tract that do not reach a dangerous level of spontaneous reports cannot serve as grounds for refusing or limiting the use of the drug in clinical practice. The main ways to reduce the incidence of PE include the preference for dosage forms with a sustained release of iron, the use of smaller doses of the drug, alternating the intake of pancreas (appointment every other day), control of the use of concomitant drug therapy. The persisting poor tolerance of SF, as well as the lack of effect, may serve as an indication for the administration of iron-containing complexes orally or parenterally to the pancreas.
Efficacy and tolerability of iron preparations in the prevention and treatment of anemia in pregnant women Obstetrics and Gynecology
This article discusses the efficacy and acceptability of oral preparations for the treatment of iron deficiency anemia during pregnancy. Information is given on the rate of recovery of hematological parameters, the frequency and severity of side effects of various salts of ferrous iron and hydroxide of the polymaltose complex of ferric iron. It has been shown that, with the same clinical and laboratory efficacy, ferric iron preparations in the composition of the polymaltose hydroxide complex show a higher degree of tolerance and safety in the prevention and treatment of iron deficiency in pregnant women.
Anemia is one of the most common pathological conditions during pregnancy and the postpartum period. Depending on the degree of industrial development of the country, the frequency of anemia in pregnant women ranges from 5.7 to 75%, averaging 41.8%. This means that every year 56 million women worldwide require treatment for anemia . At the same time, the frequency of anemia increases many times from the first trimester of pregnancy to the third.
The most unfavorable regions in terms of the prevalence of anemia in pregnant women are the regions of Africa (55. 8%), Asia (41.6%), Latin America and the Caribbean (31.1%) and Oceania (30.4%). However, even in relatively prosperous regions, such as Western Europe, anemia occurs in almost every fifth pregnant woman (18.7%) . In the Russian Federation, in recent years, the incidence of anemia during pregnancy has increased, and currently it is 35% [5, 7].
Against the background of anemia, the transfer and deposition of oxygen is disturbed, which makes it difficult to provide a vital function – respiration and leads to metabolic imbalance. With anemia during pregnancy, the frequency of preterm birth and placental insufficiency increases by 3-4 times, by 2-3 times by anomalies of labor and bleeding during childbirth, by 2 times by infectious and inflammatory complications in the postpartum period [2, 8, 11, 28].
Iron deficiency anemia (IDA) is the most common form of anemia in pregnant women, accounting for more than 90%. The female body needs 1.5-1.7 mg of iron per day, and with increased loss of iron, for example during pregnancy, with an increased amount of menstrual blood loss, etc. , the need increases. During pregnancy, the need for iron increases from 0.8 mg/day in the first trimester to 6–7 mg/day in the second half .
To meet the needs of a developing fetus, a pregnant woman needs to spend about 300 mg of iron. During a normal pregnancy, the natural loss of this trace element will be about 200-300 mg, about 500 mg more is required to ensure the physiological enhancement of erythropoiesis, 200-250 mg is lost during childbirth. During the entire pregnancy, with a normal diet, a healthy woman receives about 700-800 mg of iron with food. Therefore, it is still necessary to use 400-500 mg of iron, which are consumed from the depot. In this regard, even a slight latent iron deficiency that precedes the onset of pregnancy poses a risk of rapid depletion of the depot and the development of complications during pregnancy.
Usually, the diagnosis of anemia in pregnant women is based on the WHO recommended lower hemoglobin limit of 110 g/l. However, the number of women with a low iron reserve (serum ferritin level less than 12 mcg/l) from 15 to 24 weeks of gestation increases 6 times and continues to increase towards childbirth. At the same time, the vast majority of women (90%) have a hemoglobin level above 110 g/l, which determines the underestimation of the iron deficiency state .
Iron deficiency affects both intrauterine and extrauterine development of the child. During the normal course of pregnancy in a healthy woman, iron ions are actively transported through the placenta. However, with a lack of iron intake to the fetus due to the initial deficiency in the mother, reduced transport and absorption in placental insufficiency, complications of pregnancy, its accumulation in the depot is insufficient.
If the mother is deficient in iron, the breastfed child continues to lack iron intake. Such children are characterized by a large loss of body weight after birth and slow recovery, impaired umbilical cord fall-off and epithelialization of the umbilical wound, a higher incidence of infectious and inflammatory diseases. With IDA in the mother, the frequency of anemia in children at the age of one year reaches 68%, which adversely affects their mental and motor development, reduces the body’s resistance to infections.
The erythropoiesis cycle is a long process and therefore, in order to ensure a stable normal level of hemoglobin in the treatment of IDA during pregnancy, a long-term intake of drugs is necessary to consistently ensure its relief, saturation of the depot (replenishment of reserves) and maintenance therapy. In addition, it should be taken into account that the iron in food is absorbed only by 10–20%, therefore, it is necessary to increase the amount of iron entering the body by 5–10 times in order to meet the daily requirement .
Because of the high frequency and severity of complications of IDA, WHO recommends the routine use of 60 mg of iron and 400 mg of folic acid daily from 12 weeks of gestation until term for preventive medication. With the development of anemia, the dose of iron is doubled (UNICEF/UNU/WHO, 2001). The standard for monitoring the course of normal pregnancy (outpatient care) of the Ministry of Health and Social Development of Russia (No. 662, 2006) provides for the use of iron-containing drugs (such as iron hydroxide polymaltose or fumarate) at a therapeutic dose for 1-3 months. Some countries have developed programs for the prevention of anemia during pregnancy based on weekly iron (usually 60 mg) and folic acid (usually 2.8 mg) for 3 months at a six-month interval in women of reproductive age with a preserved mestrual cycle; daily iron and folic acid (30 mg and 0.4 mg) from early pregnancy in areas where anemia is not a common problem, and daily iron and folic acid 60 and 0.4 mg where IDA is common [17, 19]. At the end of the program, it is recommended to continue taking the drug for 6 months after delivery.
Currently, the most common form of prevention and treatment of iron deficiency and anemia is oral iron supplementation. In most cases, the parenteral route does not have absorption advantages and is indicated for malabsorption in the gastrointestinal tract or the need for urgent saturation of the body with iron (severe anemia, progressive disorders, impending blood loss). Most often for parenteral administration, iron (III) hydroxide sucrose or polymaltose complex is used [10, 12, 31]. Intramuscular and intravenous administration of iron preparations can be combined with allergic reactions, up to anaphylactic shock, pain and discoloration of the skin at the injection site, headaches and venous thrombosis [15, 16, 27].
The calculation of the required dose of the drug is carried out depending on the supply of iron in the depot according to the level of serum ferritin (SF) 1 µg/l SF=8 mg of iron. The normal content of ferritin in healthy women is 32–60 µg/l, which corresponds to 356–480 mg of iron in the depot. If the ferritin level is over 60 mcg/l, iron supplementation is not indicated. The boundary that defines a clear iron deficiency is the level of ferritin less than 12 mcg/L. At the same time, many researchers consider the content of serum ferritin to be less than 20–30 μg/l as a critically low level or even lack of iron stores in pregnant women [22, 33]. With this approach, the number of women who are indicated to take iron supplements during the preparation and during pregnancy is increasing.
IDA medications can be classified into one of two groups: ferrous or ferric. The first to appear were preparations in the form of ferrous salts: sulfate, fumarate, gluconate, ferric chloride. The widespread use of preparations based on ferrous salts is primarily due to the high degree of solubility and dissociation, which determines good absorption in the intestine.
However, oral administration of iron-containing preparations is often accompanied by side effects. The most common of these are a metallic taste in the mouth, nausea, vomiting, abdominal pain, constipation or diarrhea. Less common side effects are hypotension and hemorrhoids . Usually these side effects depend on the dose and appear when taken on an empty stomach.
In addition, it was found that the use of salt preparations of iron (II), especially for prophylactic purposes (orally), is accompanied by increasing oxidative stress [13, 29].
To reduce the frequency and severity of side effects of salt preparations of iron (II), pregnant women are forced to take them with food. However, the combination of iron and food intake is not recommended by the instructions for use, as it disrupts the absorption of the therapeutic drug. Particularly unfavorable for the absorption of iron preparations is the combination with fatty foods, dairy products, coffee and, especially, tea. Also, the absorption of iron is disturbed by its combination with calcium.
In an attempt to avoid the side effects of iron supplementation, alternative regimens have been proposed, including intermittent or low-dose regimens, but these are more effective as preventive than curative regimens [25, 27].
Since one of the main reasons for the poor tolerance of iron preparations are free ions that are part of their composition and are released during the absorption of simple salt in the gastrointestinal tract, in recent years, non-ionic iron preparations – ferric iron in combination with substance of high molecular weight. These drugs include iron (III) hydroxide polymaltose. Due to the large molecular weight, polymaltose hydroxide diffuses through the mucosa of the gastrointestinal tract 40 times slower than ferrous iron, which penetrates the concentration gradient. The structure of the complex is similar to that of the natural iron compound, ferritin, and the iron of this complex is absorbed only by active absorption, mainly in the duodenum and jejunum. Iron-binding proteins located on the surface of the intestinal epithelium absorb iron (III) from the complex through competitive ligand exchange. The mechanism of active absorption does not allow overdose or intoxication with the drug. The complex of iron (III) hydroxide polymaltose is stable, does not release iron ions under physiological conditions and does not have the pro-oxidant properties inherent in iron (II) salts. These qualities explain the lower frequency of side effects and the higher level of acceptability of drugs based on it. Unlike iron salts, food components do not reduce the bioavailability of iron in the polymaltose complex , and therefore iron (III) preparations of polymaltose hydroxide can be taken with food, which not only does not reduce, but increases its absorption .
Comparing the effectiveness of iron sulfate (II) with that of polymaltose complex (III) hydroxide in children from 1 to 6 years old, A.V. Bopche et al. (2009) indicated a higher increase in hemoglobin levels in children receiving ferrous iron. However, the incidence of side effects was 17% versus 7.6% for the ferric iron complex. At the same time, the frequency of gastrointestinal side effects in ferrous sulfate was 2.5 times higher . Similar results were obtained by B. Yasa et al. (2011), who, when studying the efficacy, tolerability, and acceptability of ferrous sulfate treatment, found that it was also more than twice as likely to cause side effects as polymaltose complex (HPC) hydroxide. At the same time, ferrous sulfate was characterized by a more frequent combination of several gastrointestinal side effects (nausea, constipation, abdominal pain, Fig. 1) . As a result, the acceptability of HPC according to the Wong-Baker scale was significantly better (1.63±0.56 versus 2. 14±0.75; p = 0.001, fig. 2).
In another study conducted in adults, with no difference in hemoglobin levels achieved within 2 months of treatment, the incidence of side effects in the group of patients treated with ferrous sulfate was 34.1%, while in those taking iron HPA in the equivalent dose, it was 2 times lower (14.9%; p <0.001) .
While monitoring the protocol for managing patients with “Iron deficiency anemia”, N.I. Nekrasova et al. (2009) showed that the incidence of constipation and epigastric discomfort was more than 3 to 10 times higher with ferrous sulfate than with polymaltose hydroxide. At the same time, due to the severity of side effects, 14% of patients refused further treatment with ferrous sulfate. As a result, despite the higher cost, the treatment of iron HPC turned out to be economically justified, especially with concomitant pathology of the gastrointestinal tract.
The study of the effectiveness of the oral form of iron (III) HPA (200-300 mg/day) in the treatment of IDA of varying severity in pregnant women showed that the first signs of anemia correction appear already at the end of the first week of treatment. First of all, this was noted in women with mild anemia, in whom normal hemoglobin levels were achieved in 15% of cases. In addition, in most cases with mild anemia and in every third woman with moderate anemia, the appearance of reticulocytosis was noted . It should be noted that the improvement in clinical data was somewhat ahead of hematological parameters. Two weeks later, hemoglobin values returned to normal in 394% of women, and after 28 days only 9.09% had signs of anemia, while in one pregnant woman the low level of hemoglobin did not correspond to the normal values of ferritin, which indicated the absence of iron deficiency. Prophylactic administration of 100 mg iron(III) HPA in the risk group prevented the development of IDA in 87% of women at risk for this complication.
Effective prevention and treatment of iron deficiency combined with favorable clinical results: rapid resolution of clinical manifestations of anemia, less incidence of placental insufficiency and preeclampsia.
In a study of similar design, V.A. Burleva et al. (2006) showed that the intake of 100 mg of iron in the composition of the GPC by pregnant women with latent iron deficiency allows maintaining the required levels of serum iron, ferritin, without changes in the content of transferrin and the coefficient of saturation of transferrin with iron. The intake of 200–300 mg of iron in IDA allowed a significant increase in the levels of serum iron, ferritin, and an increase in the saturation coefficient of transferrin with iron.
In 2011, the results of a multicenter randomized controlled trial of the efficacy and safety of the polymaltose complex and ferrous sulfate in pregnant women with IDA were obtained . The results showed that after taking equivalent doses of iron preparations (III and II), an increase in hemoglobin values by 60 and 9Day 0 of treatment was similar, while ferritin levels were higher in the iron polymaltose group. Compliance (in terms of the number of returned packages of drugs) was significantly worse in the ferrous sulfate group (1. 53 vs. 2.97; p = 0.015). Finally, the incidence of side effects was also significantly higher with ferrous salt treatment (29.3 vs. 56.4%; p = 0.015; Fig. 3).
Iron succinate and gluconate, as well as sulfate, show a high rate of recovery of hemoglobin levels, but are inferior to HPA in tolerability [20, 21]. In an experimental study, a comparison of iron sulfate, aminochelate, and GPA showed that the latter has the least toxicity to the tissues of the gastrointestinal tract . Also, HPA showed higher tolerance, better absorption and predictability of the hematological response compared to ferrous fumarate .
Thus, with the same clinical and laboratory efficacy with ferrous salts, ferric iron preparations in the composition of HPA show a higher degree of tolerance, which, in the absence of the risk of overdose and the need to adhere to the fasting regimen, increases the degree of their compliance and expands the possibilities of use in prevention and treatment of iron deficiency conditions in pregnant women.
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Baev Oleg Radomirovich, Doctor of Medical Sciences, Professor, Head of the Maternity Department of the Federal State Budgetary Institution Scientific Center for Obstetrics, Gynecology and Perinatology. academician V.I. Kulakov them. academician V.I. Kulakov of the Ministry of Health and Social Development of Russia; Professor of the Department of Obstetrics, Gynecology, Perinatology and Reproductology of the First Moscow State Medical University.