Iron Overdose in Pregnant Women and its Treatment

Musaratafrin Saiyed

Department of Pharmacology, A. R. College of Pharmacy and G. H. Patel Institute of Pharmacy,

Vallabh Vidyanagar, Anand, Gujarat, India – 388120.

*Corresponding Author E-mail: mssaiyed@arghpharmacy.ac.in

ABSTRACT:

During pregnancy, Iron requirements increase significantly to support the growth of the foetus and placenta, as well as maternal erythropoietic expansion. Iron supplementation is universally recommended for a viable pregnancy, irrespective of maternal Iron status. A food fortification strategy delivering about 10mg Iron per day lowers the proportion of women under risk of Iron deficiency to the range of 6 per cent to 39 per cent in many states. Combining fortification with weekly supplementation would lower the risk to between 1 per cent and 5 per cent. Food fortification and supplementation would expose many women to Iron levels that exceed the tolerable upper level of 45mg per day, producing Iron overload which can be prove to be toxic. Large epidemiological studies show a U-shaped association between maternal ferritin, a marker of Iron stores, and risk of adverse outcomes of pregnancy such as low birthweight, stillbirth, preterm birth (<37 weeks), very preterm birth (<32 weeks’ gestation), and neonatal asphyxia.

KEYWORDS: Iron overdose, Maternal Women, Foetus Growth and Desferrioxamine.

INTRODUCTION:

Iron is essential for normal human physiology, as it is involved in oxygen transport as well as cell growth regulation and differentiation. Iron is a necessary component of haemoglobin, an erythrocyte (red blood cell) protein that transports oxygen from the lungs to the tissues.¹ Iron aids muscle metabolism and healthy connective tissue as a component of myoglobin, another protein that provides oxygen.² Iron is also required for physical growth, brain development, cellular functioning, and hormone synthesis.³

Dietary Reference Intakes (DRIs) were developed by the Food and Nutrition Board (FNB) of the National Academies (previously National Academy of Sciences) and provides intake guidelines for iron and other minerals. The daily iron requirement of the body differs by age group.

Nonpregnant women aged 14 to 18 years, Nonpregnant women aged 19 to 50 years, Pregnant women of all ages, and Breastfeeding mothers all require 15 mg, 18 mg, 27 mg, and 9 to 10 mg of Iron per day, respectively.⁴ DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include (i) Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals. (ii) Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA. (iii) Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals. (iv) Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.^5,6

Table 1: Iron toxicity stage based on time of ingestion, symptoms and clinical manifestations

Stages	Amount of Iron	Time line	Associated symptoms
1	10 - 20 mg/kg of ingested elemental iron	1 - 6 hours after ingestion:	Nausea, vomiting, abdominal pain, diarrhea Intestinal ulceration, edema, small-bowel infarction and necrosis
2		6 - 24 hours after ingestion:	Resolution of GI symptoms, lethargy, tachycardia, hypotension, metabolic acidosis
3	40 mg/kg or greater	12 - 24 hours after ingestion:	Shock from hypovolemia, vasodilation, poor cardiac output, hyperventilation, seizures, coma
4	300 mcg/dL or above	2 - 3 days after ingestion:	Hepatotoxicity, renal failure, cardiac failure
5	500 mcg/dL or above	2 - 8 weeks after ingestion:	Gastric outlet obstruction secondary to strictures and scarring

Iron supplementation is considered necessary during pregnancy. Due to increasing blood volume, fetal growth and depletion of vitamins, minerals and metabolic cofactors, diet alone may not provide enough necessary elements for proper growth. Iron containing supplements are often thought of as benign and are readily available in many forms through retail stores and prescriptions.⁷

Iron was reported to be one of the most widely overdosed medications in pregnant women along with analgesics (particularly acetaminophen), sedatives, antibiotics, and antihistamines. It is important for the clinician to recognize the dangers of iron over use and to understand patient management in an overdose situation, especially in pregnancy.⁸

Mechanism of Iron overdose:

As a transition metal, iron is highly involved in the reduction-oxidation reaction. Iron readily shifts from the ferric (Fe³⁺) to ferrous (Fe²⁺) state by accepting and donating electrons. Between the two different forms of iron, ferric and ferrous, ferrous is better absorbed in the gastrointestinal tract, particularly in the duodenum. Via transferrin (transported iron) and ferritin (stored iron), the absorption of iron is closely regulated.^9,10 Serum iron level peaks at 2 to 4 hours post-ingestion, but serum concentrations of enteric-coated or sustained-release formulations are erratic and warrant serial levels. Approximately 10% of ingested iron is absorbed from the intestine and is subsequently bound to transferrin. Normal serum iron levels range from 50 to 150 micrograms/dL, and total iron-binding capacity (TIBC) ranges from 300 to 400 micrograms/dL. In Iron overload conditions, high Iron concentrations in plasma exceed the Iron-binding capacity of transferrin, and NTBI appears in circulation, damaging cells and tissues through the generation of reactive oxygen species.¹¹

Clinical Manifestations of Iron overdose:

Clinical manifestations of iron toxicity can be divided into five different stages and is associated with the timing of iron ingestion as well as presenting symptoms. [Table 1]

Stages:^12,13

1^st: Initial gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and diarrhea will be common. Severe overdoses may present with early and significant hemodynamic instability.

2^nd: The second stage of iron toxicity involves metabolic acidosis as a result of ongoing cellular damage. While gastrointestinal symptoms may resolve, patients will likely become lethargic, hypotensive, and tachycardia.

3^rd: The third stage represents worsening hemodynamic instability and death may ensue should the patient present for care late or if the iron toxicity is in-adequately managed.

4^th: The fourth stage involves direct cytotoxicity to various organ systems. As severe iron toxicity may cause wide distribution of iron to nearly all organ systems, hepatic toxicity, renal toxicity, and even cardiac toxicity can be observed.

5^th: Failure to appropriately respond to acute iron toxicity may lead to death.

Literature suggests that 10 - 20 mg/kg of ingested elemental iron can cause mild toxicity resulting in gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and diarrhea.

Elemental iron ingestions of 40 mg/kg or greater is considered severe toxicity.

In addition, serum iron concentration of 300 mcg/dL or above can present as moderate toxicity. Serum iron concentration of 500 mcg/dL or above represents severe toxicity and above 1000 mcg/dL can be lethal.

Potential risks of Iron overdose in Pregnant Women:

Iron poisoning during pregnancy can increase the risk of adverse outcomes for both the mother and the fetus. Excessive iron intake can interfere with the absorption of other essential nutrients, potentially leading to nutritional imbalances for both the mother and the fetus.^(14,15) In Iron overload conditions, high Iron concentrations in plasma exceed the Iron-binding capacity of transferrin, and non-transferrin-bound Iron (NTBI) appears in circulation, damaging cells and tissues through the generation of reactive oxygen species. As placental absorption is a saturable process, the foetus remains protected from the effects of Iron overload throughout the pregnancy.^16,17

Adverse Pregnancy Outcomes: These may include preterm birth, low birth weight, and developmental issues for the baby. It also increased the risk of spontaneous abortion (miscarriage) during pregnancy.^18,19

Fetal Growth: The foetus is at risk only when there is maternal clinical decompensation such as Hypotension, Liver failure or Pulmonary failure occurs. Organ failure is associated with higher risk of spontaneous abortion, preterm delivery and even maternal death. Iron toxicity can interfere with the normal growth and development of the fetus, leading to intrauterine growth restriction (IUGR) and related complications.^20-22

Organ Damage: Pregnant women with iron poisoning are at a higher risk of experiencing organ damage, particularly to the liver and kidneys, which can lead to complications for both the mother and the developing baby.²³

Risks to the Placenta:

The placenta can be affected by iron poisoning, potentially leading to placental dysfunction and impairing its ability to supply nutrients and oxygen to the fetus.^24,25

Increased Risk of Maternal Complications: Severe iron poisoning can lead to maternal complications, including cardiovascular problems, central nervous system effects, and other adverse reactions, which can threaten the mother's health and potentially the baby's well-being.²⁶

Need of therapy:

Maternal danger and toxicity should receive immediate evaluation, studies, and therapy. Fears of potential teratogenicity should not interrupt initiation of such treatment, as fetal safety is dependent on maternal health.

Presentations may vary widely as symptoms may differ based on time of ingestion, amount and type of iron pills ingested, as well as if there were any significant co-ingestants involved in the situation.

Iron overdose in pregnancy can be fatal and antidote treatment if appropriate should not be withheld. The majority of second and third trimester iron overdoses, treated with desferrioxamine or other antidotes, will have a normal pregnancy outcome. The risk of spontaneous abortion is low but cannot be excluded.⁸

Common Iron rich foods:

Chickpea, Spinach, Onion Stalks, Fenugreek Leaves, Mustard Leaves, Mint, Lentil, Bengal Gram Whole, Soyabean, Til, Pumpkin, Mutton etc.²⁷

Treatment for iron Overdose:^28-31

· Magnesium Hydroxide: In volunteers ingesting 5 mg/kg of elemental iron, magnesium hydroxide was observed to slow iron absorption, but it did not change peak serum iron levels in volunteers ingesting 10 mg/kg iron.

· Sodium polystyrene sulfonate: A resin, showed a slight trend toward slowed peak serum iron levels (5.7 vs 3.6 hours) when compared with 6 crossover volunteer controls ingesting 10 mg/kg of elemental iron. Peak serum iron levels trended lower, but again, the difference was not significant: 298 and 370 Kg/dL, respectively.

· Activated charcoal: is not recommended for heavy metal poisonings and is not effective at binding iron.

· Gastric Lavage: Gastric lavage is not routinely recommended. The American Academy of Clinical Toxicology (AACT) has revised a position paper in 2004 noting lack of evidence for clinical benefit.

Management:

Polyethylene glycol is the preferred agent for gut decontamination.³²

Intravenous fluids and sodium bicarbonate may be needed for fluid and electrolyte balance.

A 1981 in vitro study showed that increasing gastric pH to 8 could decrease available free iron in the gut. However, animal studies failed to show changes in serum iron levels in rats or in pigs. No successful case reports have reported using oral bicarbonate for the purpose of retarding iron absorption. It should be noted that although oral sodium bicarbonate is not recommended, intravenous (IV) sodium bicarbonate is used routinely to combat metabolic acidosis in significant iron poisoning.^33,34

Patients with systemic symptoms should be given intravenous desferrioxamine.³⁵

Deferiprone is an orally active iron chelator used in the treatment of iron overload in patients with thalassaemia for whom desferrioxamine is unsuitable or ineffective. It may be given by mouthing doses of 25 mg/kg three times daily.³⁶

An initial dose of 1 g is given, either intravenously at a maximum rate of 15 mg/kg per hour, or by intramuscular injection; subsequent doses of 500mg may be given, by infusion over 4 to 12 hours or intramuscularly at intervals of 4 to 12 hours, to a maximum of 6 g in 24 hours. Doses above 100 mg/kg daily are not recommended.³⁷

Published evidence suggests that for an equivalent dose, a longer infusion time results in increased iron excretion. Intravenous infusions can be given whenever the patient comes into hospital for a blood transfusion. Small doses (<200 mg) of vitamin C increase the effectiveness of desferrioxamine probably by facilitating iron release from the reticulo-endothelial system. Higher doses of vitamin C are reported to increase the cardiotoxicity of iron overload. Patients with cardiac failure should not be given vitamin C with desferrioxamine. Desferrioxamine should not be given concurrently with prochlorperazine as prolonged unconsciousness may result. There are two oral agents (desferiprone and deferasirox) licensed for iron overload.³⁸

Deferoxamine is a potent iron chelator, capable of removing intracellular iron and iron from ferritin and hemosiderin. It does not bind iron from cytochromes or hemoglobin. The medication is metabolized by plasma enzymes and is renally excreted.³⁹

CONFLICT OF INTEREST:

We have no conflict of interest to disclose.

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Received on 07.08.2023 Modified on 09.02.2024

Accepted on 14.06.2024 ©Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 2024; 14(3):263-267.

DOI: 10.52711/2231-5659.2024.00043