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Fatal Folic Acid Toxicity in Humans



Folic acid is B-9 vitamin. Folic acid is prescribed commonly for pregnant women to prevent neural tube defects in the fetus,patients under chemotherapy, pernicious anemia and to reduce the risk of stroke and cardiovascular disease. Acute or chronic ingestion of a large dose of folic acid generally manifests as neurological complications, which are reversible. In this present case, a 23-year-old pregnant woman committed suicide by consuming folic acid tablets and succumbed to death within 36 h. Postmortem toxicological analysis detected folic acid in viscera. Death following acute consumption of folic acid is rare and has been not reported in the literature, to the best of our knowledge
Gerard Pradeep Devnath,
M.B.B.S., M.D.; Senthil Kumaran,
M.B.B.S., M.D.; R. Rajiv,
M.Sc., M.Phil.;
Kusa Kumar Shaha,
M.B.B.S., M.D.; and Ashok Nagaraj,
M.B.B.S., M.D.
Fatal Folic Acid Toxicity in Humans
ABSTRACT: Folic acid is B-9 vitamin. Folic acid is prescribed commonly for pregnant women to prevent neural tube defects in the fetus,
patients under chemotherapy, pernicious anemia and to reduce the risk of stroke and cardiovascular disease. Acute or chronic ingestion of a
large dose of folic acid generally manifests as neurological complications, which are reversible. In this present case, a 23-year-old pregnant
woman committed suicide by consuming folic acid tablets and succumbed to death within 36 h. Postmortem toxicological analysis detected
folic acid in viscera. Death following acute consumption of folic acid is rare and has been not reported in the literature, to the best of our
KEYWORDS: forensic science, folic acid, pregnant woman, suicide, toxicological analysis, histopathology
Suicide among pregnant women is not an uncommon scenario.
Expectant mothers who commit suicide are mostly likely juve-
nile, single, belonging to the low socioeconomic status, or drug
addicts. Suicides commonly noted in their second trimester of
first pregnancy. Poisoning is the most common method adopted
by the pregnant women (1).
Folic acid is prescribed for pregnant women in their first tri-
mester to prevent neural tube defects in the fetus (2). Folic acid
tablets are relatively safe with wide therapeutic margin. Acute
toxicity is uncommon due to consumption of large doses, which
manifest as gastrointestinal disturbance and central nervous sys-
tem features, which are reversible (25). Chronic toxicity is seen
in patients with pernicious anemia on folic acid drugs. However,
neither acute nor chronic toxicity is rarely fatal. Death due to
consumption of large doses of folic acid has not been reported
in the literature (2,3). We highlight a case of death in pregnant
women due to folic acid poisoning and its complication.
Case Report
A 23-year-old female consumed 3040 white-colored tablets
following a family dispute. The patient presented in a state of
shock with the rigid abdomen. There was no history of the
deceased suffering from typhoid, tuberculosis or cancer, or use
of any medications such as NSAIDs. The patient was clinically
diagnosed to have gastrointestinal perforation with metabolic aci-
dosis. However, the exact details of the drug consumed were not
available; the victim was treated for an iron overdose, based on
clinical and laboratory investigation. The patient survived for
36 h in total and expired despite treatment.
At autopsy, there was no evidence of any external injury. The
abdomen had one liter of blood-tinged fluid mixed with pus.
Two ileal perforations of size 1 cm diameter, separated by a dis-
tance of 4 cm, and placed 42 cm proximal to the ileocaecal
junction with the intestinal mucosa being hemorrhagic were
found (Fig. 1). The stomach contained 100 mL of brown-colored
fluid along with an intact white-colored tablet; the gastric
mucosa is hemorrhagic (Fig. 2). The tablet was recovered and
preserved for toxicological analysis. The liver showed yellowish
discoloration, and the kidneys were congested. A male fetus with
a crown-heel length of 29 cm and weight 650 g with red,
wrinkled skin was present in the uterine cavity.
Sections from the liver, kidney, gastric mucosa, loop of the
intestine with the perforation site, and mesentery were sent for
histopathological examination. Histopathology reports of liver
showed submassive hepatic necrosis. Kidney showed massive
acute tubular necrosis (50%), with inflammatory infiltrate in
interstitium evident of subcortical infarction. Gastric wall
showed erosion of lining epithelium with lympho-plasmacytic
infiltrate. Perforation site showed extensive ulceration of the lin-
ing epithelium with dense fibrinous exudates involving the full
thickness of intestinal wall and areas of ischemic infarction.
Mesentery shows areas of hemorrhagic infarction. Toxicological
analysis report of the viscera (stomach, intestine, liver, and kid-
ney) detected folic acid. Half of tablet recovered from the stom-
ach was found to be folic acid tablet. When the clinical,
pathological, and histopathological findings were suggestive of
iron poisoning, toxicology analysis was positive for folic acid.
Hence, the above-reported histopathological features may be due
to the unique toxic effects of folic acid, with no literature data
available to substantiate, may be first of its kind to be reported
in the literature.
Folic acid is available as monocomponent tablets or in combi-
nation with other vitamins and minerals. Strengths usually
Department of Forensic Medicine and Toxicology, Jawaharlal Institute of
Postgraduate Medical Education and Research (JIPMER), Puducherry
605006, India.
Scientific Officer, Regional Forensic Science Laboratory (Villupuram),
605602, Tamil Nadu, India.
Received 20 Jan. 2017; and in revised form 2 Feb. 2017; accepted 6 Feb.
1©2017 American Academy of Forensic Sciences
J Forensic Sci,2017
doi: 10.1111/1556-4029.13489
Available online at:
available are 100 lg, 250 lg, 400 lg, 800 lg, 1 mg, and
5 mg. Folic acid is absorbed in the proximal portion of the
small intestine following oral administration. (6) Blood folate
level reaches peak activity after oral administration within
3060 min. Average folate concentrations in plasma range
from 9 to 45 nmol/L, and concentrations below 9 nmol/L are
considered folate deficient (6). Enterohepatic circulation of
folate has been demonstrated and is mainly concentrated in
the liver (7).
Oral folic acid usually is not toxic. Even with doses as high
as 15 mg/day, there have been no substantiated reports of side
effects. There are few reported cases of severe allergic reactions
characterized by nausea, vomiting, itching, erythema bron-
chospasm, hypotension, and shock. Undesirable gastrointestinal
and central nervous system effects have also reported. But in
none of the above cases, the fatality was not reported. (25)
From 1998 to 2003, Texas Poison Centre received 650 cases
involving folic acid as a single-ingredient product. Of which,
55% were human exposure and 94.8% had no adverse effects
(8). There is only one reported case of pregnant women who
committed suicide by consuming folic acid at the dose of 120
150 mg. However, there were no toxic effects reported in either
the mother or the fetus in the above case (9). In this instance,
the fatality was following consumption of 3040 tablets, lead-
ing to small intestine perforation, substantiated by the fact that
folic acid absorption is maximum in the small intestine. There
is one reported case of small intestine perforation following
folic acid tablet consumption according to FDA (10). In this
case, the perforation is mostly likely due to the local effect of
the drug. Submassive hepatic necrosis was present which is
due to enterohepatic circulation of folic acid and its metabo-
lism in the liver (8). Common cause for acute hepatic necrosis
is drugs/toxins, and folic acid was detected in liver, strongly
supporting that hepatic necrosis is due to folic acid. Acute
tubular necrosis has been demonstrated in experimental mice
following administration of folic acid in various studies, coin-
ciding with the finding of massive acute tubular necrosis in
this case (11,12).
Toxicological analysis was extensively carried out in this sam-
ple. Initial tests were carried out in line for iron, and all tests
were negative for iron, including atomic absorption spectrometry
(AAS) being the confirmatory test for iron. Subsequently, the
test sample in UV spectrophotometer gave a peak at 283 nm
indicative of folic acid. Following which a thin-layer chromatog-
raphy was performed, and the plate viewed under UV and folic
acid appeared as dark zone under 254 nm. There are many ana-
lytical data regarding folic acid detection in pharmaceutical folic
acid preparation and samples. The results of these many analyti-
cal data matched with our test results (13). With all the available
toxicological technique, the tests were carried out, and folic acid
was detected in stomach, liver, kidney, blood, and in the tablet
recovered from the stomach. Based on the clinical features,
autopsy findings, and histopathological features of this case, sup-
ported by a toxicological analysis report, we concluded that the
death was due to fatal folic acid poisoning and complications
The present case, after a complete workout, turned out to be a
case of folic acid poisoning. With a scant literature available to
back up the folic acid poisoning, we conclude that acute folic
acid ingestion can also be fatal, based on this case findings.
Hence, the above-reported histopathological findings and autopsy
findings may be unique manifestations of folic acid poisoning in
1. Czeizel AE. Attempted suicide and pregnancy. J Inj Violence Res
2. Kaushansky K, Thomas J. Hematopoietic agents: growth factors, miner-
als, and vitamins. In: Brunton LL, Lazo JS, Parker KL, editor. Goodman
& Gilmans the pharmacological basis of therapeutics, 11th edn. New
York, NY: McGraw Hill, 2006;145862.
3. Hunter R, Barnes J, Oakeley HF, Matthews DM. Toxicity of folic acid
given in pharmacological doses to healthy volunteers. Lancet 1970;295
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(accessed August 2016).
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FIG. 2–– Stomach containing an intact white-colored tablet even after
stomach wash, with hemorrhagic mucosa.
FIG. 1–– Perforation site shows extensive hemorrhage and ulceration.
8. Forrester MB. Folic acid calls to poison centers in Texas, 19982003.
Hum Exp Toxicol 2005;24(8):4237.
9. Czeizel AE, Tomcsik M. Acute toxicity of folic acid in pregnant women.
Teratology 1999;60(1):34.
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folic acid in mice. Experientia 1985;41(1):723.
12. Lakshmaiha N, Bamji MS. Half-life and metabolism of 3H-folic acid in
oral contraceptive treated rats. Horm Metab Res 1981;13(7):4047.
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Additional information and reprint requests:
Gerard Pradeep Devnath, M.B.B.S.
Department of Forensic Medicine and Toxicology
Jawaharlal Institute of Postgraduate Medical Education and Research
... In many countries, during maternal/fetal health programs; medicines such as iron, folic acid, vitamin D are given free of charge. Although many of these drugs are given as replacement therapy, they are known to have serious effects at toxic doses [12,18,26]. Acute iron and folic acid toxicity in pregnancy are relatively well-known because they are more common, and cases with a different course from asymptomatic to mortal course have been reported [12,21,26]. ...
... Although many of these drugs are given as replacement therapy, they are known to have serious effects at toxic doses [12,18,26]. Acute iron and folic acid toxicity in pregnancy are relatively well-known because they are more common, and cases with a different course from asymptomatic to mortal course have been reported [12,21,26]. The fact that these drugs are free and easy to access may cause them to be preferred frequently for SA, and it was observed that they were used at a high rate (20%) in our series too. ...
Background: Maternal death, fetal death and suicidal attack (SA), each one of these topics are an important public health problem. A suicide attack attempt during pregnancy includes all these important issues together and requires additional attention. Some factors may show regional differences such as suicidal method, distribution of attempts according to the gestational week and the most common preferred drugs. The predetermination of these variables may allow taking preventive measures and advantages can be gains on maternal-fetal health. Methods: The data of pregnant women who were admitted to 3 different university hospital emergency departments in same city between 2015 and 2020 after a SA was investigated. SAs features and distribution of attacks based on variables such as age, gravidity and gestational week etc. was recorded. In addition, obstetric/non-obstetric injuries and pregnancy outcomes was also analyzed. Results: The mean age of 78 cases was 26.9 ± 6.4 (17-44) years. SAs were detected most frequently in the 1st trimester (42.3%) and at least in the 3rd trimester (20.5%). The most preferred SA method (89.7%) was high-dose drug intake. The most commonly preferred drugs were paracetamol, iron/folic acid replacement therapy drugs and antidepressants. Conclusions: Pregnant women are at risk of SA, especially in the first trimester. Contrary to popular belief, 75% of pregnant women who have SA do not have a known psychiatric disease diagnosis before. Therefore, psychiatric evaluation should be a part of routine pregnancy follow-up examination, especially in the first trimester. In this way, pregnant women which have increased risk factors for SA such as alcohol addiction, unwanted pregnancy, and depressive mood can be detected early. In this special patient group, the most commonly SA method is high-dose drug intake. Knowing the high dose treatments for frequently used drugs such as paracetamol by emergency physicians and obstetricians, educating medical staff about treatments can save additional time for mother and fetus and can be a life saver approach.
Full-text available
The aim of the Budapest Monitoring System of Self-Poisoning Pregnant Women was to evaluate the potential congenital abnormality inducing effect of extremely large doses of drugs among pregnant women who attempted suicide. This system was appropriate to describe the characteristics of these pregnant women as a secondary finding from this model. All self-poisoned patients were cared for at a toxicological inpatient clinic in Budapest, between 1960 and 1993. Of a total of 1,044 pregnant women identified from the three different periods of the project, only 19 (1.8%) died. Women who survived were visited at home to reveal birth outcomes, and their exposed children were examined medically to identify congenital abnormalities and tested to estimate their cognitive-behavioral status. The previous or subsequent children of these pregnant women were used as controls with a similar examination protocol. In general, self-poisoned pregnant women were young (peak age was between 18 and 20 years), 62% had their first pregnancy, 55% were unmarried, they had lower socioeconomic status, 46% were smokers and 22.5% drinkers, but depression/panic disorder occurred only among 17 pregnant women. Suicide attempts with drugs were most frequent in the fourth post-conceptional week and second month of pregnancy. In general they used smaller doses of drugs for suicide than non-pregnant age-matched women. Of 1,044 self-poisoned pregnant women, 926 had known pregnancy outcomes and 411 (44.4%) delivered live-born babies. The self-poisoning model appears to have several benefits (e.g., dose-response estimation of drugs) in comparison with other methods when evaluating teratogenic/fetotoxic effect of drugs. It is suggested that an international monitoring system of self-poisoned pregnant women should be established to provide a larger data base. ‎
A trial to elucidate the effect of folic acid in pharmacological doses (15 mg. daily) on serum-vitamin-B12 levels in a group of fourteen healthy volunteers was abandoned after 1 month of a projected 3-month period because of the unexpected development of increasingly disturbing toxic effects in the majority. Most of the subjects experienced mental changes, sleep disturbance and gastrointestinal symptoms. Possible mechanisms of these effects are discussed.
Folic acid (FA) or pteroyl-L-glutamic acid, chemically known as N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid, is a water-soluble B vitamin that helps build healthy cells. In this study, a new, simple, easy, accurate, precise, economic and sensitive UV spectrophotometric method for the determination of folic acid in commercial tablets and during dissolution tests is presented. Using a phosphate buffer solution at pH 9.0 it was possible to determine the concentration of folic acid in commercial tablets at a lambda(max) of 282.5 nm in a linear range of 1.0-17.5 mu g ml(-1) with a R-2 > 0.9999 and recovery between 100.6 and 101.1%. The method was also optimized for the quantification of folic acid in dissolution tests in the same linear concentration range. The pH effect on the UV spectra of folic acid solutions was eliminated with a first derivative. This procedure allowed the direct measurement of samples from the dissolution vessel (pH approximately equal to 6) without any pH correction. This method was based on the first derivative of the absorbance at lambda = 377.2 nm, yielding an R-2 > 0.9997 with recovery percentages similar to those presented before. The statistical comparison between the proposed and the HPLC reference method showed excellent agreement and indicates no statistically significant difference in accuracy and precision at a 0.05 significance level.
The present review summarises the neurotoxicological effects of folic acid. Some studies in animals have shown that folic acid is neurotoxic and epileptogenic when applied directly to the brain. One poorly controlled and not further reproduced study from 1970 reported neurotoxic symptoms like malaise, sleep disturbances, and mental changes in 14 healthy volunteers who took daily 15 mg of folic acid for one month. Five years later seizures were reported in a patient with poorly controlled epilepsy after high intravenous doses of folic acid. There are no further data that indicate that oral folic acid is directly neurotoxic in humans. Clinical studies, where daily doses of 5 to 15 for up to 3 years were applied, did not shown any evidence of folate associated neurotoxicity. It is outlined that rather a deficiency in folic acid, that induces a decrease in the synthesis of S-adenosyl-homocysteine and accumulation of homocysteine, may lead to neurotoxicological damage. Het huidige literatuuroverzicht vat de neurotoxische effecten van foliumzuur samen. Enkele dierexperimentele studies gaven aan dat foliumzuur, indien direct toegediend in de hersenen, neurotoxisch en epileptogeen is. In 1970 maakte een, overigens slecht gecontroleerde en niet gereproduceerde, studie melding van neurotoxische symptomen, zoals malaise, slaapverstoring en mentale stoornissen in veertien gezonde vrijwilligers, die een maand lang dagelijks 15 mg foliumzuur oraal kregen toegediend. Vijf jaar later werden convulsies gemeld na hoge intraveneuze toediening van foliumzuur aan een patient met een slecht gecontroleerde epilepsie. Overigens zijn er geen gegevens, die duiden op een direct neurotoxisch effect in de mens bij oraal foliumzuurgebruik. Klinische studies, waarbij patienten langdurig (tot 3 jaar lang) 5 tot 15 mg per dag kregen toegediend gaven geen aanwijzing voor aan foliumzuur gerelateerde neurotoxiciteit. Tenslotte wordt uiteen gezet, dat een deficientie in foliumzuur, die de synthese van S-adenosylhomocysteine remt en stapeling van homocysteine veroorzaakt, wel kan leiden tot neurotoxische schade.
Oral folic acid (pteroylglutamic acid) is generally regarded as not toxic for normal humans but it may cause neurological injury when given to patients with undiagnosed pernicious anemia. The vitamin should be given with caution to drug-treated epileptic patients because seizure control may be affected. Some studies suggest that folic acid supplements interfere with intestinal zinc absorption in humans and animals but others do not confirm such an effect. The weight of current evidence favors the view that daily supplements of 5-15 mg folic acid do not have significant adverse effects on Zn nutriture in healthy nonpregnant subjects. Because antifolate medications are now being used to treat a wide range of malignant and nonmalignant disorders, further investigation is needed concerning folate metabolism and the safety of supplements in patients with these disorders.
The toxicity of folic acid (PGA) was studied in different inbred strains of mice. LD50 values of PGA by the i.p. route showed a unique toxicity pattern. In some strains, convulsions, ataxia and weakness were observed. Histopathological study in strains S/RVCri, BDF1, DBA/2 and DBA/2fNCri showed acute renal tubular necrosis.
Half-life and tissue distribution of injected tritium labelled folate was examined in oral contraceptive (OCA) treated and control rats to elucidate the mechanism by which OCA treated rats show increased urinary excretion as well as tissue levels of folate. Urinary excretion of folate within the first 12 hours of injection was higher but subsequent excretion lower in OCA treated rats. Faecal excretion of folate was also lower in treated rats. Thus, the half-life of the rapid turnover labile pool of folate appears to be reduced, whereas that of the slow turnover stable pool is raised by OCA treatment. Concentration of labelled folate was higher in the liver and kidneys of treated rats but it was not affected in tissues such as intestine, bone and brain. The concentration of soluble folate binders in the kidney was raised by OCA treatment and the activity of dihydrofolate reductase in the liver (a folate binder) also tended to be higher though the difference was not significant. The observation suggest that OCA may alter folate turnover by changing the concentration of folate binders in the tissues.
Folate nutritional status depends on intake from food and supplements as well as on the bioavailability of the various ingested forms of this vitamin. Although many advances in the understanding of folate bioavailability have occurred in recent years, many areas of uncertainty remain, especially with respect to naturally occurring dietary folate. This review includes a summary of factors that affect folate absorption and utilization, currently used and promising methods suitable for the assessment of bioavailability, significant findings on which current understanding is based and research needs.