By John D. MacArthur
New research and diverse evidence implicate fluoride and fluorosis in the pathogenesis of preeclampsia, the dangerous pregnancy complication caused by the abnormal placenta.
Eclampsia, a convulsive disorder of pregnancy, was described by ancient civilizations of China, Egypt, and India. Late in the 19th century, it was recognized that eclampsia was preceded by new onset hypertension during the second half of pregnancy, hence the term preeclampsia.1 Increasing since 1980, preeclampsia and related hypertensive disorders of pregnancy affect about 5% to 8% of all births in the US.
Preeclampsia is associated with high maternal and fetal/neonatal morbidity and mortality, especially in developing countries. Each year, preeclampsia is responsible for approximately 18% of all maternal deaths and more than 10,000 infant deaths in the US, whose infant mortality rate is one of the highest in the industrialized world.
The abnormal placenta is the major cause of this life-threatening pregnancy complication. Its removal puts an end to the disease. Despite a long history and extensive research, the cause of preeclampsia remains unknown.
Something else that’s been around for millennia is fluoride and fluorosis, the visible evidence of an individual’s susceptibility to fluoride’s adverse systemic effects, but they have never been associated with preeclampsia … nor ruled out … nor considered – even though US fluoride researchers have long known that placentas of women who drink fluoridated water contain significantly higher concentrations of fluoride. In a 1952 issue of Science magazine, Harold C. Hodge (chief toxicologist for the US Army’s Manhattan Project) reported that women who drank artificially fluoridated water (1.0–1.2 ppm fluoride) averaged 2.09 ppm fluoride in their placentas, compared with 0.74 ppm fluoride in the placentas of women who drank nonfluoridated water (0.06 ppm fluoride). Maternal blood fluoride levels were also nearly three times higher (0.040 vs. 0.014 ppm) because of fluoridation.2
More recent clinical research shows that the placenta can accumulate fluoride in healthy women who are exposed in pregnancy to relatively low fluoride concentrations in water and in air. The placenta acts as a natural barrier to the passage of larger quantities of fluoride to the fetus. Fluoride content of the placenta can be significantly higher than that of maternal serum, while cord blood has the least fluoride.3,4
Preeclampsia is a progressive disorder with mild to severe consequences, and epidemiological studies clearly confirm that genetic factors are involved.5 Dental fluorosis also has mild to severe consequences, and animal studies show that there is a genetic component in the pathogenesis of dental fluorosis and in bone response to fluoride exposure.6 In humans, severity of dental fluorosis varies individually at the same level of intake.7 Black children in the US have significantly higher rates and more severe forms of dental fluorosis than either white or Hispanic children. When African American women have preeclampsia, its effects are severe and present earlier than in other races.
Most fluoride research is dental research, especially in English-speaking countries that artificially fluoridate their drinking water. A PubMed search for papers published in 2014 yields 2013 results for fluoride and 2687 for placenta. A search for fluoride placenta yields only 11 results in the past 10 years. One is relevant to preeclampsia, Tskitishvili et al. (See “Angiogenic Factors and Fluoride,” below.)
Very little is known about how the human placenta is affected by fluoride’s multiple mechanisms of cytotoxicity, but placental fluorosis is certainly a possibility.8 Like dental fluorosis, a woman’s vulnerability to placental fluorosis would depend on individual genetic, metabolic, and environmental factors.
Endoplasmic Reticulum Stress
This century’s science is revealing that preeclampsia and dental fluorosis share the same key subcellular mechanism of pathophysiology: endoplasmic reticulum stress. Within a cell, the endoplasmic reticulum (ER) is the organelle responsible for the biosynthesis, folding, and assembly of all secretory and membrane-bound proteins. ER function is highly sensitive to extracellular stimuli. During environmental, developmental, or genetic stress, the cell’s folding capacity can become overwhelmed and cause misfolded proteins to accumulate, a condition known as ER stress.9,10
Buhimschi et al. have identified misfolded proteins specific to preeclampsia in the urine of pregnant women, weeks before their preeclampsia becomes clinically apparent.11 Note: Early in the 20th century, proteinuria was identified as the second cardinal feature of preeclampsia.1
ER stress activates a defense mechanism called the “unfolded protein response” that reduces protein synthesis to decrease the burden on the ER. Cells with high secretory activity, such as blast cells, have a large amount of ER and are more susceptible to ER stress.
Fluoride Causes ER Stress in Fluorosis
Ameloblasts are cells present during tooth development that secrete large amounts of proteins that later mineralize to form tooth enamel.
Researchers at the Forsyth Institute in Massachusetts, a fluoride research center for the past century, found that fluoride initiates an ER stress response in ameloblasts that interferes with protein synthesis and secretion – culminating in dental fluorosis. Beginning with the lowest dose tested, they observed an increase in the magnitude of ER stress with increasing doses of fluoride.12
Osteoblasts are cells that secrete the protein matrix for bone formation. In its comprehensive 2006 report, “Fluoride in Drinking Water,” the US National Research Council (NRC) said, “Fluoride is a biologically active ion with demonstrable effects on bone cells, both osteoblasts and osteoclasts.”13 In the pathogenesis of skeletal fluorosis, fluoride causes ER stress during osteoblast maturation.14
The area enclosed by the membrane of the ER includes a network of interconnecting flattened saclike structures called cisternae. Fluoride has been shown to cause dilated cisternae in the brains of rats, as well as in the brain tissue of human fetuses from an endemic fluorosis area.15,16 In fetuses whose mothers all had dental fluorosis, the major subcellular pathology was varying degrees of cistern dilation in glandular epithelial cells of livers, adrenal glands, and thyroid glands.17
ER Stress in Preeclampsia
Trophoblasts are the precursor cells of the human placenta. The extensive secretory activity of syncytiotrophoblasts, the outer trophoblast layer responsible for nutrient exchange, renders them vulnerable to ER stress.
At the University of Cambridge’s Center for Trophoblast Research, Burton and Yung confirmed high levels of ER stress in placentas from cases of early-onset preeclampsia (<34 weeks’ gestation). Reduced protein synthesis caused by ER stress has a severe detrimental effect on placental development by causing decreased levels of many hormones, growth factors, and regulatory proteins – leading to the placental insufficiency and dysfunction of preeclampsia.18
ER stress is specific to syncytiotrophoblasts, the cells in direct contact with maternal blood – the source of fluoride exposure. Electron micrographs of syncytiotrophoblasts in the normal placenta show the cisternae have only minimal dilation. In preeclamptic placentas, the cisternae are widely dilated.18 The precise cause of ER stress in preeclampsia is not known.
Research into the effects of environmental fluoride pollution on human placentas found a richness of fluoride deposits in the placenta that were approximately proportional to the intensity of the pollution. The primary change was a deterioration of cytochrome c oxidase in the villous syncytiotrophoblast, which consequently resulted in a lack of energy supply and placental insufficiency.19
Vascular Calcification, Fluorosis, and Hypertension
PET/CT scans show that vascular calcification and fluoride uptake are significantly correlated in most arterial walls. In coronary arteries, fluoride uptake is considerably higher in patients with cardiovascular events.20 A significant positive association was found between excess fluoride exposure from drinking water and prevalence of carotid artery atherosclerosis in adults living in fluoride endemic areas.21
In patients with calcific aortic stenosis, the uptake of 18F-sodium fluoride identifies active tissue calcification and predicts disease progression.22 The elastic properties of the ascending aorta are impaired in patients with fluorosis.23 Aortic stiffness is a marker of cardiovascular disease, including hypertension, the cardinal feature of preeclampsia.
Recent evidence shows that excess fluoride intake from drinking water appears to exert an increase in primary hypertension.24 Sun et al. showed that with the increase in water fluoride concentrations, the risk of essential hypertension in adults grows in a concentration-dependent manner. With fluoride in water at 0.84 mg/l, the prevalence of hypertension was 20.16%. At 1.55 mg/l, it was 24.54%. At 2.49 mg/l, it was 32.30%.25
Preeclampsia serves as a sentinel marker for women who will experience premature cardiovascular and cerebrovascular diseases.26 Since 1984, more women than men have died each year from heart disease.
Women are also disproportionately affected by arthritis, the leading cause of physical disability. The prevalence rate for arthritis in the US is 33% higher in women than in men.27 The NRC reported that fluoride is readily incorporated into the crystalline structure of bone and will accumulate over time, which can result in arthritic symptoms of joint stiffness and pain.28
Placental and Pineal Calcification: Melatonin and Fluoride
Placental calcification is associated with a 40-fold increase in the incidence of IUGR, (intrauterine growth restriction), which is also a consequence of placental insufficiency. In cases of IUGR complicated by preeclampsia, placental infarcts in the third trimester were significantly increased.29
Fluoride concentrations in the water of most tissues are 40% to 90% of plasma concentrations but can exceed 100% in tissues with calcium deposits, such as the placenta late in pregnancy.30 Chlubek et al. found a high positive correlation between fluoride and calcium concentrations in the placenta.3
Calcium is the nutritional supplement found most effective in the prevention of preeclampsia.1 As an antidote to fluoride poisoning, calcium is used to reduce absorption and enhance excretion of fluoride.31
“As with other calcifying tissues, the pineal gland can accumulate fluoride… with the fluoride concentrations being positively related to the calcium concentrations in the pineal gland,” said the NRC. “Fluoride is likely to cause decreased melatonin production.”32
Melatonin is essential for proper trophoblastic function and development.33 Decreased maternal blood levels of melatonin are found in preeclamptic compared with normal pregnancies. Lanoix et al. have shown that the human placenta produces melatonin and expresses its receptors. In preeclamptic placentas, the researchers found a significant inhibition of melatonin’s rate-limiting enzyme that correlated with decreased melatonin levels.34
Oxidative Stress: Fluoride, Melatonin, Acetaminophen
Preeclamptic placentas exhibit a greater extent of both ER stress and oxidative stress.35 Oxidative stress is a recognized mode of fluoride toxicity that has been observed in several types of cells and also in different organ systems in animals and in people living in areas of endemic fluorosis.36 Increasing oxidative stress in children with fluorosis is associated with increasing fluoride concentration in their drinking water.31
Melatonin has ameliorated oxidative damage to the placenta and to the fetus in experiments using nonhuman mammals.37 Animal research confirms that melatonin can upregulate the antioxidant defense system impaired by fluoride-induced oxidative stress in the liver, heart, and kidney of female rats.38
Melatonin has been referred to as a “suicidal” antioxidant. Once oxidized, it cannot be reduced to its former state.39 By reacting with fluoride, the melatonin available to the placenta is reduced.
Acetaminophen, the medication most commonly used by pregnant women for fevers and pain, is associated with an increased risk of preeclampsia when taken during the third trimester.40 Acetaminophen can cause oxidative stress, even at low doses, but co-exposure with fluoride has a synergistic effect.41 Together, acetaminophen and fluoride (in subtoxic doses) enhance oxidative stress and kidney damage in rats, as compared with rats treated only with fluoride or with acetaminophen. Acetaminophen also significantly decreases urinary fluoride excretion, which is how the body rids itself of previously absorbed fluoride.42
Note: Rodent studies are relevant to humans, because a much higher concentration of fluoride is required to cause dental fluorosis in a mouse than in a human (25 vs. 2 ppm).12
Angiogenic Factors and Fluoride
During mid-gestation, the maternal uterine spiral arteries must be transformed into low-resistance, high-capacitance blood vessels that can provide increasing amounts of oxygen and nutrients to the growing fetus. Poor spiral artery remodeling due to an abnormal balance of proangiogenic and antiangiogenic factors causes the hypertension seen in preeclampsia.
The fetus secretes adrenomedullin, a proangiogenic vasodilator, into the placenta. In normal human pregnancies, adrenomedullin is elevated approximately 5-fold in the maternal plasma, but often blunted in pregnancies complicated by preeclampsia.43 Sodium fluoride has been shown to completely block the effect of adrenomedullin in pregnant rats.44
Fetal fluoride levels in blood and amniotic fluid depend on maternal fluoride exposure. The use of fluoride supplements (1.5 mg/day) doubles fetal blood concentrations.7 When pregnant women consume 1.25 mg of fluoride per day, the fluoride concentration in their amniotic fluid is significantly higher than in women who consume 0.25 to 1.0 mg fluoride.45 Fluoride levels in amniotic fluid – which are considerably higher at term than earlier in the third trimester – are positively correlated in a dose-response relationship with fluoride content and pathology of fetal bones, with significantly greater fluoride levels in fetuses born to mothers who have dental fluorosis.46,47
Soluble endoglin (sEng) is an antiangiogenic protein whose concentrations are elevated in serum and in amniotic fluid of women with preeclampsia.48 Tskitishvili et al. found that amniotic tissue cultures treated with sodium fluoride show significantly higher expression levels of sEng, at any dose and time-point tested.49
Inflammation: Periodontal Disease, Preeclampsia, and Dental Fluorosis
Maternal periodontal disease with systemic inflammation as measured by hs-CRP (high-sensitivity C-reactive protein) is increased in preeclampsia and represents a marker of its severity.50,51 Women with a history of periodontal treatment are more likely to develop severe preeclampsia than women without a prior history of treatment.52 Periodontal treatment exposes women to extremely high concentrations of topical fluoride (22,600 ppm), some of which is absorbed into the bloodstream and placenta.
Plasma levels of hs-CRP are significantly higher among patients with fluorosis compared with controls.53 A clinical study found a strong association of occurrence of periodontal disease in people who had dental fluorosis. As the severity of fluorosis increased, periodontitis increased from 8.5% to 35.8%. Also, periodontitis was significantly more common in females.54 Many studies and published documents have shown that increased fluoride exposure is directly linked to increased periodontal disease.55
Preeclamptic women with periodontal disease are at greater risk for preterm delivery.56 Maternal fluoride consumption is also a risk factor for preterm birth, a leading cause of long-term neurological disabilities in children. The societal economic burden associated with preterm birth is more than $25 billion per year in the US.57 Preeclampsia is the underlying cause of about 25% of all medically indicated preterm deliveries.
Another pro-inflammatory factor in preeclampsia is elevated liver enzymes, which are significantly higher in early-onset preeclampsia.58 Elevated liver enzymes have been found in children, based on the levels of fluoride in drinking water (in a dose-response manner) and on their degree of dental fluorosis.59
Fluoridated Water, Dental Fluorosis, and Preeclampsia
A case-control study found a significant association between fluoride levels in drinking water, dental fluorosis in mothers, and low birth weight of newborns. Preeclampsia was significantly associated with low birth weight (23.1% in cases vs. 11.6% in controls).60
Systemic exposure to fluoride through drinking water is associated with an increased risk of dental and bone fluorosis in a dose-response manner – without a detectable threshold.61 British researchers estimate the prevalence of dental fluorosis of all levels of severity to be 15% in nonfluoridated areas and 48% in fluoridated areas.62
From 1987 to 2004 in the US, the prevalence of moderate and severe dental fluorosis nearly tripled from 1.3% to 3.6%.63 There was also a 13.5% increase in the percentage of Americans receiving public water that was fluoridated (from 60.5% to 68.7%).64
During the same 18 years in the US, the incidence rate of preeclampsia rose by 25%: from 23.6 to 29.4 cases per 1000 deliveries.65 Rates of severe preeclampsia are steadily increasing. In the largest US cohort study (120 million births), the prevalence rate for severe preeclampsia nearly quintupled from 0.3% in 1980 to 1.4% in 2010.26
The limited available population data reveal that, from 1996 to 2004 the preeclampsia rate averaged 19% higher in the two most fluoridated regions of the US (South and Northeast), than in the two least fluoridated regions (Midwest and West): 31.7 vs. 26.6 cases per 1000 deliveries. The preeclampsia rate averaged 40% higher in the South than in the West: 34.1 vs. 24.3 cases per 1000 deliveries.65 In 2004, the average fluoridation rate in the South’s 16 states was 81%, compared with 46% in the West’s 13 states.
Note: The age-adjusted death rate in 2010 for essential hypertension and hypertensive renal disease was 9% higher in the 22 states fluoridated at 80% or more (average 92%) than in the 27 states fluoridated at less than 80% (average 56%).66
Fluoridated Water, Hypothyroidism, and Preeclampsia
In 2015, a major population-level study analyzed data from 99% of England’s 8020 general medical practices. It found a positive association between fluoride levels in water and patients diagnosed with hypothyroidism. High hypothyroidism prevalence was 30% more likely in practices located in areas with fluoride levels in excess of 0.3 mg/l. Those located in the West Midlands (a wholly fluoridated area) were nearly twice as likely to report high hypothyroidism prevalence in comparison with Greater Manchester (nonfluoridated area).67 The study did not include undiagnosed subclinical hypothyroidism, which is associated with many health problems, including preeclampsia and ADHD.
Preeclampsia is often complicated with subclinical hypothyroidism. Many studies have shown a relation between the level of thyroid hormones and development and severity of preeclampsia.68 In an analysis of pregnancy outcomes in 24,883 women, after adjusting for confounding factors, there was a significant association between subclinical hypothyroidism and severe preeclampsia.69 A 2013 retrospective cohort study of 223,512 pregnancies found that primary hypothyroidism was associated with increased odds of preeclampsia (OR = 1.47).70
Singh et al. tested drinking water and body fluids for fluoride content, plus thyroid hormone and TSH levels, in children with dental fluorosis. They observed that high fluoride exposure can cause functional abnormalities of the thyroid. “Different degrees of dental fluorosis could be observed, with significant deviation in the serum thyroid hormone levels.”71 Note: ER stress has been detected in the thyroid glands of fetuses whose mothers had dental fluorosis.17
Hypothyroidism is associated with ADHD and is considered a potential cause of the disorder. Also published in 2015 was the first population-based study to examine the relationship between exposure to fluoridated water and ADHD prevalence. A multivariate regression analysis showed that artificial water fluoridation prevalence was significantly positively associated with ADHD prevalence. After socioeconomic status was controlled, each 1% increase in artificial fluoridation prevalence in 1992 was associated with approximately 67,000 to 131,000 additional ADHD diagnoses from 2003 to 2011 in the US.72
FDA: Fluoride and Pregnancy
The FDA classifies fluoride as an unapproved drug in Pregnancy Category C: “Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans.” The FDA says that a drug in category C “may pose risks similar to a drug in Category X,” which carries the warning: “The risks involved in use of the drug in pregnant women clearly outweigh potential benefits.”73
As for any potential benefits of swallowing fluoride, after reviewing the best available evidence for the effectiveness of water fluoridation, the FDA would only allow a weak claim: “Drinking fluoridated water may reduce the risk of tooth decay” – a far cry from the inflated sales pitch of fluoridation promoters.74,75
Since 1966, the FDA has prohibited claims that prenatal fluoride supplements benefit the teeth of children.76
Fluoride is added to the drinking water of more than 200 million Americans. This EPA-regulated water contaminant now pervades the nation’s processed-food-and-beverage-chain, essentially making the US artificially fluoride endemic.
The actual amount of fluoride that pregnant women typically consume per day is unknown.
Research Needed
To begin with, measure fluoride levels in routine blood and urine tests. For women who previously experienced preeclampsia, determine if their drinking water was fluoridated. Did they regularly drink tea or beverages manufactured with fluoridated water? How severe was their preeclampsia? Do they have dental fluorosis, a biomarker of their genetic susceptibility to fluoride?
A next step is to compare the concentration of fluoride in preeclamptic placentas with the severity of preeclampsia, as well as with placentas from normal pregnancies.
Preventing Preeclampsia
Preeclampsia used to be called “toxemia,” until 20th-century science failed to identify the causative substance. The current name preeclampsia (preconvulsions) continues to reflect our failure to determine the etiology of this life-threatening disease of the placenta. This century’s science suggests that “placental fluorosis” may be a far more accurate term.
Bottom line: Not ingesting fluoride poses absolutely no risk (or lack of benefit) to the placenta or fetus; however, consumption of fluoride may very well increase a woman’s risk of preeclampsia and its dangerous short-term and lifelong consequences for her and her child.
Women who are pregnant (or intend to be) should not swallow fluoride in supplements, in dental products, or during dental procedures. They should not consume fluoridated water or beverages manufactured with it.
Notes
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John D. MacArthur’s previous contributions to the Townsend Letter include three reports in October and November 2013: “Too Much Copper, Too Little Zinc, and Cognitive Deterioration in Alzheimer’s Disease” (with George J. Brewer, MD), “Fluoride and Preterm Birth,” and “Overdosed: Fluoride, Copper, and Alzheimer’s Disease.”
