Periodical Medical Hypothesis: The Iodine-Selenium Connection In Respiratory Distress And Sudden Infant Death Syndromes

Tagged:  

Medical Hypothesis: The Iodine-Selenium Connection In Respiratory Distress And Sudden Infant Death Syndromes

Respiratory distress syndrome (RDS) is the leading cause of neonatal death throughout the developed world and sudden infant death syndrome (SIDS) is responsible for the greatest mortality in the postneonatal period. These two syndromes appear to have numerous risk factors in common, suggestive of a common cause. In earlier publications, this author has demonstrated that SIDS has a global distribution pattern that is very similar to that of goiter prior to the introduction of iodine prophylaxis. In the United States, for example, SIDS is twice as common in those states that previously suffered heavily from goiter that in those that did not. It is hypothesized, therefore, that SIDS and probably RDS are caused by T4 and/or T3 deficiencies, which in turn reflect inadequate availability of iodine to the fetus and infant. The effects of this deficiency appear to be exacerbated by either a lack, or an excess, of selenium. Elevated infant mortality clearly occurs under such circumstance s in the developing world and it is suggested here that, as shown by widespread maternal goiter, such imbalances are also relatively common in the developed world. Evidence is presented which demonstrates that L-thyroxine and L-triiodothyronine supplementation have been used both to speed fetal lung maturation and to reduce mortality from RDS in a few progressive pediatric hospitals. Furthermore, SIDS victims exhibit thyroid gland abnormalities, T4 deficiencies and subtle developmental deficits which are consistent with a role for iodine inadequacy in this syndrome.

Introduction

Respiratory distress syndrome (RDS) or, as it is sometimes called, hyaline membrane disease, is the leading cause of neonatal death throughout the developed world,( 1), while sudden infant death syndrome (SIDS) is responsible for the greatest mortality int he postnatal period.( 2) To illustrate, in Italy 7.8% of all newborns (up to the 28th day of life) develop RDS.( 3) Among those that do, mortality is some 46.5%.( 3) Similarly, the United States, RDS and its associated complications are estimated to be responsible for between 10,000 and 40,000 neonatal deaths annually, while SIDS mortality is approximately 5,500 each year.( 4, 5)

These two syndromes appear to have many risk factors in common.( 6) Both occur most frequently, for example, in premature, low birth weight males.( 7, 8) Each is commonest in multiple births( 7, 9, 10) and seems linked to low maternal age, high parity and reduced socioeconomic status.( 6, 8, 11) Clinically, both syndromes are associated with developmental deficits, including inadequacy or abnormality of lung surfactant.( 12-14) Furthermore, in infant that has successfully survived RDS has a very elevated risk of subsequent death from SIDS.( 15)

A Working Hypothesis

These similarities are suggestive of a common cause(s).( 6) However, although the literature on RDS and SIDS is voluminous, none of the postulated hypotheses appear to explain adequately, the diverse clinical dimensions of either disorder, nor their epidemiological and clinical similarities.

For this reason, the author used Pearson Correlation to compare the spatial distributions of SIDS in the United States at the state scale, for each of the years 1983 to 1987 and for the period as a whole, with the incidence and/or prevalence and/or mortality of 83 other diseases or disorders.( 16) In addition, SIDS mortality was correlated with the spatial distributions of 221 geographical variables, ranging from levels of particular elements in soils to variations in industrial and agricultural production. The data banks involved have been described in detail elsewhere.( 17, 18)

By far the strongest Pearson correlations obtained, either with SIDS in specific years or for the period 1983 to 1987 as a whole, were with male goiter in military recruits during World War I. For SIDS deaths during the entire 1983 to 1987 period, for example, the association as r=0.75778, p=0.0001. Similar strong positive correlations were found between SIDS mortality for the five year period and both iodine deficient (r = 0.56409, p = 030001) and selenium enriched (r = 0.54627, p = 0.0001) soils. The latter associations were of particular interest since in the South Island of New Zealand, where SIDS is especially common, soils are both iodine and selenium depleted.( 19-21)

On the basis of these correlations it is hypothesized that maternal and hence infant iodine deficiency, (exacerbated in some cases by excesses or deficiencies of selenium) is the ultimate cause of SIDS. Such deficiencies would probably result in maternal goiter, accompanied by depressed fetal serum thyroxine (T4) and/or triiodothyronine (T3). Since it is well-known that a serious lack of iodine in pregnant women can result in the birth of cretins( 22) that display a wide spectrum of extreme clinical deficits,( 23) it would not be surprising if fetal and infant serum T4 and/or T3 deficiencies were responsible for the subtle neurological, cardiorespiratory and metabolic developmental deficits seen in SIDS autopsies.( 24-27)

As previously pointed out, RDS and SIDS have many risk factors in common. It is further pustulated, therefore, that maternal and hence fatal iodine deficiency and selenium imbalance also may be the ultimate cause of RDS. If so, this would explain, at least in part, why so few SIDS deaths are recorded during the first month of life.( 28, 29)

During this initial period, T4 and/or T3 deficient neonates probably tend to die of RDS, not SIDS. It would explain also why infants who survive RDS are still at very high risk from subsequent SIDS.( 15)

Thyroid Hormone Deficiency and Infant Death

There is no doubt that, throughout much of the developing world, depressed maternal serum T4 and/or T3 levels are associated with elevated infant mortality.( 30) In the Jimi River District of Papua and New Guinea,( 31) for example, a maternal serum total T4 level < 25 ng/ml was found to be associated with an infant mortality rate of 36.0%, compared with 16.4 % for infants of mothers with levels higher than this. Similarly, the same study established an infant death rate of 50.0% for the children of mothers whose total serum T3 < 850 pg/ml, compared with 13.6% mortality for those with more elevated T3 levels. It is not surprising, therefore, that in regions of endemic goiter, in Zaire, Peru, Ecuador and New Guinea, field trials with iodized oil have significantly reduced the number of stillbirths and neonatal deaths.( 30) In Zaire,( 30) for example, perinatal and infant mortalities were 188 and 250 per 1000 among offspring of mothers who did not receive iodine during pregnancy, compa red to 98 and 167 for those whose mothers were given this trace element. Using evidence from such field trials, Clugston and coworkers( 32) were able to estimate annual stillbirth and neonatal death rates related to iodine deficiency, throughout the WHO South -east Asia region, based on goiter prevalence. They calculated that maternal and hence fetal iodine deficiency was responsible for 101,800 stillbirths and 93,500 neonatal deaths, each year, in the region's eight member countries; the equivalent of 5.0 mortalities per 1000 live births. Since these figures do not include Chinese infant mortalities nor, of course, those of Africa and Central and South America, the annual global infant death total, caused by iodine deficiency, must, at a minimum, be several hundred thousands.

Since the selenoenzyme deiodinase is required to catalyze the conversion of T4 to T3, it is not surprising that some regions of high infant mortality, such as Zaire,( 30) are deficient not only in iodine, but also in selenium.( 34) Indeed, animal studies tend to suggest that both elevated and depressed maternal dietary selenium levels may lead to increased stillbirths, abnormalities and higher offspring mortality.( 35-37)

Goiter In The Developed World

Since iodine and selenium requirements peak during pregnancy, it is then that any dietary inadequacy becomes most obvious. For this reason, goiter occurs frequently in pregnant women, even in the developed world.(3841) In Canada,( 38) for example, the prevalence of goiter among pregnant women is some 4.9%, varying from a low of 2.3% in Quebec to a high of 12.5% in New Brunswick. Nor are all these cases grade I. Nationally, some 28.6% of goiter in pregnant Canadian women is either WHO grade II or III. There appears, however, to be little unique about such high Canadian goiter prevalence. To illustrate, Crooks and colleagues( 39) reported that 70% of pregnant females in Aberdeen, Scotland were goitrous, while in Dublin, Ireland( 40) the prevalence of goiter was found to be 58% among expectant mothers. Goiter also is common in pregnant women in the United States, where it shows racial preferences. In San Diego( 41) for example, while 14% of black teenagers presented for prenatal care had goiter, only 2% of pregnant whites had this condition. Goiter was found also in 4% of San Diego's pregnant Mexican-American teenagers.

Alterations in maternal thyroid function are complex and not fully understood. It is clear, however, that maternal iodine deficiency and associated goiter and hypothyroxinemia do not lead necessarily to increased infant mortality. This appears to be because the thyroid gland seems capable of adapting to the greater need for iodine during pregnancy and can keep thyroid hormone levels in both mother and fetus normal.( 42) However, as Pharaoh and colleagues( 31) demonstrated in New Guinea, there are threshold levels of iodine (and probably selenium) intake resulting in depressed maternal total and free T4 and/or T3, below which cretinism, stillbirth and infant mortality appear the norm rather than the exception. How frequently such deficiencies occur during pregnancy in the developed world is unclear. However, Delange and coworkers( 43) have shown that newborn infants are far more sensitive than adults to iodine deficiency. This hypersensitivity can be explained by the particularly lo w iodine pool of the neonate thyroid, which results in a markedly accelerated turnover rate of intrathyroidal iodine. Evidence will now be presented that suggests such infant iodine deficiency results in death in the developed world far more often than generally is believed.

Thyroid Hormone Deficiency in RDS

RDS is a self-limited clinical syndrome that occurs most often in preterm infants.( 6, 44) Such neonates initially display normal respiration but tachypnea and mild cyanosis signal the onset of distress, usually several minutes to a few hours after birth. Increasing respiratory distress persists and death may occur, usually within 24 to 48 hours.( 2, 6) Evidence clearly shows that this syndrome results from surfactant deficiency,( 14, 45) combined with lung immaturity.( 44)

The association between RDS and premature birth and low birth weight( 6, 7) is suggestive of fetal and neonatal T4 deficiency. To illustrate, Thorpe-Beeston and colleagues( 46) compared blood T4 levels in 49 small for gestational age fetuses at 21 to 38 weeks gestation, with T4 levels in 62 appropriately sized fetuses. They discovered thyroid stimulating hormone (TSH) levels were higher and T4 levels significantly lower in the fetuses displaying subnormal development. This finding is consistent with the increased birth weights seen in Zaire( 30) in infants of mothers receiving injections of iodized oil during pregnancy, as compared to those of an untreated control group. In this case, iodine prophylaxis appeared responsible for a 203 g (7.7%) gain in average birth weight.

Experimental evidence appears to show also that T4 deficiency is the fundamental cause of both lung immaturity and surfactant inadequacy in infants suffering from RDS. To illustrate, the administration of intra-amniotic T4 enhances fetal growth and maturation,( 47) and can be used to increase surfactant microviscosity until lung maturity has been reached.( 14, 45) This technique, for example, was used to accelerate lung maturity in two premature triplet pregnancies at the Chaim Sheba Medical Center, Tel-Hashomer, Israel.( 14)

If indeed deficiencies of T4 and possibly T3 are involved in the etiology of RDS, then infants dying of this clinical syndrome should display subnormal serum levels of one or both of these two thyroid hormones. This appears to be the case. Schonberger and colleagues( 48) at the University of Mainz, Germany, for example, established that 13 premature infants with severe respiratory distress had hypothyroid T4 values. As a consequence, on admission to intensive care, every second neonate born after < 37 weeks gestation and weighing < 2200 g was given a daily prophylactic dose of 25 æg L-thyroxine and 5 æg L-triiodothyronine. Untreated neonates acted as a control group. The death rate among the treated group was 6.6% and among the untreated group 29%. The probability that the difference in mortality between the two groups was due to chance was < 0.5% (x( 2)-test, p < 0.005). These results are consistent with the work of Redding and Pereira( 49) who reported depressed serum T4 in premature newborn infants with respiratory distress syndrome, and Cuestas and coworkers( 50) and later researchers( 51, 52) who found low T4 and T3 in the cord blood of newborns with this syndrome. As a result of their research project, Schonberger and colleagues( 48) ensured that all premature infants subsequently admitted to their intensive care unit weighing < 2200 g or born before 37 weeks gestation were given daily thyroid hormone treatment. As a consequence, mortality rates among such infants fell from 29% to 9.5%.

Similar supportive evidence for a key role for T4 deficiency in neonatal death has come from Marsh and coworkers( 54) at the University of Carolina who prospectively determined serum T4 values in 97 premature, low birth weight infants. They established that 8 infants with a serum T4 value of < 2.5 æg/dl experienced a death rate of 50%, while 89 neonates with serum T4 levels higher than this suffered only 4.5% mortality. The relationship was so marked that very low T4 levels were predictive of mortality independent of birth weight, gestational age or required supplemental fraction of inspired oxygen > 60%. This suggests a threshold value of serum T4 below which the risk of infant mortality is strongly increased. This, of course, is very consistent with the critical maternal serum T4 levels established in areas of endemic goiter.( 30, 31)

Lucas and coworkers( 54) similarly studied 280 English infants with a mean birth weight of 1330 g and gestation of 30.3 weeks. Plasma T3 concentrations were assayed while these infants were in special care units in Cambridge, Ipswich, King's Lynn, Norwich and Sheffield. It was discovered that mortality rates were significantly related to plasma T3 levels during the first 18 months of life. In infants whose plasma T3 fell below 0.23 æg/dl, 14 out of 61 (23%) died, compared to 12 out of 219 (6%) in those whose plasma T3 remained above this concentration (x( 2)test, p < 0.0001). Surviving low plasma T3 infants also showed significant mental and motor scale disadvantages at 18 months' corrected age, suggesting physical and mental impairment. Lucas and co-researchers( 54) pointed out that if data adjustments were made for birth weight, gestation and requirement for mechanical ventilation, the relationship between plasma T3 concentration and mortality was lost. However, this latter statistical step seems very illogical since birth weight,( 30) gestation( 46) and the production of surfactant( 14, 45, 55) are all adversely affected by thyroid hormone deficiency. They are, therefore, dependent variables and cannot be used to explain away the significance of their causal independent variable. Even if they could, this would be of little assistance to infants dying from T3 deficiency.

Thyroid Hormone Deficiency in SIDS

SIDS is the chief cause of death in infancy, in the developed world, after the first month of life.( 56) It is defined by exclusion, with the most generally accepted definition being that decided at the Second International Conference on Causes of Sudden Death in Infants, held in Seattle, Washington in 1969.( 57) At this conference, it was agreed that SIDS consisted of "the sudden death of any infant or young child, which is unexpected by history, and in which a thorough postmortem examination fails to demonstrate any adequate cause for death." It has been argued since that acceptance of an infant death as SIDS also should include an examination of the scene of death and a detailed review of clinical history.( 58)

The literature provides extensive evidence that the root cause of SIDS is a maternal nutritional deficiency or deficiencies.( 10) To illustrate, SIDS occurs more often in twins than singletons.( 9, 10) It is particularly frequent in infants from multiple pregnancies, especially if they weigh < 2000g at birth.( 59) When birth weights of twins in a pair are significantly different, it is usually the lighter of the two, if any, that dies of SIDS.( 60) For these reasons Beal( 10) pointed out that the best possible explanation of these phenomena "is that some factor is at a critical supply level from the mother during pregnancy. A twin receives only half of this supply, and a smaller twin probably receives less than half." If true, the resulting nutritional deficiency may render the lighter infant even more susceptible to SIDS.

As previously described, this author believes that fetal and hence infant T4 and/or T3 deficiencies are the root causes of both RDS and SIDS. Evidence has been presented elsewhere( 16) to show that in the case of SIDS this hypothesis meets eight of the Bradford Hill cause and effect criteria. The ninth, specificity of association, is impossible to fulfill since both iodine and selenium imbalances are known to result in a diversity of human disorders, both together and in isolation.( 30) Rather than repeat the evidence of a SIDS/iodine-selenium association in detail here, emphasis is placed on corollaries that must follow if the hypothesis is correct.

First, since iodine deficiency is the major cause of maternal and fetal T4 inadequacy( 30, 31) and selenium lack depresses T3 levels,( 30) if the preceding hypothesis is correct, SIDS ought to be commonest in environments where both these elements are scarce. In the developed world, where statistics are reliable, SIDS occurs most often on the Indian Reservation of King County, Washington (with a rate of 8.0 per 1000 live births) and in Canterbury, New Zealand. In the latter city the SIDS rate is 7.9 per 1000 live births.( 61)

Both locations are known to be iodine and selenium deficient.( 19, 21, 62-64) Conversely, the world's lowest SIDS rate appears to be recorded in Stockholm, Sweden( 65) at 0.06 per 1000 live births. Interestingly, a study of iodine urinary levels in infants from 14 European cities and from Toronto, Canada established that depressed concentrations were least common in Stockholm( 66) where only 5.9% of infants provided samples measuring < 5 æg/dl. This figure compared with 11.9% in Toronto and 100% in Freiburg and Jena. Clearly, therefore, the international SIDS mortality extremes are consistent with the iodine-selenium hypothesis.

Secondly, it follows that if SIDS is due to inadequate iodine intake and/or selenium excess or deficiency, infants dying from this cause should exhibit thyroid gland abnormalities. Riss and Weiler( 67, 68) examined the thyroid glands of 176 SIDS cases aged one year or younger, finding only 14% with normal colloid content. Partially depleted follicles were found in 35% and depleted follicles in 51%. This evidence of raised thyroid activity was only obvious in infants dying after the first month and is clearly consistent with the involvement of thyroid hormone deficiency in SIDS mortality.

Third, if inadequate infant serum T4 and/or T3 occurs prior to death in SIDS then this should be apparent postmortem. The available evidence appears to support a T4 deficiency in many SIDS victims prior to death. In 1981, for example, Chacon and Tildon( 69) described elevated serum T3 levels in autopsied SIDS victims. They reported that 88% of 50 cases had serum T3 > 2.5 ng/ml, with a mean of 4.06 ng/ml. These values were compared with the 1.8 ng/ml in a control group of infants dying from known causes. Peterson and colleagues( 70) also demonstrated elevated T3 in SIDS cases and suggested that this hormone might serve as a useful postmortem diagnostic marker for crib death. Comparable results were obtained by Riss and research colleagues( 68) who reported on blood taken from 53 infants within 18 hours of death. They described a 3.7-fold increase in T3 in 11 SIDS cases, compared to 32 infant controls dying of known causes. This evidence of elevated T3 in SIDS cases has been criticiz ed on the basis that T4 continues to convert to T3 after death.( 71, 72) However, this phenomenon does not seem to adequately explain the major differences in serum T3 in SIDS and non-SIDS cases so soon after death.

Fourth, since thyroid hormones are essential for growth and development, if deficiencies are involved in SIDS, one would anticipate that infants dying from this cause would have low birth weights and display evidence of developmental deficits. This is definitely the case. Millar and coworkers,( 8) for example, linked the birth and death records of 904 infants dying in Canada during the period 1986 to 1988. For each SIDS case three controls who survived infancy were chosen at random. Subsequent analysis established that in Canada the risk of SIDS was inversely related to both birth weight (p = < 0.001) and duration of pregnancy (p < 0.001). An infant weighing < 2000 g at birth, for example, had some ten times the risk of dying of SIDS compared to one weighing > 4500g (p < 0.001). Not only do SIDS victims tend to have a low birth weight, they also display a very wide range of developmental deficits. These subtle abnormalities, however, are often only apparent at autopsy.( 24-27) Ind eed as Barnett and Hunter( 73) pointed out "There is a growing body of evidence that SIDS victims are not completely normal and healthy, as was once believed. A variety of new information from several disciplines strongly suggests that the infant who dies suddenly and unexpectedly may do so because of subtle developmental, neurology, cardiorespiratory and metabolic defects that converge at a particularly vulnerable time."( 11) This viewpoint was repeated by Willinger( 74) in his concluding remarks to the State of the Art Conference on the Sudden Infant Death Syndrome held in Gothenburg, Sweden in 1992. He pointed out that infants who succumb to SIDS have a nervous system that is impaired in structure and function and which, therefore, adversely affects heart rate and respiration. In addition, neuroendocrine bodies (secretory structures in the lungs that sense oxygen levels and regulate lung development) are overdeveloped in SIDs infants. Of course, thyroid hormones are crucial to both th e development of the nervous system( 21, 23, 30) and maturity of the lungs.( 12, 14, 45, 55)

Conclusions

Maternal and subsequent fetal iodine deficiency are known to be responsible for hundreds of thousands of stillbirths and infant deaths every year.( 30-32) The evidence presented here suggests, however, that contrary to the conventional wisdom, such losses are not limited to the developing world, but also occur in industrialized countries, despite their iodine prophylaxis and neonatal screening programs.( 30)

Although screening for congenital hypothyroidism is essential, it generally comes too late for neonates who die from RDS soon after birth.( 1, 6, 48) Such programs generally appear to identify, but fail to treat infants with transient hypothyroidism.( 57, 75, 76) This seems significant for two major reasons. First, even transient shortages in thyroid hormones can result in later childhood deficits.( 77, 78) Secondly, it seems likely that these infants, if subsequently stressed by low dietary iodine( 16) (or selenium deficiency( 19) or excess,( 16) goitrogens,( 30) exposure to cold or infection,( 79) cigarette smoke( 60) or prone sleeping position,( 81, 82) seem most likely to succumb to SIDS.( 83) All of these infant stressors either reduce the availability of iodine and hence reduce serum thyroid hormone levels, or increase the need for T4 and/or T3.

Correspondence:

Harold Foster, Ph.D., Professor

Department of Geography

University of Victoria

P. O. Box 3050

Victoria, British Columbia V8W 3P5

Canada

604-721-7327

Fax 604-721-6216
References

(1.) Kliegman RM, Behrman RE (1992) Hyaline membrane disease (idiopathic respiratory distressed syndrome). In: Behrman RE, Vaughan CV (eds) Nelson Textbook of Pediatrics 13th ed. WB Saunders, Philadelphia, pp 394-399.

(2.) Finlay FO (1993) Current concepts of the etiology of SIDS. Br J Hosp Med 49(10):727-732.

(3.) Luerti M, Parazzini F, Agarossi A, Bianchi C, Rocchetti M, Bevilacqua G. (1993) Risk factors for respiratory distress syndrome in the newborn. A multicentre Italian survey. Study Group for Lung Maturity of the Italian Society of Perinatal Medicine, Acta Obstet Gynecol Scand 72(5):359-364.

(4.) National Sudden Death Syndrome Resource Center Statistical Fact Sheets. 1983 to 1987, McLean, Virginia.

(5.) Anonymous (1993) Variations in the incidence of sudden infant death syndrome (SIDS), United States, 1980-1988. Stat Bull Metrop Insur Co 74(1):10-18.

(6.) Caddell JL (1993) Hypothesis: Possible links between the respiratory distress syndrome of the premature neonate, the sudden infant death syndrome, and magnesium deficiency shock. Magnesium Research 6(1):25-32.

(7.) Usher R (1961) The respiratory distress syndrome of prematurity. Clinical and therapeutic aspects. Pediatr Clin North Am 8:525-538.

(8.) Millar WJ, Hill GB (1993) Prevalence of and risk factors for sudden infant death syndrome in Canada. Can Med Assoc J 149(5):629-635.

(9.) Arsenault PS (1980) Maternal and antenatal factors in the risk of sudden infant death syndrome. Am J Epidemiol 3:278-284.

(10.) Beal S (1989) Sudden infant death syndrome in twins. Pediatrics 84(6):1038 1044.

(11.) Peterson DR, Van Belle G, Chinn NM (1979) Epidemiologic comparisons of the sudden infant death syndrome with other major components of infant mortality. Am J Epidemiol 119:699-707.

(12.) Epstein MF, Farrell PM (1975) The choline incorporation pathway: Primary mechanism for de nova lecithin synthesis in fetal primate lung. Pediatr Res 9:658-665.

(13.) Morley C, Hill C, Brown B (1988) Lung surfactant and sudden infant death syndrome. Ann NY Acad Sci 533:289-300.

(14.) Dan U, Barkai G, Reichman B, Goldman B, Mashiach S (1991) Induction of fetal lung maturation with intra-amniotic thyroxine in multiple pregnancy. Prenat Diagn 11(5):317-322.

(15.) Taeusch HW, Ballard RA, Avery ME (1991) Sudden infant death syndrome. In: Taeusch HW, Ballard RA and Avery ME (eds) Schaffer and Avery's Diseases of the Newborn. WB Saunders, Philadelphia. p 473.

(16.) Foster HD (1993) Sudden infant death syndrome: The Bradford Hill criteria and the evaluation of the thyroxine deficiency hypothesis. The Journal of Orthomolecular Medicine 8(4):201-225.

(17.) Foster HD (1986) Reducing cancer mortality: A geographical perspective. Western Geographical Series 23:29-49.

(18.) Foster HE (1992) Health, Disease and the Environment. Belhaven Press, London, pp 30-40.

(19.) Logan JW (1988) Selenium and the north-south gradient of cot death. N Z Med J (859):832.

(20.) Reid G (1993) Te Aroah New Zealand, personal communication.

(21.) Underwood EJ (1971) Trace Elements in Human and Animal Nutrition. 3rd ed. Academic Press, New York, pp 281-322.

(22.) Pharaoh POD, Butterfield IH, Hetzel BS (1971) Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet 1:308-310.

(23.) Boyages SC, Halpern J-P (1993) Endemic cretinism: Towards a unifying hypothesis. Thyroid 3(1):59-69.

(24.) Reid GM, Tervit H (1991) Sudden infant death syndrome (SIDS) and disordered blood flow. Med Hypotheses 36:395-299.

(25.) O'Kusky JR, Norman MG (1992) Sudden infant death syndrome: Postnatal changes in the numerical density and total number of neurons in the hypoglossal nucleus. J Neuropathol Exp Neurol 51(6):577-584.

(26.) Molz G, Brodzinowski A, Bar W, Vonlanthen B (992) Morphologic variations in 180 cases of sudden infant death and 180 controls. Am J Forensic Med Pathol 13(3):186-190.

(27.) Kopp N, Eymin C, Denorey L, Martin D, Jordan D (1993) Pathology and biochemistry of the central nervous system in sudden infant death syndrome: A short review. In: Lagercrantz H, Tunell R, Wennergren G (eds) State of the Art Conference on the Sudden Infant Death Syndrome. Acta Paediatr Suppl 389:86-87

(28.) Froggatt P (1970) Epidemiologic aspects of Northern Ireland study. In: Bergman AB, Beckwith JB, Ray CC (eds) Proceedings of the Second International Conference on Causes of Sudden Death in Infants. University of Washington Press, Seattle, 32:46.

(29.) Kraus JF, Borhani NO (1972) Post-neonatal sudden unexpected death in California: A cohort study. Am J Epidemiol 95:497.

(30.) Hetzel BS (1989) The Story of Iodine Deficiency: An International Challenge in Nutrition. Oxford University Press, Oxford.

(31.) Pharaoh POD, Ellis SM, Ekius RP, Williams ES (1976) Maternal thyroid function, iodine deficiency and fetal development. Clin Endocrinol 5:159166.

(32.) Clugston GA, Dulberg EM, Pandav CS Tilden RL (1987) Iodine deficiency disorders in South east Asia. In: Hetzel BS, Dunn JT, Stanbury JB (eds) The Prevention and Control of Iodine Deficiency Disorders. Elsevier, Amsterdam, pp 273-308.

(33.) Corvilain B, Contempre B, Longombe AO, Goyens P, Gervy-Decoster C, Lamy F, Vanderpas JB, Dumont JE (1993) Selenium and the thyroid: How the relationship was established. In: Arthur JR (ed) Interrelationships Between Selenium Deficiency, Iodine Deficiency and Thyroid Hormones. Am J Clin Nutr_57 (2S):244S-248S.

(34.) Contempre B, Dumont JE, Ngo Bebe, Thilly CH, Diplock AT, Vanderpas J (1991) Effect of selenium supplementation in hypothyroid subjects of an iodine and selenium deficient area: The possible danger of indiscriminate supplementation of iodine-deficient subjects with selenium. J Clin Endocrinol Metab 73(1):213-215.

(35.) Oldfield JE (1987) Contributions of animals to nutrition research with selenium. In: Combs GF Jr, Spallholz JE, Levander OA, Oldfield JE (eds) Selenium in Biology and Medicine: Third International Symposium, Beijing. People's Republic of China. Van Nostrand, Reinhold, New York, Part A:33

(36.) Rosenfeld I, Beath OA (1964) Selenium; Geobotany, Biochemistry, Toxicity and Nutrition, Academic Press, New York.

(37.) Franke KW, Moxon AL, Poley WE, Tully WC (1936) A new toxicant occurring naturally in certain samples of foodstuff. XII Monstrosities produced by the injection of selenium salt into hens' eggs. Anat Rec 65:15-22.

(38.) Murray TK (1977) Goitre in Canada. Can J Public Health 68:431-432.

(39.) Crooks J, Aboul-Khair SA, Turnbull AC, Hytten FE (1964) The incidence of goitre during pregnancy. Lancet 2:334-336.

(40.) Drury MI (1986) Hyperthyroidism in pregnancy. J R Soc Med 79:317-318

(41.) Long TJ, Felice ME, Hollingsworth R (1985) Goitre in pregnant teenagers. Am J Obstet Gynecol 152:670-674.

(42.) Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen HE, Rasmussen OS, Larsen KP, Eriksen GM, Johannesen PL (1993) Amelioration of some pregnancy associated variations in thyroid function of iodine supplementation. J Clin Endocrinol Metab 77(4):1078-1083.

(43.) Delange F, Bourdoux P, Laurence M, Peneva L, Walfish P, Willgerodt H (1993) Neonatal thyroid function in iodine deficiency. In: Delange F (ed) Iodine Deficiency in Europe. Plenum Press, New York, 199-209.

(44.) Jobe A (1983) Respiratory distress syndrome - new therapeutic approaches to a complex pathophysiology. Adv Pediatr 30:93-130.

(45.) Reading RA, Douglas WHJ, Stein M (1972) Thyroid hormone influence upon lung surfactant metabolism. Science 175:994.

(46.) Thorpe-Beesten JG, Nicolaides KH, Snijders RJ, Felton CV, McGregor A (1991) Thyroid function in small for gestational age fetuses. Obstet Gynecol 77(5):701-706.

(47.) Hofmann GE, Romaguera J, Williams RF, Adamson K, Norfolk VA, San Juan PR (1993) Amniotic fluid epidermal growth factor concentrations. The effect of intra-amniotic thyroxine for acceleration of fetal maturation. Acta Obstet Gynecol Scand 72(4):252-257.

(48.) Schonberger W, Grimm W, Emmrich P and Gempp W (1981) Reduction of mortality rate in premature infants by substitution of thyroid hormones. Eur J Pediatr 135:245-253.

(49.) Redding RA, Pereira C (1974) Thyroid function in respiratory distress syndrome (RDS) of the newborn. Pediatrics 54:423.

(50.) Cuestas RA, Lindall A, Engel RR (1976) Low thyroid hormones and respiratory distress syndrome of the newborn. N Engel J Med 295:297.

(51.) Klein AH, Stinson D, Foley B, Larsen PR (1977) Thyroid function studies in preterm infants recovering from the respiratory distress syndrome. J Pediatr 91:261.

(52.) Jakobsen BB, Peitersen B, Hummer L (1979) Serum concentrations of thyrotropin, thyroid hormones and thyroid-binding proteins during acute and recovery stages of idiopathic respiratory distress syndrome. Acta Paediatr Scand 68:257.

(53.) Marsh TD, Freeman D, McKeown RE, Bowyer FP (1993) Increased mortality in neonates with low thyroxine values. J Perinatol XIII(3):201-204.

(54.) Lucas A, Rennie J, Baker BA, Morley R (1988) Low plasma triiodothyronine concentrations and outcome in preterm infants. Arch Dis Child 63:1201-1206.

(55.) Wu B, Kikkawa Y, Orzalesi MM, Kaibara M, Zigas CJ, Cook CD (1973) The effect of thyroxine on the maturation of fetal rabbit lungs. Biol Neonate 22:161.

(56.) Hoffman HJ, Hillman LS (1992) Epidemiology of the sudden infant death syndrome: Maternal, neonatal and postneonatal risk factors. Clin Perinatol 19(4):717-737.

(57.) Beckwith JB (1970) Discussion of the terminology and definition of the sudden infant death syndrome. In: Bergman AB, Beckwith JB, Ray CG (eds) Proceedings of the Second International Conference on the Causes of Sudden Death in Infants. University of Washington Press, Seattle, pp 14-22.

(58.) Willinger M, James LS, Catz C (1991) Defining the sudden infant death syndrome (SIDS): Deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Ped Pathol 11:677-684.

(59.) Rintahaka PJ (1985) Sudden infant death syndrome in Finland in 1969-1980. National Board of Health, Finland, Helsinki 3:53.

(60.) Goldinq J, Limerick S, MacFarlane A (eds) (1985) Sudden Infant Death: Patterns, Puzzles and Problems. Open Books Publishing Co, Taunton, Somerset, England.

(61.) Reid G (1988) Sudden infant death syndrome: A study of two high incidence populations. Paper presented in Graz, Austria June 1988. Copy supplied by author, personal correspondence.

(62.) Subcommittee on Selenium, Committee on Animal Nutrition, National Research Council (1983) Selenium in Nutrition. National Academy Press, Washington.

(63.) Pendergrast WJ, Milmore BK, Marcus SC (1961) Thyroid cancer and thyrotoxicosis in the United States: Their relation to endemic goitre. J Chronic Dis 13:22-38.

(64.) Dolamore BA, Brown J, Darlow BA, George PM, Sluis KB, Winterbourn CC (1992) Selenium status of Christchurch infants and the effect of diet. N Z Med J 105(932):139-142.

(65.) Fohlin cited by Faldes-Dapena MA (1980) Sudden unexplained infant death 1970 through 1975: An evolution in understanding. US Dept of Health, Education and Welfare Publication No (HSA) 805255:7-10.

(66.) Delange cited by Hetzel op cit reference 30, 169.

(67.) Riss M, Weiler G (1990) Age dependent morphologic findings of the thyroid in sudden death. J Leg Med 103(7)507-512.

(68.) Riss M, Weiler G, Benker G (1986) Comparative histologic and hormonal studies of the thyroid gland with special reference to sudden infant death (SIDS). J Leg Med 96(1):31-38.

(69.) Chacon MA, Tildun JT (1981) Elevated values of triiodothyronine in victims of sudden infant death syndrome. J Pediatr 99(2):758-760.

(70.) Peterson, DR, Green WL, Van Bell G (1983) Sudden infant death syndrome and hypertriiodothyronemia: Comparisons of neonatal and postmortem measurements. J Pediatr 102(2):206-209.

(71.) Schwarz HL, Chasalow FI, Erickson MM, Hillman RE, Yuan RE, Hillman LS (1983) Elevation of postmortem triiodothyronine in sudden infant death syndrome and in infants who died of other causes: A marker of previous health. J Pediatr 102(2):200-205.

(72.) Lee WK, Strzelecki J, Root AW (1983) Postmortem changes in serum concentrations in triiodothyronine in rats. J Pediatr 102(2):257-259.

(73.) Barnett HL, Hunter JC (1983) Sudden infant death syndrome. US Department of Health and Human Services, National Institutes of Health Publication No 82-2304.

(74.) Willingsr M (1993) Concluding remarks: State of the Art Conference on SIDS, Gothenburg. Acta Paediatrica Suppl 389:128-129.

(75.) Fanaroff A, Martin R (1987) Neonatal-Perinatal Medicine. CV Mosby Co, St. Louis, pp 1108-1109.

(76.) Chowdhry P, Scanion J, Auerbach R, Abbassi V (1984) Results of controlled double-blind study of thyroid replacement in very low-birth-weight premature infants with hypothyroxinemia. Pediatrics 73:301-305.

(77.) Dechamps C, Reynaud EJ, Gaulme J, Vanlieferinghen P, Labbe A, Glanddier Y, Collange C (1991) Morbidity and psychomotor development at 2 years of age in children bern in Puy-de-Dome in 1983. Study of children groups defined by perinatal risk. Ann Paediatr 38(5):323-329.

(78.) Meijer WJ, Verloove-Vanhorick SP, Brand R, Van Den Brande JL (1992) Transient hypothyroxinaemia associated with developmental delay in very preterm infants. Arch Dis Child 67(7):944-947.

(79.) Ponsonby AL, Jones ME, Lumley J, Dwyer T, Gilbert N (1992) Sudden infant death syndrome: Factors contributing to the difference in incidence between Victoria and Tasmania. Med J Aust 156(252)-254.

(80.) Schoendorf KC, Kiely JL (1992) Relationship of sudden infant death syndrome to maternal smoking during and after pregnancy. Pediatrics 90:905-908.

(81.) Mitchell EA, Ford RPK, Taylor BJ, Stewart AW, Becroft DMO, Scragg R, Barry DMJ, Allen EM, Roberts AP, Hassal IB (1992) Further evidence supporting a causal relationship between prone sleeping position and SIDS. J Paediatr Child Health 28(S)9-S12.

(82.) Wigfield RE, Fleming PJ, Berry PJ, Rudd PT, Golding J (1992) Can the fall in Avon's sudden infant death rate be explained by changes in sleeping position? BMJ 304:282-283.

(83.) Brooks JC (1993) Unraveling the mysteries of sudden infant death syndrome. Curr Opin Pediatr 5:266-272.

~~~~~~~~

By Harold D. Foster

Share this with your friends