Serum 25-Hydroxyvitamin D Concentrations in Sudden Infant Death Syndrome

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ARTICLES 1137

Serum

25-Hydroxyvitamin

D Concentrations

in

Sudden

Infant

Death

Syndrome

Laura S. Hillman, MD, Marilyn Erickson, PhD, and

John

G.

Haddad, Jr, MD

From the Edward Mallinckrodt Department of Pediatrics and the Department of

Medicine, Washington University School of Medicine; Division of Neonatology, St Louis Children ‘s Hospital; and Division of Metabolism, The Jewish Hospital of St Louis, St Louis

ABSTRACT. Among the many theories put forth to

ex-plain sudden infant death syndrome (SIDS) is a theory

of vitamin D deficiency. 25-Hydroxyvitamin D (25-OHD)

serum concentrations were measured in 31 SIDS and 24 postmortem control infants. 25-OHD was 19.0 ± 7.9 mgI

ml in SIDS, 16.9 ± 5.2 ng/ml in acute death control infants, and 1 1.9 ± 4.4 ng/ml in in-hospital deaths. For

four “near miss” infants the mean serum 25-OHD

con-centration was 211 ± 4.1 ng/ml. The mean serum

25-OHD concentration of 39 living premature or small-for-gestational-age infants at 3 months of age was 26 ± 9.9. Serum calcium and serum copper concentrations were

also the same in SIDS and control infants. Parathyroid

hormone was measured in ten and was detectable in five

SIDS infants. These data eliminate a simple vitamin D deficiency or a 25-OHD deficiency as a significant contri-bution to the pathophysiology of SIDS. Pediatrics 65:

1137-1139, 1980; sudden infant death syndrome,

25-hy-droxyvitamin D, vitamin D.

Although much of the research in sudden infant death syndrome (SIDS) is being directed toward a search for abnormal physiology that may be present at birth, there is evidence that environmental

fac-tors play at least a triggering role. Carpenter and Emery’ were able to cut the SIDS mortality in a high-risk group to one third that of the control

group by simply instituting an intensive health sup-port system for the mother and infant after birth. In the search for potentially modifiable postnatal factors, nutrition has received much attention, pre-dominantly by nonmedical- and nonresearch-ori-ented groups.

Received for publication Aug 9, 1979; accepted Sept 27, 1979.

Reprint requests to (L.S.H.)Department of Pediatrics, St Louis Children’s Hospital, 500 S Kingshighway, P0 Box 14871, St Louis, MO 63178

A theory of vitamin D deficiency was put forth by Kraus et al2 in 1971. This was based on the marked incidence of SIDS in the winter and the finding that SIDS infants spent less time outdoors than control infants. The second rationale for

con-cern about vitamin D was the theory that hypocal-cemia could contribute to SIDS by the triggering of laryngospasm as a terminal event.3 Third, an

in-creased incidence of microscopic rickets was de-scribed in a series of northern European SIDS victims.4 Fourth, even in the absence of rickets, vitamin D deficiency leads to linear growth

retar-dation.5 Our data in premature infants show a direct correlation between 12-week serum concentration of 25-hydroxyvitamin D (25-OHD), the major cir-culating metabolite of vitamin D, and one-year height percentile corrected for gestational age.6 Re-cently, Sinclair-Smith et al7 have described growth

arrests in the rib costrochondral junctions of SIDS infants, and a general postnatal growth retardation

has also been demonstrated in SIDS.8 Fifth, SIDS is more common in premature infants and has a peak incidence at 3 months of age.9”#{176}25-OHD is low in the rickets and osteopenia often seen in premature infants at around 3 months of age.’ ‘ We

thus measured serum 25-OHD, calcium, magne-sium, phosphorus, copper, zinc, and parathyroid hormone (PTH) in SIDS and control infants.

METHODS

Blood was collected at postmortem examination; it was then spun and the serum was frozen. SIDS infants were autopsied by the pathologists of the medical examiner’s office and the diagnosis of SIDS was made by their pathologists. Medical examiner control cases were infants less than 1 year of age who had died suddenly and in whom a definitive cause of death could be ascertained; they were

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1138 PEDIATRICS Vol. 65 No. 6 June 1980 autopsied by the pathologists of the medical

ex-aminer’s office. In-hospital controls were infants less than 1 year of age who had died in the hospital and were autopsied by the university service. 25-OHD was assayed by the competitive protein bind-ing assay of Haddad and Chyu.’2 Calcium, magne-sium, copper, and zinc were measured by atomic absorption using flame and carbon rod methods.’3.’4 PTH was measured by a radioimmunoassay which measures the C-terminal end.’5

RESULTS

The results are summarized in the Table. The mean ± SD of 25-OHD serum concentration was

19.0 ± 7.9 ng/ml for the 31 SIDS infants, 13 ± 6.3 ng/ml for the 24 control infants, 11.9 ± 4.4 for the 17 in-hospital control infants, and 169 ± 5.2 ng/ml for the 7 medical examiner control infants. The mean and SD of 25-OHD serum concentrations for four near miss infants was 21.1 ± 4.1 ng/ml, normal adults, 24.0 ± 9.7 ng/ml, and for 39 living premature or small-for-gestational-age infants at 3 months of age, 26.0 ± 9.9 ng/ml. Serum calcium was within the physiologic range with SIDS infants, 9.9 ± 2.0

mg/100 ml, and control infants, 9.8 ± 2.3 mg/100

ml. Serum magnesium, phosphorus, and zinc levels were all markedly elevated as expected post mor-tem, and there were no differences between SIDS

infants and control groups. Serum copper levels were 154 ± 76 mg/100 ml (mean ± SD) in nine SIDS infants and 131 ± 61 mg/100 ml in 16 control infants (normal adult = 143 ± 25 mg/100 ml). PTH

was detectable and within normal range in five of

ten SIDS infants studied. The mean age of the 31 SIDS infants at death was 14.5 ± 8.9 weeks; the deaths occurred throughout the year. The mean age of the seven medical examiner control infants was 22 ± 16.6 weeks.

DISCUSSION

The process of death and the time lag to autopsy limit the value of using postmortem serum samples for studying metabolic processes. This is, in part, the reason why research into metabolic theories of SIDS has been limited. 25-OHD is relatively stable in serum; thus looking at postmortem samples seemed worthwhile. Of crucial importance, how-ever, is having a control group in which to evaluate the effects of death and processing per se. This

always poses a problem for SIDS studies since normal infants who die suddenly (other than SIDS infants) are few, and in-hospital control infants are

often chronically ill prior to death. In this study this was true with the seven sudden death medical examiner control infants having normal serum 25-OHD (17 ± 5.2 ng/ml), and the 17 in-hospital con-trol infants having low normal serum 25-OHD (12

± 4.4 ng/ml). The SIDS infants had serum 25-OHD concentrations similar to those of the other medical

examiner cases and higher than those of in-hospital control infants. Although the mean concentration of 25-OHD of the SIDS infants, 19 ± 79 ng/ml, is close to the adult mean concentration of 24 ± 9.7, it is less than the mean concentration of other infants at 3 months, 26 ± 9.9. This difference may be postmortem artifact; however, it probably rep-resents the higher number of deaths occurring in winter and a generally lower socioeconomic status seen in SIDS infants. The living patients, 3-month-old infants, were on formula plus 400 IU of vitamin D as a vitamin supplement. The dietary intake of vitamin D in the SIDS infants is unknown; however, supplements were probably used less frequently.

Four surviving near miss infants had a similar mean concentration of 25-OHD, 21 ± 4.1 ng/ml.

These data are adequate to state safely that vitamin D deficiency, as reflected by serum

25-TABLE. Serum 25-OHD, Calcium, and Copper Conc

sied Infants, and Living Control Infants (Mean ± SD)

entrations in S IDS Infants,

Autop-Specimen N 25-OHD Calcium Copper n

(ng/ml) (mg/100 ml) (mg/100 ml)

Autopsied infants

SIDS 31 19.0 ± 7.9 9.9 ± 2.0 154 ± 76 9

Medical examiner controls 7 16.9 ± 5.2 9.4 ± 2.3 188 ± 50 5

In-hospital controls 17 11.9 ± 4.4 9.9 ± 2.3 113 ± 56 11

(Total controls)t (24) (13.0 ± 6.3) (9.8 ± 2.3) (131 ± 61) (16)

Living patients

“Near miss” 4 21.1 ± 4.1 Normal ...

3-month-old premature or small- 39 26.0 ± 99 9.8 ± 1.0 96 ± 36 39

for-gestational-age infants

Normal adults 42 24.0 ± 9.7 9.7 ± 0.8 143 ± 25 17

* Values apply only to copper.

t

Totals for medical examiner and in-hospital control infants are shown in parentheses.

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PEDIATRICS Vol. 65 No. 6 June 1980 1139

OHD, is not a general problem in SIDS infants and probably does not contribute to the underlying

pathophysiology. This does not rule out any

prob-lem in the further metabolism by the kidney to 1,25-hydroxyvitamin D (1,25(OH)2D), the most ac-tive form of the vitamin. However, it would be

unusual to have a defect in an enzymatic system

giving the high occurrence of SIDS, two to three!

1,000 live births. A maturational delay of the

1-hydroxylase would be possible but unlikely since

many sudden infant deaths occur when infants are several months of age.

One of the major factors regulating the conver-sion of 25-OHD to 1,25(OH)2D and calcium

home-ostasis is PTH. Geertinger’6 put forth a theory of

absent parathyroid glands in SIDS; this theory was subsequently disproved by Valdes-Dapena.’7

How-ever, the parathyroid may be present but not se-creting active hormone. Unfortunately, PTH is much more subject to autolysis such that one would

expect postmortem samples to be low or

undetect-able. Indeed, our finding of measurable PTH in five of ten samples assayed is probably adequate to

refute any theory of generalized PTH deficiency. Postmortem mineral concentration data are also

of very little value; however, SIDS infants and control infants had similar values and there were no gross deficiencies. The fact that the

concentra-tion of serum copper was normal is against copper deficiency as important in the costochondral junc-tion changes reported in SIDS. Direct analysis of

tissue minerals is needed. One study’8 has found normal concentrations of copper, zinc, and

magne-sium in liver.

RELEVANCE

In a disease entity where multiple theories abound, the ruling out of even one theory is prog-ress. Vitamin D deficiency can probably now be excluded as a possible cause of SIDS. Parents of SIDS infants frequently ask whether they could have prevented the death by doing something dif-ferently, such as giving vitamins; thus, ruling out vitamin D deficiency is useful information. Unfor-tunately, at this time, support and the knowledge that they were not at fault is all we have to offer

those parents and others who have suffered the tragedy of SIDS.

ACKNOWLEDGMENT

This work was supported by National Institutes of

Health grant ROl HD09998-03.

REFERENCES

1. Carpenter R, Emery J: Identification and follow-up of infants at risk for sudden death in infancy. Nature 250:729, 1974 2. Kraus A, Steele R, Thompson M, et a!: Further

epidemio-logic observations on sudden unexpected death in infancy in Ontario. Can J Public Health 62:210, 1971

3. Beckwith B: Observation on the pathological anatomy of the SIDS, in Bergman AB, Beckwith JB, Ray CG (eds): Sudden

Infant Death Syndrome: Seattle, University of Washington

Press, 1970

4. Geertinger P: Sudden unexpected death in Copenhagen. Dan Med Bull 14:109, 1967

5. Slykes F, Hamil B, Poole M, et al: Relationship between vitamin D intake and linear growth in infants. Proc Soc Exp Biol Med 37:499, 1937

6. Hillman L, Huebener D, Haddad J: Long term effects of low 25-hydroxy-vitamin D (25-OHD) serum concentrations in premature infants: a preliminary report, in Proceedings of

the Fourth Workshop on Vitamin D, Berlin, Walter

De-Gruyter, 1979, p 331

7. Sinclair-Smith C, Dinsdale F, Emery J: Evidence of duration and type of illness in children found unexpectedly dead. Arch Dis Child 51:424, 1975

8. Peterson D, Benson E, Fisher L, et al: Postnatal growth and the sudden infant death syndrome. Am J Epidemiol 99:389, 1974

9. Peterson D: Sudden unexpected deaths in infants, an

epi-demiologic study. Am J Epidemiol 84:478, 1966

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Proceedings of the Second International Conference on

Causes of Sudden Deaths in Infants. Seattle, University of

Washington Press, 1970, p 47

11. Hoff N, Haddad J, Teitelbaum S, et aJ: 25-Hydroxyvitamin

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12. Haddad JG, Chyu KJ: Competitive protein-binding radioas-say for 25-hydroxycholecalciferol. J Clin Endocrinol Metab

33:992, 1971

13. Analytical Methods for Flame Spectroscopy. Springvale,

Vic, Australia, Varian Techtron Pty, Ltd, 1972

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Springvale, Vic, Australia, Varian Techtron Pty, Ltd, 1975

15. Hruska K, Kopelman R, Rutherford W, et al: Metabolism of immunoreactive parathyroid hormone in the dog. J Clin

Invest 56:39, 1975

16. Geertinger P: Sudden unexpected death in infancy. Pediat. rics 39:43, 1967

17. Valdes-Dapena M, Weinstein D: The parathyroids in sudden unexpected death in infants. Acta Pathol Microbiol Scand

[A] 79:228, 1971

18. Lapin C, Morrow G, Chvapil M, et al: Hepatic trace elements

in the sudden infant death syndrome. J Pediatr 89:607, 1976

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1980;65;1137

Pediatrics

Laura S. Hillman, Marilyn Erickson and John G. Haddad, Jr