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Letters to the Editor |
Quest Diagnostics Nichols Institute San Juan Capistrano, California Harbor UCLA Medical Center Torrance, California
In their letter above, Gabriella Morreale de Escobar and Susana Ares (the authors) take issue with the terminology "physiologic" hypothyroxinemia for the hypothyroxinemia of prematurity (HOP), contending that HOP is not physiological relative to the intrauterine condition and that it inappropriately discourages corrective treatment. They point out that in utero the premature infant would "avoid the hypothyroxinemic state and, as a result of high circulating TSH levels, would promote thyroidal maturation."
There is no question that the intrauterine and extrauterine environments differ dramatically. With reference to the pituitary-thyroid axis, there is a marked reduction in serum TSH levels in neonates of any gestation age as they equilibrate to the extrauterine environment (1, 2, 3, 4, 5). The mechanisms for this permanent readjustment remain unclear. Several factors presumably are involved, including increased serum T3 and free T3 concentrations, decreased metabolism of thyroxine to inactive analogues, decreased extrahypothalamic production of TRH, readjustment of the thyroid hormone negative feedback control "setpoint" for TSH secretion at the hypothalamic-pituitary levels, and perhaps altered bioactivity of secreted TSH. Whatever the mechanisms, "normal" TSH levels are reequilibrated to the extrauterine environment at much lower values than third trimester fetal concentrations.
Free T4 concentrations are more variable during the extrauterine transition. In healthy preterm infants of more than 30–32 weeks gestation, free T4 levels tend to increase with exposure to the extrauterine environment while levels in infants of less than 28–30 weeks gestation transiently decrease (3, 4, 5). Thereafter, free T4 concentrations in all premature infants progressively increase with postnatal age roughly in parallel with maturation of free T4 concentrations in the third trimester fetus as the authors have shown (6).
Primary hypothyroidism is manifest in premature infants, as well as term infants, by increased serum TSH levels, and it is clear that the negative feedback control system for TSH secretion is operative in most premature infants at 24–25 weeks gestation age (5, 6, 7). This implies that the vast majority of premature infants, even the very low birthweight (VLBW) infants, have thyroid hormone production adequate to maintain normal extrauterine TSH concentrations. Recent data, as the authors indicate, confirm the earlier view that neurodevelopment of premature infants of more than 27 weeks gestation age is not improved by thyroxine treatment (8). Thus, thyroid function in most premature infants equilibrated to the extrauterine environment is "physiologic" by the dictionary definition in that it is "characteristic of or appropriate to the organism’s healthy or normal functioning." The term is not used to imply recapitulation of the intrauterine state.
The focus more recently has been on the VLBW infant of less than 27 weeks gestation age. These infants have more limited organic iodine stores and, as the authors have shown in their recent elegant study, have a tendency to early negative iodine balance and an increased risk of severe transient hypothyroxinemia especially in areas of low iodine availability (6). Serum TSH levels are not usually increased, so our most sensitive marker of thyroxine deficiency may not be operative in some of these infants because of system immaturity. Perhaps 5–10% of VLBW infants have immunoassay values of free T4 less than 0.5 ng/dL (6.4 pmol/L) without increase in serum TSH levels (4). Do these infants have transient hypothalamic-pituitary (secondary-tertiary) hypothyroidism? The double blind treatment study of Van Wassenaer and colleagues (8) would support this view in that thyroxine treatment of 13 VLBW infants improved mean IQ by 18 points relative to nontreatment controls. However, this is a small series, and further detailed studies are necessary.
Thus, available recent information supports the view that thyroid reserve and function in some proportion of VLBW infants is not physiologic. The issue is not so much that their thyroid function parameters differ from their intrauterine age contemporaries but that thyroid function may be inadequate for healthy or normal functioning in the extrauterine environment. However, the criteria for this determination and for treatment remain to be defined more precisely.
The issue of morbidity and mortality related to severe HOP has been assessed in several studies as reviewed by the authors. This issue is somewhat separate from the issue of the impact of HOP on neurodevelopment. Neonatal morbidities accentuate HOP, and the early transient hypothyroxinemia of VLBW infants is conditioned in part by the extent or degree of neonatal morbidity or comorbidities (5, 9). Recent data of Klein et al. (9) show that neonatal illness is associated with increased free T4 concentrations due to inhibition of T4 binding to serum thyroxine-binding globulin (TBG), as in adults with the euthyroid sick or nonthyroidal illness syndrome. Increased free T4 with decreased TBG and total T4 levels also were observed during the first week of life in sick premature infants by Van Wassenaer and coworkers (5). These results suggest that the hypothyroxinemia associated with the euthyroid sick syndrome in VLBW infants might be differentiated from transient secondary/tertiary hypothyroidism by measurement of the free T4 level. Thus, all hypothyroxinemia in VLBW infants is not hypothyroidism, and segregating the impact of HOP and comorbidities on mortality requires more detailed analyses. Some of these studies are in process, and we await results.
Footnotes
Received November 12, 1997. Accepted November 13, 1997. Address correspondence to: Delbert A. Fisher, M.D., Quest Diagnostic Nichols Institute, 33608 Ortega Highway, San Juan Capistrano, California 92690.
References
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