Neonatal thyroid-stimulating hormone concentrations in northern Sydney: further indications of mild iodine deficiency?

We recently reported that Sydney may be an area of mild iodine deficiency. This hypothesis was based on measurement, in 261 adults, of urine iodine concentration,1 which is accepted as an indicator of iodine status by the World Health Organization (WHO).2 However, we had no outcome data to confirm whether the iodine deficiency we observed was associated with any adverse consequences in this population.

The most important consequence of iodine deficiency is its effect on neurophysiological development, both in utero and in the newborn, and it is now thought to impair brain development indirectly by producing hypothyroidism in both mother and fetus.3 WHO recommends other biological indicators, apart from urine iodine concentration, for determining the severity of iodine deficiency in a population at risk.2 One is the proportion of newborns with whole-blood thyroid-stimulating hormone (TSH) concentrations over 5 mIU/L. (In an iodine-replete population less than 3% of neonates older than 72 hours have a TSH concentration over 5 mIU/L.) Thyroid function in the newborn should reflect fetal thyroid function — if iodine deficiency during pregnancy impairs fetal thyroid function, this should result in higher TSH concentrations in the newborn.

To further investigate our hypothesis of iodine deficiency in northern Sydney, we assessed newborn TSH concentrations, which are assayed as part of a routine neonatal screening program.4 Here, we present data on TSH values in whole blood of a large sample of infants born at RNSH, and, for a small subset of neonates, examine the correlation between concentrations of maternal urinary iodine and neonatal TSH.

Our results support the hypothesis that northern Sydney is an area of mild iodine deficiency, with 8.1% and 5.4% of the two large population samples of neonates having TSH values > 5 mIU/L (WHO population prevalence range of neonatal TSH values for classification as mild iodine deficiency, 3%–19.9%).2,5

However, this conclusion should be regarded with some caution. Firstly, the time of sample collection could have influenced the concentration of TSH. In the 84 identified infants, samples for TSH measurement were collected on Day 3, which may have been before 72 hours of life. However, we were unable to find a relationship between TSH concentration and time of birth. In those samples more likely to have been collected within 72 hours of birth, both the TSH values and the proportion of neonates with TSH concentrations > 5 mIU/L were slightly higher, but not significantly so, than in samples more likely to have been collected after 72 hours. A higher TSH level would be anticipated in the samples collected before 72 hours after birth. That the proportion of TSH values > 5 mIU/L in samples more likely to have been collected after 72 hours was still high suggests that early measurement does not fully account for the high proportion of elevated TSH values. A formal study with appropriately timed TSH sampling is required to provide a definitive answer to this question.

Another reason for caution is that the WHO criteria for iodine status do not consider the methods used to assay TSH. Data from the newborn screening quality assurance program of the Centers for Disease Control and Prevention show that different assay methods may produce different results, with variations of up to 15% at a target TSH value of 25 mIU/L among eight methods.7

The vital question "Does the borderline mild iodine deficiency found in the pregnant women account for the high proportion of infants with an elevated TSH?" cannot be answered from the data we present. Moreover, our study raises several other questions and issues. If iodine deficiency is responsible for the elevated neonatal TSH, why is the relationship between maternal urine iodine concentration and neonatal TSH concentration positive? If iodine deficiency were responsible for the higher TSH values, the expected relationship should be negative. A similar lack of the expected relationship between maternal urine iodine and neonatal TSH concentrations has recently also been found in another study.8

Many studies demonstrate the benefit of having an iodine-replete population before pregnancy.9 Iodine deficiency is the leading preventable cause of intellectual impairment.5 Maternal iodine supplementation in populations with high levels of endemic cretinism results in a reduced incidence of cretinism, without significant adverse effects.10 In populations with less severe iodine deficiency without cretinism, the benefit of iodine supplementation is not as rigorously established, although evidence from a meta-analysis of studies suggests that, with iodine supplementation, an improvement in neuropsychological functioning occurs in clinically euthyroid infants from areas with endemic goitre.11 It has been argued that cretinism is merely one end of a continuous spectrum of neuropsychological impairment induced by iodine deficiency, rather than there being a threshold above which cretinism or lesser impairment in neuropsychological development does not occur.12

Iodine deficiency impairs brain development through hypothyroidism. Pop et al have shown that the infants born to mothers who had free thyroxine concentrations below the 10th percentile before week 13 of gestation had impaired neuropsychological development at 10 months and two years.13,14 In the first 12 weeks of fetal life, before fetal thyroid development the fetus depends solely on maternal transfer of thyroxine. The work of Pop et al13,14 was performed in an iodine-replete area.

A formal study of the iodine status of NSW communities should be undertaken.15 It is of vital importance to determine if mild iodine deficiency in Australia might be contributing to subtle maternal hypothyroidism in the early part of pregnancy, with subsequent limitation of neonatal brain development. For this we need to examine the biological effects of the suspected iodine deficiency and, in particular, the biological effects relevant to pregnancy and both maternal and fetal thyroid function.

Specific questions that need to be explored are:

• Is the Australian population (or significant sections of the Australian population) suffering from iodine deficiency? and

• Do milder degrees of iodine deficiency not associated with cretinism result in impaired neonatal brain development, with a resulting significant permanent decline in cognitive capacity?

Hypothyroidism early in pregnancy, secondary to iodine deficiency, will only be corrected by strategies that ensure adequate iodine intake before pregnancy.16,17

3: Correlation between natural log of neonatal whole-blood TSH values (mIU/L) and natural log of maternal urine iodine concentrations (µg/g creatinine)