TOPIC: Iodine requirements & fortification in pregnancy
Title: Iodine prophylaxis using iodized salt and risk of maternal thyroid failure in conditions of mild iodine deficiency.
Authors: Moleti MC, Lo Presti VP, Campolo MC, Mattina F, Galletti M, Mandolfino M, Violi MA, Giorgianni G, De Domenico D, Trimarchi F, & Vermiglio F .
Reference: Journal of Clinical Endocrinology & Metabolism 93: published April 15, 2008 as doi:10.1210/jc.2008-0352
Mild-to-moderate iodine deficiency during pregnancy can cause transient maternal hypothyroidism & impaired mental development of the progeny. These unfavourable effects are preventable by iodine supplementation. In Europe, less than 50% of pregnant women receive iodine-containing supplements, thus representing dietary iodized salt, the only carrier of iodine for most women in this life stage.
Longitudinal study to investigate the effects of long-term iodized salt consumption on maternal thyroid function during gestation.
The authors prospectively evaluated thyroid function in 100 consecutive TPO-Ab-negative pregnant women from a mildly iodine-deficient area. Sixty-two women who had regularly used iodized salt for at least 2 years prior to becoming pregnant and 38 women who commenced iodized salt consumption upon becoming pregnant were classified as long-term (LT) and short-term (ST) iodine supplemented, respectively.
Long-term iodized salt consumption resulted in a very low prevalence of maternal thyroid failure (MTF) in LT women. Conversely, short-term iodine prophylaxis does not seem to protect against the risk of MTF, the prevalence of which was almost 6-fold higher in ST than in LT women. The relative risk reduction amounted to 82.5%, this measure indicating the extent to which long-term iodine prophylaxis using iodized salt would reduce the risk of MTF in ST women.
Prolonged iodized salt significantly improves maternal thyroid economy and reduces the risk of maternal thyroid insufficiency during gestation, probably because of an almost adequate restoration of intra-thyroidal iodine stores.
This article by our colleagues from Italy concerns a group of 100 euthyroid, thyroid antibody-negative women selected amongst a larger cohort. More specifically, the original group comprised 395 consecutive pregnant women living in the North Eastern part of Sicily. From this total, 295 women were excluded for various reasons: nodular goiter, autoimmune thyroiditis, thyroid dysfunction, and hypothyroidism after thyroid surgery. Questioned about the biases potentially induced by excluding ' of this initial group, the authors replied that the study was performed in an area previously known to be moderately-severely iodine deficient, with a prevalence of goiter in school-age children reaching 65% in the late 1970s. Therefore, the high frequency of thyroid disorders that led to excluding a large fraction of the population was a long term consequence of long lasting iodine deficiency, hence rendering the group of normal women investigated herein perhaps even more interesting.
The women were divided into 2 groups, respectively of 62 & 38 women, classified as having benefited from long-term 'LT' or short-term 'ST' iodine fortification. The classification was based on the adequacy of the daily iodine intake that resulted from introduction of iodized salt in households. LT women consumed iodized salt regularly since at least 24 months (5 years on average), while ST women commenced using iodized salt only upon becoming pregnant. Iodized salt consumption made a significant difference in the iodine intake, clearly confirmed by the measurements of urinary iodine concentrations (115 'g/L versus 63 'g/L), i.e. an estimated daily iodine intake of 190 'g versus 105 'g, respectively in LT & ST women. Following the recently revised WHO criteria for adequacy of iodine nutrition requirements (special issue of Public Health Nutrition, December 2007), it is of importance to note that the LT group was not strictly iodine sufficient: these 2 groups corresponded epidemiologically to 'almost adequate' (LT) and 'moderately iodine-restricted' (ST) women.
The first interesting result was that serum free T4 was significantly higher and TSH lower in LT, compared to ST women, throughout pregnancy. With the progression of gestation, free T4 decreased progressively in both groups although mean free T4 values remained within reference limits in both groups until the 3 rd trimester. Between trimester 1 & 3, serum free T4 values decreased by ~20% in LT & ST women. Based on other studies in iodine-deficient pregnancies, one would anticipate serum free T4 values to be proportionally reduced to a greater extent in the most iodine-deprived group. Why was it not so: because of the particular design of the present study. For women who developed mild thyroid failure 'MTF' (see below), the authors considered that it was ethically unacceptable to ignore the occurrence of maternal underfunction, known to be potentially harmful for both mother & fetus. Such women were therefore systematically given L-thyroxine and, consequently, they were excluded from further analysis. Thus, it is highly likely that the 'true' decrement in serum free T4 was in fact of a higher magnitude in the ST compared with LT women, if the free T4 data of those hypothyroxinemic ST women had been maintained in the analyses (i.e. in absence of treatment). Another interesting result concerns the changes in TSH. Comparing ST to LT women, the difference in mean serum TSH was already 37% in 1 st trimester (1.08 mU/L versus 0.79 mU/L) and increased to ~53% thereafter. Such pattern of TSH changes indicates progressive stimulation of the maternal thyroid by increasing TSH, and relatively more so in ST women. In turn, thyroidal stimulation presumably allowed for maintaining unchanged serum free T3 levels, as a compensatory mechanism characteristic of thyroid function changes observed in iodine deficient conditions.
The main result of the study concerns the analysis of individual patterns of thyroid function. All women were euthyroid at initial presentation (6-9 weeks) but, by the end of 1 st trimester, 8% of ST women were affected by subclinical hypothyroidism or isolated hypothyroxinemia, and given L-T4. As mentioned above, these women were excluded from further analysis, but it is worth noting that their thyroid function was rapidly restored to normal following the administration of L-T4. During 2 nd trimester, 20% of remaining ST women developed MTF and, finally, 14% of remaining ST women became hypothyroxinemic during 3 rd trimester. Altogether, MTF (defined as subclinical hypo-, overt hypothyroidism, or isolated hypothyroxinemia) was found in 37% of ST women compared with only 6% in LT women, that is a 6-fold increase in the incidence of thyroid dysfunction in women with an insufficient iodine supply, and despite the use of iodized salt once they became pregnant. A few LT women also developed MTF, presumably because their iodine nutrition status, although considerably better than for ST women, was still not fully adequate, reinforcing the notion that iodized salt consumption in the childbearing age is a necessary condition to avoid development of MTF, but not sufficient to avoid MTF in all pregnancies.
Present study is the first investigation of maternal thyroid failure in women having consumed iodized salt since a long time, compared to iodine fortification introduced during pregnancy. The results confirmed the following notions:
- it is important that women in childbearing age have an adequate iodine supply before pregnancy, with an average intake of 150 'g/day, in order to start a pregnancy with replenished intra-thyroidal iodine stores;
- it is important to increase the iodine intake to 200-300 'g/day during pregnancy, and the use of iodized salt alone, once pregnant, does not allow to fulfil this goal;
- if iodine fortification is carried out during pregnancy (and not before), the glandular machinery will remain triggered and a lag period of at least one trimester will be required before observing a clear improvement in thyroid function;
- and finally, in order to avoid thyroid underfunction and goiter formation in such circumstances, it would be advisable to provide more iodine more rapidly with the aim to reduce the inevitable lag period (mentioned above) or, alternatively and as was done in present work, to treat selected women with L-thyroxine (the authors referred to this alternate approach as ' the timely institution of thyroxine administration ').
Summary and commentary prepared by Daniel Glinoer (Related to Chapter 14 of TDM)