Recent data from the "NHANES 3" study indicated that iodine nutrition was adequate in the overall population in the U.S. of A., with a median urinary iodine concentration (UIC) of 160 µg/L (1). However, the same national survey also showed that the iodine intake tended to be somewhat lower in women in the child bearing age, with a median UIC slightly above 100 µg/L. Furthermore and importantly, among the women aged 15-45 yrs, 5-12 % had a UIC below 50 µg/L. Therefore, and although complete data are not yet fully available, this indicates that a significant fraction of young women must have a UIC below 100 µg/L. Thus, the iodine nutrition status is probably marginally restricted or even moderately deficient in a non negligible fraction of the " to-be-pregnant " female population in the United States.

Concerning the iodine nutrition situation in Europe, several studies have confirmed the risks associated with iodine deficiency (ID) in women during pregnancy. Altogether, these studies have emphasized the need to assess the actual iodine nutritional status regionally, because mild ID tends to present as a "geographical pocket" condition, with wide variations between different areas within a given country. Conceptually, one important medical aspect of this problem is that the threshold range for ID to induce maternal thyroidal consequences (hypothyroxinemia & raised serum TSH, maternal & fetal goiter formation, consequences for fetal development, etc) is relatively narrow, corresponding to a daily iodine intake between 75-100 µg in the pregnant state (see recent Reviews in 2-4).

When feasible, primary prevention of ID is preferable. This implies, however, the provision of sufficient iodine to the general population in order for a pregnancy to start with an "at ease" situation for the maternal thyroid economy (i.e. replete intrathyroidal iodine stores). When primary prevention is not possible (and this is usually a public health & political issue), it is necessary to employ simple ways to increase the iodine intake during pregnancy as early as possible. The Recommended Daily Allowance (RDA) is ~225 µg of iodine/day during pregnancy (5). Thus, after assessing the iodine nutritional status in any concerned area, simple but effective measures should be implemented. In Belgium for instance, 50-75 µg of iodine/day are obtained naturally from the diet. With iodised salt now freely available, and even though the salt intake ought to be restricted during a pregnancy, 4 gr of salt will bring another 60 µg of iodine/d. However, since the use of iodised salt is not mandatory in most European countries, this measure can be implemented only on a voluntary basis and hence, constant and proactive education of the public (and the doctors) is necessary. Also, it is advisable to inform pregnant women to eat more fish, etc, perhaps contributing another 10-15 µg of iodine/day. Together, therefore, a quantitatively important complement must come from multivitamin pills specifically prepared for pregnancies. Such pills have now replaced most older formulae in Belgium and they contain 125-150 µg of iodine. By combining relatively simple measures, it should be easy to reach the RDA for iodine. Finally, it is important to keep in mind that reassessments are needed to ensure that the ultimate goal has been achieved (and this is rarely done) and also to continue monitoring the iodine nutrition status in the pregnant populations. In the United States, iodine-containing multi-vitamin formulae represent only one-third of prescription prenatal vitamins and two-thirds of shelf-available preparations but, from the presently available (anecdotal) information, it seems that pregnant women may not all presently use them.

Our first conclusion from the workshop in Atlanta was that the use of iodine supplements should be promoted during pregnancy in the U.S. of A. and women advised to use multivitamin pills containing 150 µg of iodine during pregnancy. Only the future will tell how our this proposal will be implemented in the United States. Concerning most European countries where ID is even more prominent than in the U.S. of A., iodine-containing "pregnancy" pills should be made available in every country (which is presently not yet the case). Furthermore, the medical community, as well as young women, should be duly informed of the necessity to prescribe and use them.

2. The outcome of pregnancy in mothers with thyroid dysfunction (overt & subclinical hypothyroidism)
 
From a substantial body of data available from both retrospective and prospective studies, it appears clearly that 6-12 % of child bearing age women have thyroid antibodies, 1-2.5 % of pregnant women have subclinical hypothyroidism (SCH) and 0.3-0.5 % of unselected pregnancies have clinical hypothyroidism (CH), with/without symptoms, that are undiagnosed before pregnancy. New epidemiological data were presented at the CDC meeting by Dr Ken Leveno (from Dept Ob-Gyn., Univ. Texas). Among 17.000 women enrolled at their prenatal clinic before 20 wks gestation, their results showed that 2.5% had a supranormal serum TSH. Among them, over 90% had a normal serum free T₄ (SCH) and 10% a lowered serum free T₄ (CH). It is of interest to note that these prevalences, obtained recently in a prospective study in an iodine-sufficient area, were quite similar to those obtained ten years ago in Europe in an area with mild iodine restriction (6).

The next important question pertains to the frequency and importance of obstetrical complications in women with SCH/OH and the beneficial impact of early detection and treatment. The study from Texas (referred to above) also showed that the prevalence of preterm birth, intensive neonatal care admission and respiratory distress syndrome were significantly increased in pregnancies with SCH & CH, with a relative risk that was almost double, compared to healthy control pregnancies. Dr Jorge Mestman (from USC in Los Angeles) also presented new data on 143 hypothyroid pregnant women. Among them, 11 were newly diagnosed cases, 35 women were known to have hypothyroidism but had stopped taking l-T₄ (corresponding to CH), and 40 women were treated for hypothyroidism but their replacement dose had not been adequately adjusted (corresponding to SCH). Their study showed that the frequency of both gestational hypertension and prematurity were markedly increased and that there was a trend for the risk of obstetrical complications to be increased with the absence of (or a delay in) re-establishing normal thyroid function.

Our second conclusion from the workshop was that the frequency and type of adverse effects on the outcome of pregnancy, related to both SCH and CH, may vary amongst different studies (mainly miscarriages, low birth weight with or without associated prematurity, gestational hypertension, and fetal death). However, there was a good consensus among the members of the panel that the evidence supporting the notion that both SCH and CH are associated with adverse effects on the outcome of pregnancy was strong. Hence, thyroid dysfunction should be detected (by thyroid function testing) and treated (with l-T₄).

With regard to l-T₄ treatment of hypothyroid pregnant women, recent data from Reed Larsen's group in Boston indicate that l-T₄ requirements are increased in almost all of them, as early as 5-8 weeks gestation, with a plateau ~50% higher reached by mid-gestation (7). These results (first presented at the 2003 ATA meeting) confirm occasional observations already reported by other investigators and emphasize the need to adjust the dosage of l-T₄ as early as possible during pregnancy, and thereafter monitor thyroid function until at least mid-gestation (we would advise until the end of the 2^nd trimester).

With regard to screening, it was considered that universal screening before pregnancy was not practically feasible, except in selected high risk patients who plan for their pregnancy. Thus, thyroid function tests should be carried out as soon as possible after the first missed menstrual period and, after SCH or CH has been confirmed, the patients should be referred to an endocrinologist or at least have the possibility to contact experienced consultants (by telephone or e-mail, for instance). The panel came to the conclusion that it was probably too early to propose a systematic national screening of thyroid dysfunction in the U.S. of A., but that large prospective and randomised pregnancy studies should be undertaken to assess: a) the clinical importance of SCH; and b) whether treatment of SCH improves pregancy outcome.

Practically, four clinical conditions can be recognized. The first is clinical hypothyroidism (i.e. elevated TSH & lowered free T₄ with/without thyroid antibodies).

This condition requires active treatment with ~150 µg l-thyroxine/day (2-2.4 µg/Kg/d), followed by close monitoring of thyroid function and adequate adjustment of the dosage to maintain euthyroidism. The second is subclinical hypothyroidism (i.e. raised TSH & "normal" free T₄ with/without thyroid antibodies). Even though the evidence is slightly less strong for SCH than for CH, it is still good enough to warrant l-thyroxine treatment in these women (8). The third is thyroid autoimmunity (TAI) features with euthyroidism (i.e. normal TSH & free T₄ with thyroid antibodies). There is limited - but reasonably good - knowledge of what happens to such women when followed during gestation. A fraction of them are able to maintain euthyroidism, while the others progressively develop SCH (or even CH). The evolution depends on underlying factors that are not entirely understood, among which are the duration and intensity of the autoimmune attack, the residual functional capacity of the maternal gland to adapt, and finally perhaps also superimposed iodine deficiency (9). TAI with normal thyroid function can be diagnosed only by systematic screening programs, and arguments can be defended both in favour and against such screening. This question therefore needs further study and, in the mean time, the best attitude is probably to refer women with thyroid autoimmunity and normal thyroid function to experienced endocrinologists and use common sense to decide on whether to treat such women or simply monitor the evolution of thyroid function during later gestational stages (10). It is worth mentioning that if the need for national screening programs is presently undecided and more research obviously needed on the potential maternal and fetal consequences, one can already strive today for a better education and information of the public and medical community. Screening programs can also be organized locally (as they already are in several European hospitals nowadays). Finally, it is perhaps worth considering voluntary screening, whereby pregnant women would accept to pay the cost of measuring serum TSH, free T₄ and TPO-Ab in early pregnancy. Finally, the fourth category is the most controversial and difficult to apprehend. It concerns the pregnant women with an early (1st trimester) low free T₄ and a strictly normal serum TSH in the absence of thyroid antibodies. As of today, it is only safe to state that not enough is known about the reality, importance, and the underlying causes of such biochemical abnormality. More research is therefore needed to examine whether this condition truly exists, what these subjects really have and what the risks are for both the mother and offspring. Taking the lower percentile of a normal free T₄ range is, by definition, not sufficient to define a true abnormality or a disease. This can only be done within the framework of a research project to assess potentially deleterious associations with disease in such women. Studies are currently ongoing on this topic, as in the "CATS" study, recently undertaken in Wales by Dr John Lazarus. For the moment, all we can say is that we need to keep an open mind, since studies such as those of Dr Victor Pop have indicated that isolated abnormally low maternal free T₄ values (between 5-7 pmol/L) at 12 weeks gestation may be associated in some cases with a lower index of development, up to 3 years of age (11, 12).

3. Neuropsychological performance of the offspring

The study by Haddow et al., published in the New England Journal of Medicine in 1999, shows very clearly that maternal hypothyroidism, when present already in the first half of gestation and not adequately corrected thereafter, is associated with a lower global IQ in the school-age children of these mothers (13). Because of the complex processes that take place to ensure the progressive and normal maturation of the fetal brain, it is accepted that any cause of significant maternal hypothyroxinemia and, in turn, significant reduction in the transfer of maternal thyroid hormones to the fetal compartment, may be associated with deleterious and perhaps irreversible effects. What remains to be better appreciated by future studies is " what is really responsible for what " ? For instance, global IQs measured at 5-6 years of age seem to be more directly related to elevated maternal serum TSH values during late gestation, while other cognitive defects (such as poorer visual performance or delayed responses to various stimuli, etc) seem to be more directly related with earlier (i..e. first trimester) maternal TSH alterations. Thus altogether, the evidence available today points again to the crucial importance of detecting early and treating adequately MTD.

Having reviewed the evidence, it was the feeling of the participants to the workshop that the neuropsychological consequences of maternal hypothyroxinemia in the progeny probably represent a multifactorial condition. Presently available observations may be explained in part by the obstetrical consequences associated with undiagnosed hypothyroidism during pregnancy (for instance premature delivery, gestational hypertension, lower birth weight, smaller head circumference, etc), in part by the direct consequences of an insufficient maternal transfer of thyroid hormones to the developing brain, and finally in part also by crucial environmental factors among which one factor (but it is not the sole one) is undiagnosed hypothyroidism during several years in the postpartum with all its familial implications (postnatal maternal care of the infant, psychostimulating its intelligence in the first years of life, etc). Thus in summary, our conclusions are that the evidence is presently insufficient - or unconvincing - to directly relate maternal hypothyroxinemia to the neuropsychological performances in the offspring and that further research is needed in this field.