Gestational hypothyroxinemia and the beneficial effects of early dietary iodine fortification.

The article by Pere Berbel and his Spanish coworkers, published in this issue of Thyroid (1), is fascinating both for the results reported and its clever study design, unique among all other studies published so far on the consequences of iodine deficiency (ID) during pregnancy. Because this study combines data on specific maternal aspects with information on infant neurodevelopment, the present editorial was written jointly by two authors representing these different disciplines. ID is considered to be one of the most frequent causes of preventable mental retardation in children worldwide. Because ID is now recognized as a major public health issue for both maternal and fetal=child health, micronutrient fortification with dietary iodine has been listed as priority number 3 among 30 proposals that constitute major worldwide challenges for which solutions presently exist. These proposals, entitled ‘‘2008 Copenhagen Consensus,’’ have been recently established by a panel of eight of the world’s most distinguished economists, including five Nobel laureates (2). The developing brain needs thyroid hormone (TH) throughout pregnancy and TH receptors are present in fetal brain tissue as early as the first trimester. Limited TH secretion does not occur until the second trimester, hypothalamopituitary regulation of TH production not until the third trimester, and full function not until term. Consequently, the fetal brain has to rely on maternal supply of TH and this reliance continues until delivery (3). During the first trimester of pregnancy, maternal thyroxine (T4) is the fetus’s only source of T4, whereas by the third trimester mother and fetus both supply T4. In fetal brain, the active TH interacting with nuclear receptors is triiodothyronine, derived from maternal T4 by deiodination. Epidemiological studies have shown that children born to women with mild to moderate hypothyroxinemia exhibit neurological alterations and reduced IQ scores, as well as an increased incidence of attention problems (4). Because of the central role of iodine in TH production, children whose mothers had mild to moderate ID may also be at risk. Indeed, a recent study of children from a region in Sicily with mild to moderate ID reported an association between first trimester ID and reduced IQ as well as attention deficit hyperactivity disorder in as many as two thirds of the children (5). However, because most studies were carried out in the context of maternal hypothyroidism (i.e., with elevated serum TSH) or isolated hypothyroxinemia (i.e., with normal serum TSH), and in light of the review by Glinoer and Delange (6) also reporting subtle neuro-psychiatric and intellectual deficits in infants=children born to mothers residing in conditions with mild to moderate ID, further study is warranted (7). In the study by Berbel et al. (1), the authors examined the consequences of a period of isolated hypothyroxinemia in pregnant women from a coastal region in Spain that had mild ID. In this study, mothers of all children were given dietary iodine fortification, but the timing varied. The authors hypothesized that a brief delay in instituting iodine fortification would still lead to disturbed offspring neurodevelopment since the time window was beyond when most neocortical proliferation, which requires TH, had occurred. The study design was quite complicated and deserves close scrutiny to comprehend the findings. In particular, the inclusion criteria involved a number of successive selection=exclusion steps. The original cohort consisted of 345 pregnant women who were stratified into three groups on the basis of their serum free T4 levels (normal range: 0.71–1.85 ng=dL) and the time when iodine supplementation (with 200 mg KI orally per day) was introduced. In all groups, iodine supplementation continued until end of breast-feeding. Eighteen months after delivery, a neurodevelopmental evaluation was carried out on a restricted group of highly selected infants. Group 1 encompassed 92 women who were enrolled at 4–6 weeks gestation and received iodine supplementation throughout pregnancy until discontinuing breast-feeding. From this group, 64 women (70%) who did not have hypothyroxinemia were first identified and from them, 43 women with a serum free T4 above the 20th percentile at both 4–6 weeks gestation and term were selected. Next, to establish homogeneity across groups, select children were excluded for presence of specific factors (other than maternal hypothyroxinemia) that might have a negative impact either before or after birth, on subsequent neurodevelopment. The list of exclusion criteria included factors relating to medical history during gestation, at delivery and during lactation; nutritional