Susana Ares

The Changing Role of Maternal Thyroid Hormone in Fetal Brain Development

This review briefly summarizes: (1) the changes in maternal thyroid function that are imposed by the presence of the fetus and the high concentrations of human chorionic gonadotropin essential for the maintenance of the pregnancy, which result in high first trimester free thyroxine and triiodothyronine, requiring doubling of the iodine intake; (2) the changes in the fetal compartment up to midgestation, which result in increasing concentrations of triiodothyronine in the cerebral cortex generated locally from thyroxine by high activities of type 2 iodothyronine deiodinase; (3) the important role of the maternal contribution of thyroxine to the fetal circulation after onset of secretion of hormones by the fetal thyroid; and (4) the consequences of the interruption of the maternal supply of thyroid hormones that occur with prematurity. Efforts to devise appropriate strategies to avoid or shorten the postnatal hypothyroxinemia of infants born prematurely may well result in fewer and less severe neurodevelopmental deficits.

Psychomotor Development of Children from an Iodine-Deficient Region

OBJECTIVES To assess the psychomotor development of the progeny of women from a moderately iodine-deficient area for whom thyroid function during pregnancy was measured. STUDY DESIGN The development of 86 children was assessed by the Bayley Scale of Infant Development at 12, 18, and 24 months. RESULTS Maternal serum free thyroxine (FT(4)) levels in the first trimester of pregnancy were the major determinant of psychomotor development at 18 and 24 months. Children born from mothers with FT(4) levels <25th percentile (<10 pg/mL) had an OR of 2.1 for mild-to-severe delay. Furthermore, alterations in behavior were already observed at 12 months and were related to subsequent changes in development. Neonatal thyroid status did not influence development. CONCLUSIONS This study highlights the need to implement active measures of iodine supplementation periconceptionally and during pregnancy and lactation because the negative effects on development and behavior might be prevented through preemptive action.

Iodine Status of Pregnant Women and Their Progeny in the Minho Region of Portugal

BACKGROUND Iodine sufficiency is particularly necessary throughout pregnancy, given its recognized impact on psychomotor performance of the offspring. There are no recent reports about iodine status or supplementation in Portugal, a country that the International Council for Control of Iodine Deficiency Disorders considered, in 2004, to have probably reached iodine sufficiency. The objective of this study was to evaluate in the Minho region of Portugal the iodine status of women throughout pregnancy and after delivery, and of their offspring. METHODS Urinary iodine concentration (UI) was determined in 78 nonpregnant premenopausal women, in 140 pregnant women in the three trimesters of pregnancy and after delivery, and in their 142 offspring. Milk iodine concentration was determined at day 3 and 3 months after delivery. The thyroid volume was determined in women in the third trimester of pregnancy and 3 months after delivery and in infants at 3 months of age. RESULTS Based on the World Health Organization criteria, both nonpregnant and pregnant women had iodine deficiency (ID), as documented by median UI of <75 microg/L and milk iodine concentration of <100 microg/L. Goiter was observed in 14% of the pregnant women. Concordant with the mothers ID, median neonatal UI was low (71 and 97 microg/L at 3 days and 3 months of age). CONCLUSION Portuguese women of the Minho region have an inadequate iodine intake, which may compromise the potential for full psychomotor development of their progeny. These observations suggest that iodine supplementation should be implemented throughout pregnancy and lactation in Portugal.

Parameters of thyroid function throughout and after pregnancy in an iodine-deficient population

BACKGROUND The thyroid hormone milieu is of crucial importance for the developing fetus. Pregnancy induces physiological changes in thyroid homeostasis that are influenced by the iodine status. However, longitudinal studies addressing thyroid function during pregnancy and after delivery are still lacking in mild-to-moderate iodine-deficient populations. Here we characterize the serum parameters of thyroid function throughout pregnancy, and until 1 year after delivery, in a population of pregnant women whom we have previously reported to be iodine deficient (median urinary iodine levels below 75 microg/L). METHODS One hundred eighteen pregnant women were studied. Clinical data were recorded and serum was collected. Serum total and free thyroxine (T(4)) and triiodothyronine (T(3)), thyroid-stimulating hormone, thyroxine-binding globulin, and thyroglobulin were measured. RESULTS Mean total T(4) ranged from 159 at the start of gestation to 127 nmol/L at 1 year after delivery, free T(4) from 14.2 to 17.8 pmol/L, total T(3) from 2.4 to 2.1 nmol/L, free T(3) from 6.7 pmol/L to 6.4 pmol/L, thyroid-stimulating hormone from 1.2 to 1.4 mIU/L, T(4)-binding globulin from 62.0 to 26.9 mg/L, and thyroglobulin from 11 to 10 microg/L. CONCLUSION The pregnant women in this study had an absence of the usual free T(4) spike and a smaller than expected increment in total T(4), described during pregnancy in iodine-sufficient populations. A greater number of women had subclinical hypothyroidism compared with iodine-sufficient populations. This hormonal profile, most likely due to iodine insufficiency, may result in inadequate thyroid hormone supply to the developing fetus. We conclude that care should be taken when reviewing the results of thyroid hormone tests in iodine-insufficient populations and when no gestation-specific reference values have been established. In addition, we recommend iodine supplementation in our population and populations with similar iodine status, particularly during pregnancy and lactation.

Neonatal Thyroxine Supplementation for Transient Hypothyroxinemia of Prematurity Beneficial or Detrimental

Extremely low birth-weight newborns (<1000g) experience low levels of thyroid hormone that vary inversely with the severity of neonatal illness and the extent of developmental immaturity with levels reaching a nadir at ≈7 days after birth; this phenomenon can persist for several weeks. In the absence of transplacental passage, 30–50% of these neonates cannot generate sufficient quantities of thyroid hormone to meet postnatal demands, placing them at an increased risk for developmental delay and cerebral palsy. Population surveys and interventional trials suggest that a therapeutic opening exists during a ‘window of opportunity’ corresponding to this period of diminished capacity. Variables to consider before intervention focus on the consideration that supplementation of both the substrate thyroxine and the active hormone triiodothyronine may be necessary in quantities that do not suppress thyroid-stimulating hormone release, yet overcome the persistence of increased conversion to 3,3′5′-triodo-L-thyronine, terminal deiodination, and activity of the sulfation inactivation pathways, as well as the diminished capacity of the newborn to accommodate postnatal physiologic changes. Single daily replacement doses may suppress levels of converting enzymes in the brain, suggesting that physiologic ‘mimicry’ provided by a constant infusion may be the preferred dosing option. Properly powered clinical trials targeting long-term developmental outcomes are needed to discern whether these interventions will do more than simply elevate blood levels of thyroid hormones to the target values of either the fetus or developing neonate. Identifying the appropriate indications for supplementation may alleviate individual pain and distress due to disability for several hundred extremely low birth-weight neonates each year in the US alone, and save society a pro-rated lifetime cost of nearly

Suplementación con yodo durante el embarazo y la lactancia. Toma de posición del Grupo de Trabajo de Trastornos relacionados con la Deficiencia de Yodo y Disfunción Tiroidea de la Sociedad Española de Endocrinología y Nutrición

US1 million per child.

Thyroid Hormone Supplementation in Preterm Infants Born Before 28 Weeks Gestational Age and Neurodevelopmental Outcome at Age 36 Months

Severe and mild iodine deficiency during pregnancy and lactation affects thyroid function of the mother and neonate as well as the infants neuropsychological development. Studies performed in Spain confirm that most women are iodine deficient during pregnancy and lactation. Pregnant and breast feeding women and women planning to become pregnant should take iodine supplements.

Clinical dilemmas arising from the increased intake of iodine in the Spanish population and the recommendation for systematic prescription of potassium iodide in pregnant and lactating women (Consensus of the TDY Working Group of SEEN).

BACKGROUND Thyroid hormones are required for normal brain maturation, and neonatal plasma thyroid hormone concentrations are low in infants less than 28 weeks gestation. It is not known whether treatment of such infants with thyroid hormone improves neurodevelopmental outcome. METHODS At three years corrected age, mental, motor, and neurological development was assessed in infants born at less than 28 weeks gestational age who had participated in a phase 1 trial of differing doses and modes of administration of thyroid hormone. The trials endpoints were thyroid hormone (thyroxine, T4) and thyotropin plasma concentrations in eight study arms: six treated with T4 [4, 8, and 16 μg/(kg · day)], bolus or continuous], one treated with iodine only, and one treated with placebo. Follow-up at three years was not part of the original study goals. Developmental index scores, rates of cerebral palsy (CP), and rates of adverse outcome (death or moderate to severe delay in development and/or disabling CP) were compared between the eight study groups and between groups combined by dosage level, and between infants with and without T4 supplementation. RESULTS Of 166 randomized infants, 32 (19%) died in the neonatal period. Of the 134 survivors, follow-up results were available for 89 children (66%). Mental and motor development and rates of cerebral palsy did not differ in any of the comparisons made. CONCLUSION In this study, no differences in neurodevelopment were found in relation to thyroid hormone treatment, but power was insufficient to detect any but very large differences.

Neurodevelopment of preterm infants born at 28 to 36 weeks of gestational age: the role of hypothyroxinemia and long-term outcome at 4 years

Iodine deficiency is one of themost easily preventable public health problems, but despite that, it still affects a very great number of people worldwide (1). Over half of the European population lives in countries where the iodine intake is insufficient (2, 3). Iodine deficiency in Spain has been recognized since 1899 (4), and has been found in 15 of the 17 autonomous regions of Spain where it has been studied, no information being available in the other 2. In 1980 the Spanish Society of Endocrinology and Nutrition (SEEN) formed a Working Group on Iodine Deficiency Disorders (the TDY Group of the SEEN). This group has actively studied the problem in Spain, bringing it repeatedly to the attention of Public Health authorities and promoting several monographs collecting data from the various studies carried out in Spain on iodine deficiency disorders up to 1993 (5, 6). More recently, 8 scientific societies have joined in a manifesto presented at a meeting held in Malaga, Spain, stressing the need for a more active Public Health policy to eradicate iodine deficiency disorders in Spain (See Appendix). Spain still lacks a national plan for the eradication of iodine deficiency, although certain autonomous regions have undertaken campaigns and put in practice policies to increase the urinary iodine concentration in school-age children and reduce the prevalence of goiter (7). Currently, the national Ministry of Health and the regional ministries are setting up programs to increase the consumption of iodised salt and, as in the case of Andalusia, recommend the prescription during pregnancy and lactation of a preparation containing at least 150 μg of iodine per day (8). Although many multivitamin-mineral preparations that contain different amounts of iodine are sold in Spain, a preparation of potassium iodide (Recordati formulation) has recently been promoted and subsidized by public funding with individual doses of 100 and 200 μg of iodine/tablet (130.8 μg KI and 261.6 μg KI, respectively) that helps implementation of the recommendations of the TDY Group of the SEEN for pregnant and lactating women. This has resulted in the frequent expression of concerns by gynecologists and general practitioners, as well as some specialists in endocrinology and nutrition, about the risks and benefits of the use of iodised salt in the general population and, especially, about the indications and contraindications of potassium iodide supplements during pregnancy and lactation. The aim of this report is to draw up a guideline for good clinical practice by answering dilemmas expressed by the medical community concerning the increasing use of iodine-containing products in the general Spanish population, especially among pregnant women.

Hypothyroidism and Thyroid Function Alterations During the Neonatal Period

Abstract Context: Hypothyroxinemia in premature neonates may affect long-term neurodevelopment. Objective: This study aimed to examine the effects of hypothyroxinemia of the newborn preterm infants born at 28–36 weeks of gestational age (GA) on the neurodevelopment at 4 years of age. Patients: Prospective observational cohort study conducted in Madrid, Spain. Forty-six preterm infants were included in the study. Main Outcome: The effects of the exposure to neonatal hypothyroxinemia on mental development were examined. Results: Using regression analyses we found that neonatal T4 had a positive association with general cognitive index and Verbal index, and neonatal FT4 with general cognitive and Memory indexes at 4 years of age. Conclusions: The exposure to hypothyroxinemia during the neonatal period of late preterm infants may play role in neurodevelopmental delays. Higher T4 level means a trend to higher indexes and low T4 level means a lower neurodevelopmental indexes at 4 years of age.