Lluís Vila

CONTROVERSIES IN ENDOCRINOLOGY: On the need for universal thyroid screening in pregnant women

There is a well-known controversy among scientific societies regarding the recommendation to screen for thyroid dysfunction (TD) during pregnancy. Although several studies have shown an association between maternal subclinical hypothyroidism and/or hypothyroxinemia with obstetric problems and/or neurocognitive impairment in the offspring, there is only limited evidence on the possible positive effects of thyroxine (T4) treatment in such cases. Despite the scarcity of this evidence, there is a widespread agreement among clinicians on the need for treatment of clinical hypothyroidism during pregnancy and the risks that could arise due to therapeutic abstention. As maternal TD is a quite prevalent condition, easily diagnosed and for which an effective and safe treatment is available, some scientific societies have proposed to assess thyroid function during the first trimester of pregnancy and ideally before week 10 of gestational age. Given the physiologic changes of thyroid function during pregnancy, hormone assessment should be performed using trimester-specific reference values ideally based on locally generated data as geographic variations have been detected. Screening of TD should be based on an initial determination of TSH performed early during the first trimester and only if abnormal should it be followed by either a free or total T4 measurement. Furthermore, adequate iodine supplementation during pregnancy is critical and if feasible it should be initiated before the woman attempts to conceive.

Reference Values for Thyroid Function Tests in Pregnant Women Living in Catalonia, Spain

Early detection of thyroid dysfunction during pregnancy is crucial to avoid fetal disturbances. Maternal hypothyroidism and=or maternal hypothyroxinemia can lead to impairment of fetal cerebral development (1). The pregnant state induces important changes in thyroid physiology (2), including an increase in thyroid binding globulin levels, a transient decrease in free thyroxine, a decrease in thyroid-stimulating hormone (TSH) at first trimester related to b-human chorionic gonadotropin (HCG) rise, and an increase in renal iodine clearance. These modifications of thyroid homeostasis determine specific thyroid hormone circulating patterns according to gestational age; this changing scenario in thyroid gestational physiology challenges the diagnosis of thyroid dysfunction in pregnant women because of the lack of precise reference values (RVs) obtained in specific populations and for each of the trimesters. The RVs of the available commercial kits for thyroid hormones are almost always related to the general population and therefore are not valid for pregnant women. Although there is a necessity to have specific RVs for thyroid hormones during pregnancy and during each trimester, only a few studies have been published covering specific geographical areas (3–14). Because of this relative lack of data, we conducted a study to determine the RVs of thyroid hormones in a population of pregnant women from Catalonia (Spain). Two hundred and seventy-six pregnant women were recruited consecutively in the first trimester of gestation and a further 130 women were selected in their final trimester. Their mean age was 29 4 years; 4.7% were multiparus and the rest were nulliparus or uniparus. Women previously treated with thyroxine or with a known thyroid disorder or had a family history of thyroid disorder were excluded. More than 90% of these women were born in Spain, and the rest in Morocco, Peru, and Ecuador. All were living in the same location for at least 2 years before the study. The study group covered different geographical areas of Catalonia, including the Pyrenees and a costal area where there is an acceptable iodinated status for the general population, as shown by recent epidemiologic studies aimed at investigating this condition (15). Recruitment was made through the gynecological services at primary healthcare centers and hospitals where pregnant women were being monitored. Of the 276 women initially contacted, samples were available from 220 in the first trimester and from 60 of those 220, for the third trimester measurement. Of these 220 women recruited in the first trimester, 43.1% were usual consumers of iodinated salt, while 13.4% had taken pharmacologic supplements of 150 mg potassium iodide (KI) during the first trimester and 53.3% thereafter. The study was approved by the Ethics Committee of Hospital Dos de Maig, Barcelona. Written consent was obtained from all the participants. Samples were taken during a fasting state at week 9 for the first trimester and at week 32 for the third trimester. A quimioluminescent assay (Advia Centaur, Bayer Tarrytown, NY) was used to measure free thyroxine (FT4) (RVs for nonpregnant: 0.8–2 ng=dL; intrassay coefficient of variation (CV): 5.4%), TSH (RVs for nonpregnant: 0.4–4 mU=mL; intrassay CV: 5.1%), and antiperoxidase antibodies (TPO abs) (positive> 60 IU=mL; intrassay CV: 6.6%). Total thyroxine (TT4) was measured with a radioimmunoassay (RIA) method (Diagnostic Systems Laboratories, Webster, TX; interand intrassay CVs: 7.4% and 5.1%) only in the first trimester. Urinary iodine was determined by the method described by Pino et al. (16) with interand intrassay CVs of 15.5% and 12.6%. For the calculation of RVs of FT4, TSH, and TT4, a nonparametric method was applied, in which the ordinal value despite the real value was used. The calculated reference

The implications of iodine and its supplementation during pregnancy in fetal brain development.

Iodine is an essential trace element for life. Its biological effects are a consequence of its incorporation to the thyroid hormones, which play a crucial role in fetal organogenesis, and in particular in brain development. This takes place during early gestation and involves delicate targeting throughout the central nervous system, including adequate neuronal growth, migration and myelinization at different sites, such as the cerebral cortex and neocortex, visual and auditory cortex, hippocampus and cerebellum. Pregnancy is characterized by an increased demand of thyroid hormones by the feto-placental unit in order to fulfill the necessary requirements of thyroid hormone action for normal fetal development. Up until week 20, the fetal thyroid is not fully active and therefore is completely dependent on the maternal thyroxine supply. Thus, the maternal thyroid has to adapt to this situation by producing about 1.5 fold more thyroxine. This requires that enzymatic gland machinery works normally as well as an adequate iodine intake, the principal substrate for thyroid hormone synthesis. Biological consequences of iodine related maternal hypothyroxinemia are currently very well known, by both experimental models and by clinical and epidemiological evidences. The associated disturbances parallel the degree of maternal thyroxine deficiency, ranging from increased neonatal morbi-mortality and severe mental dysfunction, to hyperactivity, attention disorders and a substantial decrease of IQ of an irreversible nature in the progeny of mothers suffering a deprivation of iodine during pregnancy. As a consequence, iodine deficiency is the leading preventable cause of mental impaired function in the world, affecting as many as 2 billion people (35.2% of the entire population). Prevention of fetal iodine deficiency - a problem of pandemic proportions- is feasible, provided that an iodine supply of 200-300 μg/day to the mother is ensured, before and throughout gestation as well as during the lactating period.

Iodine nutritional status in pregnant women of two historically different iodine-deficient areas of Catalonia, Spain

OBJECTIVE Catalonia (Spain) has a historically worse situation of mild iodine deficiency in the Pyrenees Mountains compared with the coastal region. The aim of this study was to evaluate the current iodine status in pregnant women living in these two areas. METHODS An epidemiologic prospective survey included 267 consecutive pregnancies in the Catalan mountains (n = 139) and coast (n = 128) studied during the first trimester; an additional subset of 135 women from the initial cohort was available for evaluation in the third trimester. Urinary iodine (UI) was measured, and questionnaires to determine iodized salt and sea fish consumption and potassium iodide supplementation were administered. RESULTS The median UI in the first trimester was 163 μg/L for the entire cohort, with differences between mountain and coastal regions (209 versus 142 μg/L, P = 0.007). The highest prevalence of iodized salt consumption was in the mountain area (58% versus 36.4%, P < 0.001). For the entire group, a higher median UI was found in iodized salt consumers compared with non-consumers (193 versus 134 μg/L, P < 0.001). In the third trimester, an increase of median UI was seen in those to whom iodine supplements were given during pregnancy (190 versus 154 μg/L, P = 0.015). CONCLUSION A reversal in the historically iodine-deficient situation was observed in the Catalan Pyrenees compared with the coastal area, with a globally acceptable iodine status in pregnant women of the two geographic locations. Iodized salt consumption seems to have contributed to maintaining an acceptable iodine status in this population.

Erradicación de la deficiencia de yodo en España. Cerca, pero no en la meta

B Iodine deficiency (ID) in Spain, well documented since the 1960s,1 has persisted with different grades of intensity for more than four decades. In 2004, the World Health Organization (WHO) included Spain among the countries with optimum iodine nutrition based on studies conducted during the previous five years on schoolchildren and adults from various regions.2 It is very difficult to summarize the most relevant facts leading to this substantial progress in ID correction in Spain, and one runs the risk of inadvertently omitting some of them. In addition to the prolonged and continuous activity of the working group on disorders related to iodine deficiency (IDDs)3 of the Spanish Society of Endocrinology and Nutrition, various clinical and epidemiological research findings reported in the international literature during the past decade have confirmed the significance of ID, thus promoting the search for measures to correct it. Thus, the demonstration of deficient psychoneurological development in children born to mothers with low thyroxine levels during pregnancy secondary to maternal hypothyroidism4,5 or ID during pregnancy6,7 supported the results of basic studies8,9

Detección de la disfunción tiroidea en la población gestante: está justificado el cribado universal

There is a controversy among different scientific societies in relation to the recommendations on whether universal screening for the detection of thyroid dysfunction during gestation should be performed or not. Although various studies have shown an association between subclinical hypothyroidism or hypothyroxinemia with obstetric problems and/or neurocognitive impairment in the offspring, no evidence on the possible positive effects of treatment of such conditions with thyroxin has been demonstrated so far. However, there is a general agreement about the need for treatment of clinical hypothyroidism during pregnancy and the risks of not doing so. Because it is a common, easily diagnosed and effectively treated disorder without special risk, the working Group of Iodine Deficiency Disorders and Thyroid Dysfunction of the Spanish Society of Endocrinology and Nutrition and Spanish Society of Gynaecology and Obstetrics recommends an early evaluation (before week 10) of thyroid function in all pregnant women. Given the complex physiology of thyroid function during pregnancy, hormone assessment should be performed according to reference values for each gestational trimester and generated locally in each reference laboratory. Thyrotropin determination would be sufficient for screening purposes and only if it is altered, free thyroxin or total thyroxin would be required. Adequate iodine nutrition is also highly recommended before and during pregnancy to contribute to a normal thyroid function in the pregnant women and fetus.

Cribado universal de la disfunción tiroidea en la población gestante

El cribado de la disfunción tiroidea en la población gestante es un tema de gran complejidad que ha suscitado amplios debates y posiciones contrapuestas respecto a la oportunidad o no de realizar un cribado universal versus un cribado selectivo. En el documento de consenso que se publicó se defiende la posición del cribado universal por estimar que hay suficientes evidencias que lo justifican. Algunos de nuestros argumentos son discutidos por la carta de G. Giménez-Pérez publicada en este número. Respecto a la prevalencia de hipotiroidismo, las cifras que se indican, bajo la referencia de Stagnaro et al. (0,3-0,5%), se fundamentan en los trabajos de Casey et al. y de Allan et al.. En ambos estudios la prevalencia se estableció a partir de unos valores de referencia (VR) de TSH previamente calculados o establecidos. En el estudio de Casey se definió como hipotiroidismo clínico cuando las mujeres gestantes tenían una TSH por encima del percentil 97,5 y un valor de tiroxina libre inferior al percentil 2; del total de la muestra, el 0,2% cumplía estos criterios. En el trabajo de Allan et al. se consideró hipotiroidismo clínico en todas las mujeres gestantes que tuvieran una TSH superior a 10 mU/ml; en este caso, el 0,4% de las mujeres se situaba por encima de dicho valor. Así pues, en ambos casos la prevalencia que se obtiene se basa en las mujeres que en el momento del control estaban hipotiroideas. En el documento se comenta la posibilidad de que la prevalencia pueda ser mayor, y realmente Blatt et al. (la primera edición, en versión electrónica, se publicó en 2011) observan una prevalencia de hipotiroidismo clínico del 2,4%, utilizando un punto de corte de TSH de 2,5 UI/ml, basado en VR específicos para cada trimestre de la gestación. Hay muy pocos estudios en España sobre la prevalencia de disfunción tiroidea en población gestante; por este motivo, se citan los resultados del estudio realizado en Asturias entre más de 2.000 mujeres. Aunque es cierto que el estudio no está publicado y que la referencia es de un resumen de un congreso, su relevancia radica en que, además de tratarse de una amplia población, la prevalencia de hipotiroidismo se calculó en función de sus propios VR, obteniendo un resultado de 1,96%. G. Giménez-Pérez indica que la cifra más apropiada para referirse a la prevalencia de hipotiroidismo clínico en esta población sería de 0,23%, que es la que observa Lazarus. Siguiendo las recomendaciones que la American Thyroid Association (ATA) establece para realizar el cribado de disfunción tiroidea en la gestación y adoptando esta última cifra de prevalencia, en el año 2010 en España puede haber habido alrededor de 290 mujeres con hipotiroidismo clínico menores de 30 años que no cumplieran otros criterios para realizar el cribado.

Hypothyroidism during pregnancy and its association to perinatal and obstetric morbidity: a review

Abstract There is currently no consensus among the different scientific societies on screening for thyroid dysfunction in the first trimester of pregnancy. Indeed, diagnosis and treatment of subclinical hypothyroidism during pregnancy are controversial, as no cut-off value for thyrotropin (TSH) is universally accepted. TSH measurement may be influenced by different factors throughout pregnancy, but especially during the first trimester. The association between overt hypothyroidism during pregnancy and obstetric and perinatal complications is well established. It is also accepted that thyroid hormones are important for neurodevelopment of the offspring. However, there is no scientific evidence available about the impact of subclinical hypothyroidism and its treatment during the first trimester of pregnancy on childrens neurodevelopment. In recent years, studies conducted in the offspring of mothers with subclinical hypothyroidism have reported new biochemical parameters which may eventually serve as biomarkers of offspring neurodevelopment and which are more reproducible and are measured at an earlier time than the conventional clinical tests.