Thyroid function in very preterm infants

Indices of thyroid function were measured in 108 infants born at 23-31 weeks gestation, after birth, at 24 and 72 h, and at 1, 3, 4, 5 and 6 weeks of age. This group was characterised by low serum thyroxine (T4), normal thyroid stimulating hormone (TSH), low-normal thyroid binding globulin (TBG), low free thyroxine index (FTI) and low triiodothyronine (T3). The incidence of hypothyroxinaemia defined as a serum T4 value of less than 65 nmol/l was 58% after birth, increasing to 84% at 1 week, after which there was progressive reduction to 36% by 6 weeks of age. Mean T4 values were inversely proportional to gestational age during this study period. Infants of 23-28 weeks gestation had significantly lower T4, TBG, FTI and T3 values compared to those of 29-31 weeks gestation. Infants who had hyaline membrane disease (HMD) had significantly lower T4 and FTI values compared to those without HMD for up to 3 weeks of age. Similar differences were found between deaths and survivors in the first week after birth. This study suggests that there is increasing delay in maturation of the hypothalamic-pituitary-thyroid axis control with increasing prematurity. In addition, the data suggest that infants who were extremely preterm or those with HMD had worse and more persistent abnormalities of thyroid function secondary to their illness and metabolic stress. The significance of our findings, in particular that of prolonged hypothyroxinaemia, is uncertain. The role of thyroid replacement therapy in these very preterm infants therefore need to be assessed with a randomised clinical trial.     

The thyroid gland of the newborn infant and postnatal iodine overload]

Severe iodine-induced hypothyroidism was recently diagnosed in several neonates raising the responsibility of the iodine antiseptic agents routinely used in these patients. Postnatal iodine overload due to cutaneous application of these agents (povidone iodine and fluorescinated alcoholic-iodine solution) was studied in 5 patients. Thyroid function studies were performed in iodine-overload neonates and in control neonates with comparable gestional age. Results indicated strong evidence of cutaneous absorption of iodine from the antiseptic agents used, leading to hypothyroidism in 12 of them. The frequency and the severity of thyroid dysfunction was closely related to the degree of prematurity. Full recovery was observed in all cases after withdrawal of the iodine-containing agents. It is therefore recommended to avoid any postnatal use of iodine preparations in neonates, mainly in preterm infants, and to use iodine antiseptic agents with great caution, when necessary during the neonatal period.     

Neonatal thyroid function: prematurity,prenatal steroids,and respiratory distress syndrome.

Indices of thyroid function were measured in 97 preterm infants at birth and at 5, 10, and 15 days of age. Triiodothyronine uptake, free thyroxine index, thyroxine, free thyroxine, triiodothyronine, reverse triiodothyronine, and thyroxine binding globulin values at birth correlated with gestational age, whereas thyroid stimulating hormone values did not. Treatment with steroids prenatally had no apparent effect on thyroid function at birth or postnatally. Infants developing respiratory distress syndrome had normal values for all indices at birth. These infants had significantly lower thyroxine, free thyroxine index, free thyroxine, and triiodothyronine values at 5 days of age, while thyroid stimulating hormone values remained normal. This alteration in thyroid function was interpreted as being secondary to respiratory distress syndrome. Gestational maturity and respiratory distress syndrome, if present, must be taken into account when evaluating thyroxine variables in preterm infants, whereas measurement of thyroid stimulating hormone as the screen for congenital hypothyroidism circumvents these considerations.     

Development of contrast sensitivity in infants with prenatal and neonatal thyroid hormone insufficiencies

Thyroid hormone is essential for normal brain development including structures critical for visual processing. While chick and rodent models have demonstrated abnormal visual development following prenatal thyroid hormone loss, comparable data do not exist in the human. To determine whether human infants with intrauterine and early postnatal thyroid hormone insufficiencies have compromised visual abilities, we investigated contrast sensitivity and visual acuity development in 13 infant offspring of women with hypothyroidism during pregnancy (HYPO), 16 preterm infants born between 32 and 35 weeks gestation, 12 infants with congenital hypothyroidism (CH), and 20 typically developing infants. All were assessed with the sweep visual evoked potential technique at 3, 4.5, and 6 months (corrected) age. Results showed significantly reduced contrast sensitivity but normal visual acuity in HYPO and CH groups relative to controls (p < 0.003 and p < 0.05 respectively). Stratification of the HYPO group into subgroups based on maternal TSH levels during the first half of pregnancy revealed lower contrast sensitivities for infants whose mothers' TSH values were above than below the median (p < 0.05). In the CH group, those with an absent thyroid gland and/or a newborn TSH value above 200 mIU/L had lower contrast sensitivities than did those with other etiologies or TSH levels below 100 mIU/L (p < 0.05). There were no significant effects involving the preterm group. These results indicate that thyroid hormone is important for human visual development.     

Thyroid function in premature infants of different gestational age during the first month of life (author's transl)

To assess the function of the thyroid gland in premature infants of different gestational ages during the first month of life we determined simultaneously TSH, T4, T3, and rT3 serum concentrations in 116 preterm infants (gestational ages 31st to 38th week) during each of the first 30 days of life. The serum concentrations of TSH, T3, and rT3 changed significantly during this period. The TSH and rT3 values were highly increased on the first day and decreased thereafter. The T3 values, however, increased significantly during this period. During the first month of life the T4 values remained roughly unchanged independent of the age of the children. There was no significant influence on serum concentrations of thyroid hormones by gestational age. The 65 preterm infants with adaptational disorders showed no difference in their patterns of TSH and thyroid gland activity during the first month of life compared with 51 healthy premature infants. From the 4th to the 6h day of life -- a recommended period for the screening of congenital hypothyroidism -- the differences of TSH values measured were insignificant (16-18 muU/ml). The T4 values on these days remained all above 6.8 microgram/dl.     

Thyroid hormone synthesis and storage in the thyroid gland of human neonates

The aim of this study was to evaluate the morphological and biochemical maturation of the thyroid gland in human neonates. The mean iodine concentration in the thyroid gland of very premature infants (less than 32 weeks gestational age, 0-3 days survival, n = 12) was significantly lower than in the older group (34-41 weeks gestational age, 0-30 days survival; n = 15; p < 0.05). For the whole group of neonates there was a statistically significant linear correlation between duration of life, i.e. gestational age and survival, and iodine concentration (r = 0.64, p < 0.01). Although there was wide dispersion of the results the same tendency was seen for thyroglobulin (Tg) concentration in the thyroid gland (r = 0.52, n = 21; p < 0.05). Comparative histological examination of the fetal thyroids gave results in accordance with the biochemical data as intrafollicular colloid appeared to be more abundant in more mature thyroids. The iodine content in Tg was found to be 0.63 +/- 0.22% in very preterm neonates and was slightly but not significantly lower than that found in the thyroids of the older group (0.82 +/- 0.14%; p = 0.055). The content of T4 and T3 per Tg molecule in the neonates was related to the iodine content. The differences in mean values of T4/Tg and T3/Tg molar ratios between the two groups were not significant: T4: 2.8 +/- 1.8 mol/ mol, T3: 0.29 +/- 0.12 mol/mol in very preterm neonates; and T4: 3.5 +/- 0.7 mol/mol, T3: 0.34 +/- 0.09 mol/mol in the older group. These results offer useful information for further analysis of the development of thyroid function in the human neonate.     

Iodine burden in premature infants in roentgenologically controlled positioning of central venous silastic catheters

22 sick preterm infants were enrolled in a prospective study of iodine excretion after intravenous injection of a definite amount of the radiopaque dye Conray. Measurements of TSH and T4 were performed on day 5 and 4 weeks after injection or before dismissal. For comparison iodine excretion was studied in a group of 10 pre-terms without central venous catheters. In most of the babies urinary excretion of iodine was highest on day one with an exponential decline to day three. Transient hypothyroxinemia (T4 less than 60 nmol/l) could be diagnosed in 18 infants, but no one had hypothyroidism in sick prematures after injection of iodine containing contrast agents seems to be lower than expected. Nevertheless this method of radiographic control should be avoided if possible.     

早产儿暂时性甲状腺功能低下替代治疗临床研究进展

早产儿暂时性甲状腺功能低下(THOP)发生率高,是否给予甲状腺素替代治疗存在分歧.有关THOP的临床研究提示,THOP甲状腺素替代治疗不能降低病死率、呼吸疾病发生率,可降低动脉导管未闭的发生率.胎龄小于28周THOP早产儿给予甲状腺素替代治疗可能改善神经发育预后,胎龄大于28周不能改善神经发育.未来研究应按胎龄确定早产儿甲状腺素正常值;设计良好的根据胎龄分层的临床随机研究,以明确甲状腺素替代治疗对远期神经发育的影响.     

早产儿暂时性甲状腺功能低下替代治疗临床研究进展

早产儿暂时性甲状腺功能低下(THOP)发生率高,是否给予甲状腺素替代治疗存在分歧.有关THOP的临床研究提示,THOP甲状腺素替代治疗不能降低病死率、呼吸疾病发生率,可降低动脉导管未闭的发生率.胎龄小于28周THOP早产儿给予甲状腺素替代治疗可能改善神经发育预后,胎龄大于28周不能改善神经发育.未来研究应按胎龄确定早产儿甲状腺素正常值;设计良好的根据胎龄分层的临床随机研究,以明确甲状腺素替代治疗对远期神经发育的影响.     

早产儿暂时性低甲状腺素血症与脑损伤及神经行为学相关性研究

目的 通过对早产儿甲状腺素水平测定及脑、神经行为发育测评,分析甲状腺素水平与脑损伤、神经行为学的相关性.方法 选取2009年11月至2010年4月,上海交通大学附属上海市儿童医院新生儿科收治的早产儿52例,生后6 h内留取血清样本,放射免疫法测定T3、T4、TSH值.所有患儿出生后3 d行头颅B超检查,每周复查1次,出院前行头颅MRI检查.根据头颅MRI结果将患儿分为3组:无脑损伤组(33例)、脑室内出血组(10例)、脑白质损伤组(9例).所有患儿于纠正胎龄40±2周时行新生儿20项行为神经测定.结果 3组患儿TSH均正常,排除先天性甲状腺功能减低症;共8例早产儿甲状腺功能正常,占15.4%(8/52);另44例早产儿甲状腺功能均低下,占84.6%(44/52).无脑损伤组T3、T4水平高于脑室内出血组及脑白质损伤组,并以脑白质损伤组T3、T4水平最为低下,3组间比较差异有统计学意义(P＜0.05).无脑损伤组患儿行为能力、被动肌张力、主动肌张力及总分4项得分显著高于有脑损伤的两组患儿,且脑室内出血组患儿得分又高于脑白质损伤组患儿,3组间比较差异有统计学意义(P＜0.05).结论 早产儿脑损伤越严重,甲状腺素水平越低.有脑损伤的早产儿神经行为学评分较无脑损伤的早产儿低.     

Thyroid function in healthy and sick very-low-birth-weight infants--thyrotropin and free thyroxine levels until the sixth week of age

Hypothyroxinemia in preterm infants without congenital hypothyroidism is associated with developmental delay. Longitudinal information on thyroid function in very-low-birth-weight (VLBW, <1,500 g birth weight) infants is limited: we present data on thyroid function in sick and healthy VLBW infants until 6 weeks of age. Free T(4) and TSH levels routinely obtained on days 14-21 and days 35-49 in 92 consecutive VLBW infants were correlated retrospectively with neonatal morbidity. Free T(4) levels were positively correlated with gestational age; an independent effect of neonatal disease on thyroid function was not detectable.     

Low thyroxinaemia occurs in the majority of very preterm newborns

Transient hypothyroxinaemia with normal thyroid stimulating hormone (TSH) levels is a well-known condition in preterm neonates and is generally assumed to be a harmless epiphenomenon of prematurity. This assumption is, however, based on studies that included very few neonates with a gestational age (GA) below 30 weeks. We therefore measured serum free thyroxine (FT₄) and serum TSH on days 1 and 14 in 263 neonates with a GA between 26 and 41 weeks. In 13 infants (5%), transient hypothyroidism (low FT₄ and TSH>20 mU/l on day 14) was found. In the remaining 250 patients FT₄ on days 1 and 14 but not TSH correlated positively with GA. In neonates with a GA of 35–41 weeks, FT₄ increased postnatally to levels within or above the normal adult range. In contrast, in the very preterm group (26–31 weeks) the already low FT₄ levels declined to values significantly below the range observed in term neonates. A significant proportion of these neonates had FT₄ levels within the hypothyroid range. There was no difference in thyroid function between neonates treated with povidone-iodine or chlorhexidine.Conclusion Very preterm neonates have FT₄ levels on day 14 that are much lower than is generally assumed while TSH remains in the normal range. We therefore propose to measure FT₄ in all preterms with a GA below 33 weeks, during the 2nd week of life.     

Hypothyroidism secondary to topical iodine treatment in infants with spina bifida

Four infants with spina bifida, who had not undergone surgical closure of a lumbar myelomeningocele, were assessed and investigated for hypothyroidism. From birth, all were treated once daily with an iodine-containing ointment (Betadine) as a local antiseptic applied to the spina defect. All infants showed excess urinary iodine concentration. Two infants, without clinical evidence of hypothyroidism or goitre, showed low serum free thyroxine and high thyroid stimulating hormone concentrations at a mean age of four weeks and were started on thyroxine replacement treatment. Betadine ointment and thyroxine were stopped simultaneously at a mean age of nine months, following which all infants remained euthyroid. Thyroid function tests should be monitored routinely if iodine is applied as a topical antiseptic to infants.     

Diagnosis of thyroid function in premature infants in intensive care

In 87 premature infants of an neonatal intensive care unit (gestational age 28-37 weeks) serum-T4, -fT4 and TSH were investigated on day 10, 20 and 30 and at term respectively, in addition to the usual TSH-screening (capillary specimen) on day 5. In 47 neonates (54%) T4 and fT4 were found to be low, including all infants under 30 weeks of gestational age and all ventilated infants. Screening TSH was not elevated but in some cases with iodine contamination. 12 of 13 infants in whom TRH-stimulation was performed showed significant response of TSH. We conclude that compromised thyroid function, common in prematures and infants under intensive care, is similar to the euthyroid sick syndrome in adults and does not require therapy. Replacement of thyroid hormone is only indicated in neonates with increased TSH.     

Thyroid function tests in preterm infants born to preeclamptic mothers with placental insufficiency

OBJECTIVE: Since preeclampsia causes placental insufficiency, it can be hypothesized that it decreases placental passage of thyroxine (T4) from mother to infant and thus may deepen the transient hypothyroxinemia seen in preterm infants after birth. The aim of this study was to compare thyroid function tests of preterm infants born to preeclamptic mothers with placental insufficiency with preterm infants born to mothers without placental insufficiency. METHODS: Thirty-one preterm infants born to preeclamptic mothers with placental insufficiency were included in the study (group I) and 31 preterm infants born to mothers without placental insufficiency were included as the control group (group II). Thyroid hormone levels were assayed from blood samples obtained from the women before birth and thereafter from the infants at delivery (cord) and on the 1st, 3rd, 7th, and 21st days of life. RESULTS: Cord blood triiodothyronine (T3), free T3 (FT3) and free thyroxine (FT4) levels in group I were lower than in group II, whereas thyrotropin (TSH) and thyroxine binding globulin (TBG) levels were higher. No statistical difference in hormone levels studied at postnatal 1st, 3rd, 7th, and 21st day was found between the two groups. CONCLUSION: Low levels of thyroid hormones and high level of TSH in cord blood in premature infants born to preeclamptic mothers with placental insufficiency suggest intrauterine hypothyroidism. Increase in TSH and thyroid hormone concentrations after birth reveal that the hypothalamic-pituitary-thyroid axis is intact.     

Hemorrhagic shock and encephalopathy syndrome – the markers for an early HSES diagnosis

Background

Infants born at extreme prematurity are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone described as hypothyroxinaemia, which is recognised to be a frequent phenomenon in these infants. Derangements of critical thyroid function during the sensitive window in prematurity when early development occurs, may have a range of long term effects for brain development. Further research in preterm infants using neuroimaging techniques will increase our understanding of the specificity of the effects of hypothyroxinaemia on the developing foetal brain. This is an explanatory double blinded randomised controlled trial which is aimed to assess the effect of thyroid hormone supplementation on brain size, key brain structures, extent of myelination, white matter integrity and vessel morphology, somatic growth and the hypothalamic-pituitary-adrenal axis.

Methods

The study is a multi-centred double blinded randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks corrected gestational age. The primary outcomes will be width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks corrected gestational age. The secondary outcomes will be thyroid hormone concentrations, the hypothalamic pituitary axis status and auxological data between birth and expected date of delivery; thyroid gland volume, brain size, volumes of key brain structures, extent of myelination and brain vessel morphology at expected date of delivery and markers of morbidity which include duration of mechanical ventilation and/or oxygen requirement and chronic lung disease. Trial registration Current Controlled Trials ISRCTN89493983     

Update of newborn screening and therapy for congenital hypothyroidism

Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis. Efforts are ongoing to establish the optimal therapy that leads to maximum potential for normal development for infants with congenital hypothyroidism. Remaining controversy centers on infants whose abnormality in neonatal thyroid function is transient or mild and on optimal care of very low birth weight or preterm infants. Of note, thyroid-stimulating hormone is not elevated in central hypothyroidism. An algorithm is proposed for diagnosis and management. Physicians must not relinquish their clinical judgment and experience in the face of normal newborn thyroid test results. Hypothyroidism can be acquired after the newborn screening. When clinical symptoms and signs suggest hypothyroidism, regardless of newborn screening results, serum free thyroxine and thyroid-stimulating hormone determinations should be performed.     

Randomised trial of iodine intake and thyroid status in preterm infants

BACKGROUND: Low levels of circulating thyroid hormones have been associated with poorer general and neurodevelopmental outcome in preterm babies and it has been speculated that the association is causal. Low levels of circulating thyroid hormone have been reported after inadequate intake of iodine in preterm infants being fed milk formula. AIM: To investigate whether increased iodine intake from supplemented preterm formula would improve thyroid hormone levels in preterm babies (this study) and hence improve neurodevelopmental status (planned subsequent study). METHOD: A total of 121 preterm infants were entered into a randomised controlled trial of standard (68 microg/l) versus increased (272 microg/l) iodine in preterm formula. RESULTS: The two groups were comparable at recruitment. No evidence of an effect of the intervention on thyroid hormone levels was seen up to 41 weeks after conception. CONCLUSION: Calls for increased iodine content of preterm infant formulas are not justified by this study.     

How should we be treating children with congenital hypothyroidism?

Early detection by newborn screening and appropriate L-thyroxine treatment leads to normal or near-normal neurocognitive outcome in infants with congenital hypothyroidism. Many newborns with congenital hypothyroidism have some residual thyroid hormone production, and even in those with athyreosis, transplacental passage of maternal thyroid hormone offers some protection for a time. Given the serum T4 half-life of 6 days, the neonatal T4 level will fall and disappear over the first 2-3 weeks of life. Thus, there is a crucial 'window of opportunity' to correct the hypothyroidism and minimize the time the brain is exposed to hypothyroxinemia. While there are few truly prospective, randomized clinical trials investigating treatment parameters, studies measuring IQ outcome support a starting L-thyroxine dose of 10-15 microg/kg/day. Further, studies show that the most severely hypothyroid infants are at risk for a 5-20 point decrease in IQ. Such infants may benefit from a starting dose of 12-17 microg/kg/d, which has been shown to normalize T4 in 3 days and TSH in 2 weeks. Target serum T4 or free T4 levels appear to be higher in the first two weeks of treatment. Infants require more frequent laboratory monitoring, every 1-2 months in the first 6 months and every 3-4 months until age 3 years, as the developing brain has a critical dependence on thyroid hormone in the first 2-3 years of life.     

Hypothyroxinaemia and thyroid function after preterm birth

The concentration of thyroid hormone in preterm infants is lower than that in term infants. This phenomenon is referred to as transient hypothyroxinaemia of prematurity. Low thyroid hormone levels after very preterm birth are associated with worse developmental outcome in childhood, but only one randomized controlled trial has been carried out in the surfactant era to find out whether thyroid hormone supplementation is beneficial for developmental outcome. More studies are required to find out whether thyroid hormone supplementation is beneficial, and if so, for which preterm group.