Oral Iodine Supplementation in Very Low Birth Weigh Infants. Thyroid Function and Neurodevelopmental Follow Up at 24 Months. A Randomized Clinical Trial

Research Article

Annals Thyroid Res. 2021; 7(1): 306-311.

Oral Iodine Supplementation in Very Low Birth Weigh Infants. Thyroid Function and Neurodevelopmental Follow Up at 24 Months. A Randomized Clinical Trial

Ares S1*, Arnaez J1, Saenz-Rico B2, Diez J3, Omeñaca F1 and Bernal J4,5

1Neonatology Unit, University Hospital LA PAZ, Spain

2Facultad de Educacion, Universidad Complutense, Spain

3Department of Biostatistics, University Hospital LA PAZ, Spain

4Instituto de Investigaciones Biomédicas, Universidad Autónoma de Madrid, Spain

5Center for Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Spain

*Corresponding author: Susana Ares, Neonatology Unit, University Hospital LA PAZ. Paseo de la Castellana 261. 28046 Madrid, Spain

Received: January 19, 2021; Accepted: February 05, 2021; Published: February 12, 2021


Background: The trace element Iodine (I) is essential for the synthesis of thyroid hormones. Premature babies need >30μg I/kg/day (ICCIDD recommendations). Neonates and especially preterm infants are a population at risk of suffering the consequences of iodine deficiency, because of the impact of neonatal hypothyroxinemia on brain development.

Aims: The main aim of this project is to prevent the mental retardation and increased risk of cerebral palsy of premature infants, which is partially caused by neonatal hypothyroxinemia. We gave Oral iodine supplementation in very premature babies during the neonatal period.

Methods: Population: we included 94 infants born <1500g. Intervention group: we administered 30μg I/kg /day of iodine in oral drops to 47 infants from first day of life until hospital discharge. Control group: 47 infants without supplements. The study was approved by the Ethics Committee. Samples of different formulas, maternal milk was kept for the determination of the iodine content.

Interventions: Blood, food and urine samples (collected at 1, 7, 15, 21, 30 days after birth and at discharge). Measurements: milk and urine for iodine determination (Benotti method). Blood samples: for thyroid hormones (T4, free T4, T3 and TSH) and tyroglobulin. Their neurological development was assessed at 2 years of age (Bayley Test).

Results: Iodine content of mothers´ breast milk: 15 (5.0) μg I/dL (range 1-60); Infants in the supplemented group reached the recommendations from the first days of life. Infants in the control group did not reach the recommended intake of iodine to 60 days of life. We found a positive relation between iodine intake and the concentrations of thyroid hormones until 60 days of life.

Conclusion: Thyroid function is related to iodine intake in preterm infants. Breast milk appears to be the best source of iodine for the premature infant. Preterm babies on formula preparations and with exclusive parenteral nutrition are at high risk of iodine deficiency. Therefore, supplements should be added if iodine intake is found to be inadequate. Acknowledgments. We are grateful to the Fondo de Investigaciones Sanitarias (National Grant 06/1310 for financial support).

Keywords: Hypothyroxinemia; Preterm infants; Thyroid; Neurodevelopment; Iodine deficiency


ICCIDD: International Council for Control of Iodine Deficiency Disorders; TSH: Thyrotropin;

T4: Thyroxine; T3: 3,5,3'-Triiodothyronine: Tg: Thyroglobulin; TBG: Thyroid Binding Globulin; GA: Gestational Age in weeks; BW: Body Weight; ELBW: Extremely Low Birth Weight Babies; SD: Standard Deviation: SE: Standard Error


Iodine is a trace element which is essential for the synthesis of thyroid hormones. Premature babies need >30μg I/kg /day (International Council for the Control of Iodine Deficiency Disorders recommendations ICCIDD) [1].

The thyroid hormones, thyroxine (T4) and 3,5,3´-triiodothyronine (T3), are necessary for adequate growth and development throughout fetal and extra-uterine life during the first years of life.

Their effects of on the central nervous system are mediated by the regulation of the expression of genes that synthesize proteins implicated in: cerebral neurogenesis, neuronal migration and differentiation, axonal out-growth, dendritic ontogeny and synaptogenesis, cerebellar neurogenesis, gliogenesis and myelinogenesis. Iodine deficiency may contribute to hypothyroxinemia and is recognised as cause of preventable mental retardation [2-4].

Neonates and preterm infants are a population at risk of suffering the consequences of iodine deficiency, because of the effects of the resulting neonatal hypothyroxinemia on brain development.

Transient Hypothyroxinemia Of Prematurity (THOP) is characterized by low levels of serum Thyroxine (T4) and Triiodothyronine (T3), but normal Thyroid Stimulating Hormone (TSH) levels until up to 6 weeks (wk) (evident in 41% of infants under 27 weeks gestation and in 23% of infants between 28-30 weeks gestation) [5-9].

The ethyology of transient hypothyroxinaemia may have contributions from the withdrawal of maternal-placental thyroxine transfer, hypothalamic-pituitary-thyroid immaturity, developmental constraints on the synthesis and peripheral metabolism of iodothyronines, iodine deficiency, and non-thyroidal illness.

The studies realized in the previous years in premature babies of 27-36 weeks of gestacional age, in the Neonatal Unit of La Paz revealed clearly that these infants have very low levels of Free Thyroxin (FT4) and of tri-yodo-Thyronin (T3), compared with those of term newborns. The mental development has been studied at the age of 4 of age, being low in those children who had lower concentrations during the postnatal period, especially if this situation extended during the first two months of life. A subsequent study was performed in premature babies of minor gestacional age (<30 weeks), but fed on formulae with higher iodine content. The mental development has been studied at the age of 6, 12, 18 and 24 months of age. A preliminary evaluation of the results indicates that the children with more problems of development keep on being those who had a lower iodione intake [10-23].

Parenteral nutrition is used in the clinical practice in all the immature new born babies immediately in the first hours of life. At present the preparations used for the feeding parenteral in newborn babies present a content of iodine of 1 microgram for ml. [24] and the recommendations of administration of iodine by route parenteral were established a few years ago in 1 microgram/kg/day, being these quantities lower than the recommendations for oral route, possibly being based on the possibility of toxicity of the iodine by parenteral route. In absence of other sources of iodine, the new born babies who are fed on parenteral nutrition present a deficiency of this micronutrient.

In pilot studies it has been described that the parenteral supplementation with quantities of iodine of 30 microgr/KG/day produces positive balance in the new born baby, these are sure quantities and they do not produce side effects [9,25]. There are not at present preparations with iodine content higher than 1 microgr/ ml. The parenteral supplementation of iodine needs an intravenous route, adds the maintenance of the sterility, there is more risk of infection and needs more sanitary personnel for maintenance.

These factors lead us to think that the administration of supplements by enteral route (oral drops) is effective, easier to administer, it is cheaper and does not exhibit the patient to major risks. The enteral supplementation of iodine has theoretically many advantages. Prevention of iodine deficiency and follow-up is recognized as a priority. The number of Extremely Low Birth Weight (ELBW) infants is high. Correction of their iodine deficiency and hypothyroxinemia and its consequences appears, to be an intervention with promising possibilities. Future research would be facilitated if preterm babies were followed during their stay in intensive care units with respect to their iodine nutrition and thyroid function as carefully as they are followed for other organ functions. Our aim is to determine, through a randomized controlled trial, whether nutritional supplementation with iodine solution via oral route (as a drop in the mouth) enables extreme preterm infants to achieve a positive iodine balance.

Study desing

We conducted a study of thyroid hormones in infants under 1500g of birth weight. The study was designed as a longitudinal clinical trial, one group of infants with iodine supplements and a control group. Enrollment period: January 2007 - December 2009. 47 subjects were enrolled in the Control group (no supplements). 47 subjects were enrolled in the Iodine supplemented group (30μg / kg/day of Potassium Iodine (SSKI) in oral drops). Treatment period: All treatments start within 24 hours after birth. Every study subject receives the supplement during hospitalization until discharge. Parental written consent was obtained for each study subject. Parents and clinicians were not blind from treatment assignment throughout the entire study period. The study was approved by the Ethics Committee and by the Institutional Review Boards of the enrolment center (University Hospital LA PAZ, Madrid, Spain). Excluded were mothers less than 18 years old, mothers with thyroid disease or reported substance abuse (i.e., alcoholism or use of heroin or methadone, as these substances can interfere with hormone transport in serum) and newborns with major congenital malformations or if death was expected within 48 hours.


We used Potasium Iodine in oral drops (Babyodo 30™. Dietetic food, watery solution of contained iodine 30 mcg for 0,5 ml. Babyodo 90™: Dietetic food, watery solution of contained iodine 90 mcg for 1,5 ml. LITAPHAR Labs Pharmaceuticals).

Randomization was done by a web-based computer program, which balanced gestational age and sex. The iodine drops were administered from postnatal day 1 to postnatal day at discharge. We delivered either as oral drops or in oral submucosa. All infants in the supplemented group received a dose of 30 microgr/Kg/ day, independently of iodine intake received by milk or parenteral solutions.

During hospitalization, a daily evaluation of the intake was done.

Clinical definitions and management strategies

Necrotizing enterocolitis was recorded if greater than Bell’s stage II (at least proven by abdominal X-ray), retinopathy was recorded of prematurity as greater than stage III in either eye and chronic lung disease was recorded as oxygen requirement at 36 weeks to keep oxygen saturations greater than 88–92%. Cranial ultrasounds were made throughout the hospital stay, and germinal matrix haemorrhages and white matter damage were scored according to the Extremely Low Gestational Age Neonates (ELGAN) [4,20,21].

Iodine precautions

The study protocol called for avoidance of iodinated skin cleansers for antisepsis as excess exposure to iodine suppresses thyroid hormone synthesis. Instead, alcoholic chlorhexidine (2%) was used for skin disinfection

Data monitoring

Clinical status and infant growth were recorded daily for two weeks and once per week thereafter in a web-based spreadsheet until hospital discharge. Cranial ultrasound imaging was conducted on postnatal days 1–3, 7–10 and after at least 4 weeks and was interpreted by a single radiologist, masked to the study arm.

Neurodevelopmental follow-up

At the corrected age of two years, surviving children and their parents were invited to the follow-up clinic. Development was assessed using the Bayley Scales of Infant and Toddler Development, third edition (BSITD III) [26,27]. Trained psychologists masked to the study groups administered the cognitive and motor scales. Assessment was ended in year 2012.

The cognitive scale assesses abilities such as sensorimotor development, manipulation, object relatedness, concept formation, memory, and simple problem solving, while the motor scale consists of fine motor (grasping, perceptual-motor integration, motor planning, and speed) and gross motor (sitting, standing, locomotion, and balance) subtests. The cognitive outcome is reported as the composite cognitive scale, which has a mean of 100 and a standard deviation of 15. Scaled scores are used for the Fine and Gross Motor scores separately, which have a mean of 10 and range from 1 to 19. Children were also assessed by blinded neuro-paediatricians for Cerebral Palsy (CP). The severity of CP was scored using the Gross Motor Function Classification System (GMFCS).

Moderate to severe delay in cognitive development was defined as a developmental age of more than six months below the corrected age at testing.

All infants were assessed for Auditory Evoked Potentials at 6 months of age.


Serial blood and urine specimens were collected on day 0, 3, 7, 14, 21, 42, 56, and at discharge. Samples of different milk formulas and maternal milk was kept for the determination of the iodine content. Thyroid hormone testing: Free T4 (FT4) was measured using the equilibrium dialysis technique and the other hormones by standard immunoassay technology (Roche Diagnostics). The concentration of Iodine in formula and milk samples was determined by modifications of chloric acid method Benotti and Benotti [28].

Statistical analyses

For analyses of differences between the study arms, we used both parametric and nonparametric tests. Thus, analysis of variance and the Kruskal-Wallace test were used for continuous variables, and for dichotomous variables, the chi-squared test or Fisher exact test were used. We report findings for the parametric tests. We examined cognitive and motor scores and then we made a combined measure of adverse outcomes and/ or moderate to severe cognitive delays using the BSITD III (a score on these tests of greater than one SD below the mean). Whenever it is stated that a certain variable was higher, or lower, for different groups, or that correlations existed between the variables, it is implicit that the differences or correlation coefficients were statistically significant, at P < 0.05, or less for statistical analyses, SPSS software version 18 was used.


The parents of 9 children could either not be traced or refused follow-up. Follow-up results were thus available for 89 of the children.

No differences were found in demographic and birth characteristics between groups (Table 1).