Articles
Association between borderline neonatal thyroid-stimulating hormone concentrations and educational and developmental outcomes: a population-based record-linkage study

https://doi.org/10.1016/S2213-8587(16)30122-XGet rights and content

Summary

Background

Congenital hypothyroidism causes intellectual delay unless identified and effectively treated soon after birth. Newborn screening has almost eliminated intellectual disability associated with congenital hypothyroidism. However, clinical uncertainty remains about infants with thyroid-stimulating hormone (TSH) concentrations less than the newborn screening cutoffs. We assessed the association between neonatal TSH concentrations and educational and developmental outcomes.

Methods

We did a population-based record-linkage study of all liveborn infants undergoing newborn screening from 1994 to 2008 in New South Wales, Australia, with assessments of childhood development or school performance. Very-low-birthweight babies (<1500 g) were excluded. Developmental and educational outcomes were obtained and these were linked to individual records by the New South Wales Centre for Health Record Linkage. The primary educational outcome was the proportion of students with National Assessment Program Literacy and Numeracy (NAPLAN) results lower than the national minimum standard in reading or numeracy measured at all ages, and the primary developmental outcome was the proportion of children who were classified as being developmentally high risk (vulnerable in two or more of the five developmental domains assessed by the Australian Early Development Census) at age 4–6 years. The proportions of infants with each outcome were calculated per percentile (0–100) of TSH concentration. Multivariable logistic regression was used to account for potential confounding by maternal and fetal variables known to affect neonatal TSH concentrations or neurodevelopmental outcomes.

Findings

503 706 infants had a neonatal TSH result that linked to a developmental or educational outcome. 149 569 infants born between 2002 and 2008 were linked to an Australian Early Development Census developmental outcome and 354 137 were linked to a NAPLAN educational outcome. Median follow-up for educational outcome was 10 years (IQR 8–12) and for developmental outcome was 5 years (5–6). 5·5% (14 137 of 257 752) of infants with TSH concentrations lower than the 75th percentile scored less than the national minimum standard for numeracy, and this increased with each increase of percentile group to 11·3% (15 of 133) of infants with a TSH concentration between the 99·90th and 99·95th percentile. Infants with a neonatal TSH concentration in the 99·95th percentile or higher (above newborn screening cutoff) and likely to have diagnosed and treated congenital hypothyroidism had similar results to infants with a TSH concentration lower than the 75th percentile for both educational and developmental outcomes. Infants with a neonatal TSH concentration between the 99·5th and 99·9th percentile were more likely to have special needs (adjusted odds ratio [aOR] 1·68, 95% CI 1·23–2·30), poor numeracy performance (aOR 1·57, 1·29–1·90), and developmentally high risk (aOR 1·52, 1·20–1·93).

Interpretation

We found an association between neonatal TSH concentrations lower than the present newborn screening thresholds and poor educational and developmental outcomes. This association needs further investigation to assess whether assessment and treatment of these infants might improve their long-term cognitive outcomes.

Funding

Australian National Health and Medical Research Council.

Introduction

Adequate concentrations of maternal and neonatal thyroid hormones are essential for fetal neural development and play a key part in regulating fetal growth, brain development, and metabolism. Fetal thyroid function begins at 12–14 weeks gestation; however, maternal transfer of thyroid hormones continues until full-term and has a protective role in fetal neurodevelopment until the first few days of life.1 Children of mothers with undiagnosed hypothyroidism, and even mild thyroid deficiency, were more likely to have impaired psychomotor development at 10 months,2 and lower intelligence quotient (IQ) scores at age 7 years.3

Thyroid hormone concentrations in newborn babies are affected by neonatal, maternal, and pregnancy-related factors, including maternal thyroid function and iodine status.4, 5, 6, 7 Congenital hypothyroidism is inadequate thyroid function in newborn infants and is one of the most readily preventable causes of intellectual disability in children.8 Newborn screening for congenital hypothyroidism in the first days of life, usually by testing concentrations of neonatal thyroid-stimulating hormone (TSH), provides an opportunity to identify infants with abnormal thyroid hormone concentrations, irrespective of the cause. Neonatal TSH concentrations surge in the first 30 min of life, but then fall to the adult range by 3–5 days after birth.9

Research in context

Evidence before this study

We searched PubMed for relevant English language studies using the terms “(neonatal thyroid stimulating hormone) and (cognitive development)” for articles published before December 2015. We also examined reference lists from suitable studies found. Two small retrospective cohort studies were found that examined neurodevelopmental outcomes for healthy infants with neonatal thyroid stimulating hormone (TSH) concentrations lower than the newborn screening cutoff used for diagnosis of congenital hypothyroidism. One study found, in a cohort of 178 boys, that a neonatal TSH concentration in the upper quartile was associated with poorer cognitive and memory scores at age 4 years, whereas another study did not find a significant association between elevated neonatal TSH concentrations and verbal scores at age 4 to 6 years, after adjustment for demographic and socioeconomic factors. Both studies had the limitation of low numbers of infants with neonatal TSH concentrations slightly lower than the newborn screening cutoffs.

Added value of this study

Our study is the largest population-based study examining infants with neonatal TSH concentrations lower than the newborn screening cutoff for congenital hypothyroidism, with more than 500 000 infants followed up to school-age. This comprehensive and systematic assessment allowed examination of the association between neonatal TSH concentrations and later developmental and educational outcomes. We have shown that infants with a neonatal TSH concentration lower than the newborn screening cutoff (20 mU/L in whole blood) but in the top quartile of the population have an increased likelihood of poor neurodevelopmental outcomes at school age.

Implications of all the available evidence

These results are relevant to international newborn screening programmes and provide much needed information about infants with a mild increase in TSH concentrations at screening. Further research is required into causation and to assess whether early assessment and treatment of these infants will improve long-term cognitive outcomes.

Newborn screening and early treatment for congenital hypothyroidism has almost eliminated intellectual disability associated with congenital hypothyroidism in developed countries.10 There has been much international debate about lowering screening cutoffs for congenital hypothyroidism to potentially identify infants with milder, but still clinically significant, thyroid abnormalities.11, 12, 13 There are many implications of lowering the newborn screening threshold for congenital hypothyroidism, including increased clinical workload, expense, and parental anxiety when healthy infants are recalled for further testing. Another potential harm is an increase in false-positive test results leading to overtreatment, shown to be associated with poorer neurodevelopmental outcomes,14 which needs to be balanced with the benefits of identifying infants with mildly increased or borderline neonatal TSH concentrations. Crucial to any decision about changes to newborn screening thresholds are the long-term cognitive and health outcomes for these infants, which are largely unknown.13 We aimed to assess the association between neonatal TSH concentrations and long-term educational and developmental outcomes, particularly in infants with neonatal TSH concentrations just less than the newborn screening cutoffs.

Section snippets

Data sources and study population

In this population-based record-linkage cohort study, we included all liveborn infants in New South Wales, Australia, undergoing newborn screening on days 2–4 (where the date of birth was day 0), from 1994 to 2008, with a subsequent assessment of childhood development or school performance. Neonatal TSH concentrations were obtained from the New South Wales newborn screening database. In New South Wales, 99·9% of babies have a blood sample collected, with a heel-prick, optimally 48–72 h after

Results

Of the 503 706 infants with a TSH result that linked to an outcome, 354 137 infants born from 1994 to 2002 were linked to an educational record and 149 569 infants born from 2002 to 2008 to a developmental record (figure 1). Median follow-up for educational outcome was 10 years (IQR 8–12) and for developmental outcome was 5 years (5–6). For educational outcomes, children were followed up for different time periods depending upon when they had an education record that linked to their newborn

Discussion

To our knowledge, this is the first population-based study to examine neurodevelopmental outcomes for infants with TSH concentrations lower than the newborn screening cutoffs that currently trigger investigation into congenital hypothyroidism. We show that as neonatal TSH concentrations increase from the 75th to the 99·95th percentile, the risk of having a poor educational or developmental outcome increases. However, infants with a TSH concentration higher than the 99·95th percentile—who are

References (35)

  • MV Rastogi et al.

    Congenital hypothyroidism

    Orphanet J Rare Dis

    (2010)
  • DF Gordon et al.

    Thyroid-stimulating hormone: physiology and secretion

  • J Léger

    Endocrinology and adolescence: congenital hypothyroidism: a clinical update of long-term outcome in young adults

    Eur J Endocrinol

    (2015)
  • SD Grosse et al.

    Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level?

    Arch Dis Child

    (2011)
  • SM Korada et al.

    Difficulties in selecting an appropriate neonatal thyroid stimulating hormone (TSH) screening threshold

    Arch Dis Child

    (2010)
  • H Krude et al.

    Treating patients not numbers: the benefit and burden of lowering TSH newborn screening cut-offs

    Arch Dis Child

    (2011)
  • JJ Bongers-Schokking et al.

    Cognitive development in congenital hypothyroidism: is overtreatment a greater threat than undertreatment?

    J Clin Endocrinol Metab

    (2013)
  • Cited by (0)

    View full text