Original Article

Treatment of Transient Hypothyroxinemia of Prematurity: A Survey of Neonatal Practice†

¹Department of Pediatrics, Division of Neonatology, The Regional Neonatal Center, Westchester Medical Center, New York Medical College, Valhalla, NY, USA

²Departments of Epidemiology and Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI, USA

Correspondence to: Sergio G. Golombek, MD, FAAP, The Regional Neonatal Center, Westchester Medical Center, New York Medical College, Valhalla, NY 10595, USA

^†Presented in part at the ESPR meeting, Greenwich, CT, March 2002 and at the APS/SPR meeting, Baltimore, May 2002.

Abstract

We mailed a survey on treatment practices for transient hypothyroxinemia of prematurity (THOP) to 100 randomly selected neonatologists. In the year before the survey, 13 of 62 respondents (21.0%) had treated an average of 4.5 THOP patients with thyroid hormone, and 3 had treated 10 or more patients. Randomized trials assessing the value of thyroid supplementation in THOP are urgently needed. Journal of Perinatology (2002) 22, 563-565 doi:10.1038/sj.jp.7210791

INTRODUCTION

Premature infants, especially those born before 30 weeks' gestation, often experience periods lasting from days to weeks in which circulating thyroid hormones are at very low levels.¹ In this syndrome of transient hypothyroxinemia of prematurity (THOP), TSH is usually normal and circulating thyroxine levels eventually rise to age-appropriate levels. These transiently low levels of thyroid hormones have been shown to be either markers or causes of substantially increased risks of neurodevelopmental disability in three large studies.^2,3,4,5 However, it is not yet known whether treatment with thyroid hormone during this period of hypothyroxinemia improves neurodevelopmental outcome. A few small trials have been undertaken to examine this question, but results are mixed, and no published trial has had sufficient power to properly test the hypothesis. In light of the uncertainty surrounding this issue, we undertook a survey of neonatologists to examine the extent of variation in current practice. Most endocrinologists do not currently recommend treating THOP with thyroid hormones.⁶

METHODS

We obtained a computer-generated random sample of 100 neonatologists from the US directory of neonatologists.⁷ We first randomly sampled 100 pages from this 301-page directory, and then randomly sampled one neonatologist from each page. For each neonatologist we recorded mailing address and e-mail. In July 2001, we mailed a seven-item questionnaire about THOP treatment to the 100 sampled neonatologists (Figure 1). The definition of THOP used in the questionnaire was "the drop in total T4 commonly detected by thyroid screening programs in premature infants, which is usually unaccompanied by any abnormality in TSH, and which generally returns to normal after several days or weeks." If no response was received in 3 weeks, we e-mailed the questionnaire to the sampled neonatologist, and if no response was received in 2 weeks after that, we e-mailed the questionnaire a second time. Eight surveys were returned because either the regular mail or e-mail address was no longer correct. Of the 92 neonatologists successfully contacted, 63 (68.5%) returned the survey. One neonatologist returned, but did not complete, the survey, stating that he no longer practiced neonatology. The analysis is based on the remaining 62 surveys. In a separate procedure, we also surveyed 17 attendees at a meeting on THOP management held at the 2001 Annual Pediatric Academic Societies meeting. The results of that survey are also reported below, separate from the mail survey.

RESULTS

Of the 62 respondents, 18 (29.0%) indicated that they had treated infants with THOP with thyroid hormone on at least one occasion, and 13 had treated an average of 4.5 infants in the previous 12 months. The mean age at which treatment began (n=14) was 25 days. The level of total thyroxine used to initiate treatment was reported only by 8 neonatologists (average 4.0 g/dl; range 2 to 6). Three respondents indicated that they used free thyroxine as a guide to treatment. Of the 17 neonatologists surveyed at SPR, 7 (41.2%) had treated THOP with thyroid hormone, 6 (35.3%) in the past year, initiating treatment at 13.1 days of age on average.

All treating neonatologists had consulted an endocrinologist for advice in managing THOP, and none reported using T₃.

DISCUSSION

Our survey suggests that a substantial number of neonatologists, nearly a third of those surveyed, have used thyroid hormone to treat infants with THOP, and 20% of them appear to do so with some regularity. At the same time, two-thirds of neonatologists leave THOP wholly untreated (presumably due to lack of consensus as to what are "pathologic values"). Treatment seems to have been initiated earlier, and provided more frequently, by neonatologists presumably more interested in the problem of THOP, as indicated by the findings in the smaller survey of neonatologists attending a meeting on the subject at the annual meeting of the Pediatric Academic Societies. The division of opinion in neonatal circles indicates that optimum management of THOP is currently unresolved. The study was not designed, though, to collect data regarding the specific type of practice of the responder, nor whether any specific type of practice (e.g., academic, community hospital) influenced therapeutic approach.

Randomized trials have been undertaken to examine the effect of treatment of THOP (Table 1), but in aggregate, they fail to provide clear answers to this treatment dilemma. All published trials are flawed by small sample sizes, less than ideal treatment schedules, or uncertainty about randomization. Whereas one early trial found a reduction in mortality with T₄ and T₃ supplementation⁸ (later development was not assessed), no long-term benefit of T₄ treatment was seen in trials by Chowdry et al.⁹ or Vanhole et al.¹⁰ Both latter trials, were, however, very small (12 and 34 subjects, respectively). The largest trial, studied 100 infants <30 weeks, but did not restrict treatment to infants with THOP.¹¹ Although no significant overall change in neurodevelopment was found, intriguing suggestions of benefit, as well as of potential harm, were identified. Mortality and abnormal neurologic findings were reduced by a third or more in the treatment arm, but numbers were too small for significance. A significant improvement of 18 points in Bayley mental scores at age 18 months was found in infants <27 weeks, but at the same time, a 10-point deficit was seen in infants >28 weeks. Overall, IQ was slightly higher in the placebo group.

In spite of compelling evidence that infants with THOP are more likely to develop neurodevelopmental abnormalities, current treatment guidelines do not recommend thyroid supplementation for infants with low thyroxine levels but normal TSH levels.¹² This position is eminently reasonable in the absence of firm evidence of improvement in outcomes in treated THOP babies. However, the current variation in neonatal practice suggests that it is important to undertake a randomized controlled trial of thyroid supplementation in THOP with enough power to assess whether such treatment can reduce the risk of later neurodevelopmental disabilities.

Acknowledgements

Wen-Jiang Fu PhD, Assistant Professor of Epidemiology, Michigan State University, designed and executed the sampling procedure. Lora McAdams and Jian-Ping He, MD, MS, assisted in data entry, management, and analysis.

References

1 Reuss ML, Leviton A, Paneth N, Susser M. Thyroxine values from newborn screening of 919 infants born before 29 weeks' gestation. Am J Public Health 1997; 87: (10) 1693-7, also NEJM letter. MEDLINE

2 Reuss ML, Paneth N, Pinto-Martin JA, Lorenz JM, Susser M. The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N Engl J Med 1996; 334: 821-7. MEDLINE

3 den Ouden AL, Kok JH, Verkerk PH, Brand R, Verloove-Vanhorick SP. The relation between neonatal thyroxine levels and neurodevelopmental outcome at age 5 and 9 years in a national cohort of very preterm and/or very low birthweight infants. Pediatr Res 1996; 39: 142-5. MEDLINE

4 Lucas A, Rennie J, Baker BA, Morley R. Low plasma triiodothyronine concentrations and outcome in preterm infants. Arch Dis Child 1988; 63: 1201-6. MEDLINE

5 Lucas A, Morley R, Fewtrell MS. Low triiodothyronine concentration in preterm infants and subsequent intelligence quotient (IQ) at 8 year follow up. BMJ 1996; 312: 1132-3. MEDLINE

6 Rapaport R, Rose SR, Freemark M. Hypothyroxinemia in the preterm infant: the benefits and risks of thyroxine treatment. J Pediatr 2001; 139: (2) 182-8. MEDLINE

7 United States Neonatologists and Perinatologists Directory. Section on Perinatal Pediatrics ¾ AAP ¾ CD 1998.

8 Schonberger W, Grimm W, Emmrich P et al. Reduction in mortality rate in premature infants by substitution of thyroid hormones. Eur J Pediatr 1981; 135: 245-53. MEDLINE

9 Chowdry P, Scanlon JW, Auerbach R, Abassi V. Results of a controlled double-blind study of thyroid replacement in very-low-birth-weight premature infants with hypothyroxinemia. Pediatrics 1984; 73: 301-5. MEDLINE

10 Vanhole C, Aerssens P, Naulaers G et al. L-Thyroxine treatment of preterm newborns: clinical and endocrine effects. Pediatr Res 1997; 42: 87-92. MEDLINE

11 Van Wassenaer AG, Kok JH, Endert E et al. Effects of thyroxine supplementation on neurological development in infants born at less than 30 weeks gestation. N Engl J Med 1997; 336: 21-6. MEDLINE

12 Osborn DA. Thyroid hormones for preventing neurodevelopmental impairment in preterm infants. Cochrane Database Syst Rev 2001; (4) CD001070.

13 Amato M, Pasquier S, Carasso A, van Muralt G. Postnatal thyroxine administration for idiopathic respiratory distress syndrome in premature infants. Horm Res 1988; 29: 27-30. MEDLINE

14 Amato M, Guggisberg C, Schneider H. Postnatal triiodothyronine replacement and respiratory distress syndrome of the preterm infant. Horm Res 1989; 32: 213-7. MEDLINE

Figures

Figure 1 The seven survey questions.

1. Do you ever treat premature infants with transient hypothyroxinemia of prematurity with any type of thyroid hormone?
2. In the past 12 months, how many premature infants have you treated for transient hypothyroxinemia?
3. Do you treat infants with transient hypothyroxinemia of prematurity with T4 only?
4. Have you ever used T3 in treating infants with transient hypothyroxinemia of prematurity?
5. At what age have you generally initiated treatment for infants with transient hypothyroxinemia of prematurity?
6. At what level of serum total thyroxine would you consider treatment of transient hypothyroxinemia of prematurity necessary, assuming no elevation of TSH?
7. Have you ever consulted a pediatric endocrinologist for advice in management of premature infants with transient hypothyroxinemia?

Tables

Table 1 Findings in Five Trials of THOP Treatment

October/November 2002, Volume 22, Number 7, Pages 563-565

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