Rev Esp Endocrinol Pediatr

 View / Download PDF
No Spanish version available for this Article
Rev Esp Endocrinol Pediatr 2022;13 Suppl(1):35-38 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2022.Mar.725
Thyroid function in 509 premature newborns below 31 weeks of gestational age: evaluation of a screening protocol
Función tiroidea en 509 recién nacidos prematuros con una edad gestacional de menos de 31 semanas: evaluación de un protocolo de cribado

Sent for review: 17 Mar. 2022 | Accepted: 17 Mar. 2022  | Published: 24 Mar. 2022
Ariadna Campos Martorell
Attending physician in the Paediatric Endocrinology Unit. Hospital Universitari Vall d’Hebron. Adjunct lecturer in Paediatrics. Universitat Autònoma de Barcelona. Barcelona (Spain)
Correspondence:Ariadna Campos Martorell, Attending physician in the Paediatric Endocrinology Unit. Hospital Universitari Vall d’Hebron, Adjunct lecturer in Paediatrics. Universitat Autònoma de Barcelona, Barcelona, Spain
E-mail: ariadnacampos@yahoo.es
Figure 1 - Flowchart of thyroid function screening results of premature newborns.

Introduction

Thyroid hormones are essential for the growth and development of the central nervous system, as well as for bone, pulmonary and cardiac maturation throughout foetal and neonatal life (1–3).

Preterm neonates show lower levels of thyroid hormones as compared to term neonates, in proportion to their degree of prematurity (4). The immaturity of the hypothalamic-pituitary-thyroid axis and the influence of pathology and the therapeutic measures make these infants prone to thyroid dysfunction (5,6)

Hypothyroxinemia of prematurity (HOP) refers to low levels of free T4 (FT4), generally without elevation of TSH (thyroid stimulating hormone) (4,7,8). This condition is difficult to differentiate from central hypothyroidism and from non-thyroidal illness syndrome. Although in preterms with HOP low thyroid hormone levels have been related to a worse neurodevelopmental outcome, a causal relationship has not been clearly established, as it is difficult to adjust for other comorbidities present in this population (9–12).

On the other hand, some preterm neonates and especially those with low birth weight (LBW) present congenital hypothyroidism (CH) with delayed elevation in serum TSH levels (5,13,14). The immaturity of the hypothalamic-pituitary axis, iodine overload due to some procedure, drugs and acute non-thyroidal illness can contribute to the elevation of TSH and its later occurrence in time (5,15,16). This CH will be transient in the majority of infants but it could be permanent in some cases. Moreover, it is unclear whether treatment with levothyroxine is necessary for milder elevations of TSH (13).

Although the incidences of permanent CH and central hypothyroidism are similar in preterm and term newborns, these disorders can be missed in congenital hypothyroidism screening performed using only TSH determination in a dried blood spot test taken at 48-72 hours of life, due to the aforementioned pattern of delayed TSH rise. Accordingly, guidelines of the European Society for Paediatric Endocrinology and the European Society for Endocrinology recommend a second screening for preterm neonates, low or very low birth weight neonates, and ill and preterm neonates admitted to the neonatal intensive care unit (NICU)17. The utility of the second screening, its optimal timing, whether it measures TSH alone in dried blood spot or TSH and FT4 (free thyroxine) in serum sample, the TSH cutoffs to be used, and the need to start replacement therapy still remain subjects of active debate (18).

The Neonatal Screening Programme of Catalonia centralizes all the birth centres throughout Catalonia and only mandates a TSH determination in dried blood spot; currently it does not require a routine second sample of preterm neonates or LBW neonates. Therefore, thyroid function screening (TFS) based on the measurement of serum TSH and FT4 has been implemented in our tertiary hospital NICU for preterm neonates born below 31 weeks of gestational age (GA). This protocol has been conducted in addition to routine congenital hypothyroidism screening in dried blood spot.

The aims of the present study were: first, to determine the incidence of thyroid dysfunction detected by the application of this protocol in preterm neonates below 31 weeks of GA and, second, to describe the follow-up of the treated patients at reassessment. In addition, the thyroid function of preterm neonates with low weight for gestational age was evaluated separately.

Methods

Serum TSH and free thyroxine (FT4) determinations were performed during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (FT4<0.8 ng/dL and/or TSH>5 mU/L) were followed up with repeated tests until normal levels were reported. Patients with TSH level >12 mU/L, persistently elevated TSH 5-12 mU/L and/or persistently low FT4 below 0.8 ng/dl were started on levothyroxine after confirmation and taking into account the patient's clinical condition and the preceding TFS. Oral levothyroxine replacement was administered at 4-6 mcg/kg/day for HOP and 10-15 mcg/kg/day for CH (7,17,20). Patients who were still on levothyroxine at 3 years of age were re-evaluated, and those who still showed thyroid dysfunction after three weeks without levothyroxine were assessed with a genetic study for thyroid dyshormonogenesis with Next Generation Sequencing.

Results

A total of 509 neonates were included. The median (IQR) of gestational age at birth was 28 weeks (26.4, 29.4) and the newborns’ birth weight was 1000g (800,1230). The distribution by weeks of GA was: 23 (n=3), 24 (n=30), 25 (n=54), 26 (n=59), 27 (n=94), 28 (n=91), 29 (n=91) and 30 (n=87). Fifty-six neonates (11%) were LBW. A total of 687 TFS were performed. It was necessary to repeat 104 samples due to abnormal values (n=58) or an insufficient sample (n=46).

Thyroid dysfunction was detected in 170 neonates (33%); congenital hypothyroidism (CH):20 (3.9%) [typical CH:1; delayed TSH CH:19]; hypothyroxinemia of prematurity (HOP):15(2.9%); and transient hyperthyrotropinemia:135. Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP).

Twenty preterm neonates were diagnosed with congenital hypothyroidism (1 typical and 19 with delayed TSH rise) with median (IQR) TSH levels of 25.9 (16.8,42) mU/L and mean±SD FT4 levels of 1.0±0.3 ng/dL. Remarkably, 11 out of the 20 patients received an iodine overload due to routine procedures (intestinal surgery, lumbar puncture and surgical closure of ductus arteriosus). Seven patients were LBW. It should be highlighted that all patients with delayed TSH rise presented TSH levels above 5 mU/L at the first TFS (14 patients between 13-20 mU/L and 5 patients between 5 and 12 mU/L). In relation to the Neonatal Screening Programme, all neonates were tested at a median (IQR) of 4 (3,13) days of life. Three patients showed TSH above 10 mU/L in the first dried spot sample. One patient was diagnosed with typical CH because he showed TSH levels of 18.6 mU/L in the dried spot sample and TSH levels of 66 mU/L in the serum sample. Two other patients showed TSH levels in the first sample of 13.6 and 13.2 mU/L, but displayed normal TSH levels in the second blood spot sample.

At re-evaluation after more than 3 years of follow-up, three patients were finally diagnosed with permanent CH and still need treatment
with levothyroxine. One patient was diagnosed with Williams syndrome, another one with Down syndrome and the last one was diagnosed with probable thyroid dyshormonogenesis. A variant of unknown significance (VUS) in heterozygosity c.2654G>A, (p.Arg885Gln) in exon 20 was found in the DUOX2 gene.

Fifty-six patients (11%) were LBW. These neonates were two weeks GA older than those preterm neonates born with adequate birth weight for gestational age (ABW) (p<0.001). LBW neonates presented TSH levels at first and second TFS higher than those of ABW neonates. However, no statistically significant differences were found for FT4 levels between those groups. Of the LBW neonates, only one was finally diagnosed with permanent CH corresponding to the newborn with Williams syndrome.

Fifteen neonates presented HOP during the second week of life (median [IQR] 15 [9,17] days) with TSH median (IQR) levels of 2 (1.3-3.6) mU/L and FT4 mean levels of 0.68±0.1 ng/dl. Two neonates with HOP were LBW. Only one patient (26 weeks of GA, TSH 2.1 mU/L, FT4 0.41 ng/dl) was treated with levothyroxine at 15 days of life while suffering a septic shock. On follow-up: 10 patients had the following TFS with normal levels, two patients had died and in two patients TFS was not repeated. Flowchart of thyroid function screening results are shown in Figure 1.

In conclusion this protocol was able to detect thyroid dysfunction in preterm neonates that were not detected by the application of the current programme based on TSH determination in whole-blood. Preterm neonates, especially of lower gestational age, low birth weight or those having had an iodine overload show a risk of thyroid dysfunction during a critical period of brain development, and therefore a TFS with serum TSH and FT4 is proposed. The second week of life seems to be an appropriate time and this TFS does not involve an extra blood test as it is performed at the same time as a routine blood test. CH seems to resolve spontaneously in a few months in the great majority of preterm neonates, but in some cases replacement treatment could be needed. There is a critical need for specific guidelines regarding the follow-up and reevaluation of transient CH, especially in preterm neonates.

References

1. Calvo RM, Jauniaux E, Gulbis B, Asunción M, Gervy C, Contempré B, et al. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J Clin Endocrinol Metab. 2002 Apr;87(4):1768–77.

2. 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 birth weight infants. Pediatr Res. 1996 Jan;39(1):142–5.

3. Ares Segura S. Función tiroidea en la etapa fetal, neonatal y en el recién nacido prematuro. Necesidades de yodo. Rev Esp Endocrinol Pediatr. 2014;5(2):13–22.

4. LaFranchi SH. Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction. Front Endocrinol (Lausanne). 2021;12(June):1–9.

5. Kaluarachchi DC, Colaizy TT, Pesce LM, Tansey M, Klein JM. Congenital hypothyroidism with delayed thyroid-stimulating hormone elevation in premature infants born at less than 30 weeks gestation. 2016;37(3):277–82.

6. Lafranchi SH. Screening preterm infants for congenital hypothyroidism: Better the second time around. J Pediatr. 2014;164(6):1259–61.

7. Clemente M, Ruiz-Cuevas P, Carrascosa A, Potau N, Almar J, Salcedo S, et al. Thyroid function in preterm infants 27-29 weeks of gestational age during the first four months of life: results from a prospective study comprising 80 preterm infants. J Pediatr Endocrinol Metab. 2007 Dec;20(12):1269–80.

8. Williams FLR, Visser TJ, Hume R. Transient hypothyroxinaemia in preterm infants. Early Hum Dev. 2006;82(12):797–802.

9. van Wassenaer AG, Kok JH. Trials with Thyroid Hormone in Preterm Infants: Clinical and Neurodevelopmental Effects. Semin Perinatol. 2008;32(6):423–30.

10.  La Gamma EF, van Wassenaer AG, Ares S, Golombek SG, Kok JH, Quero J, et al. Phase 1 Trial of 4 Thyroid Hormone Regimens for Transient Hypothyroxinemia in Neonates of 28 Weeks’ Gestation. Pediatrics. 2009;124(2):e258–68.

11.  Hollanders JJ, Israëls J, Van Der Pal SM, Verkerk PH, Rotteveel J, Finken MJJ, et al. No association between transient hypothyroxinemia of prematurity and neurodevelopmental outcome in young adulthood. J Clin Endocrinol Metab. 2015;100(12):4648–53.

12.  van Wassenaer-Leemhuis A, Ares S, Golombek S, Kok J, Paneth N, Kase J, et al. Thyroid Hormone Supplementation in Preterm Infants Born Before 28 Weeks Gestational Age and Neurodevelopmental Outcome at Age 36 Months. Thyroid. 2014;24(7):1162–9.

13.  Cavarzere P, Camilot M, Popa FI, Lauriola S, Teofoli F, Gaudino R, et al. Congenital hypothyroidism with delayed TSH elevation in low-birth-weight infants: Incidence, diagnosis and management. Eur J Endocrinol. 2016;175(5):395–402.

14.  Kaluarachchi DC, Allen DB, Eickhoff JC, Dawe SJ, Baker MW. Increased Congenital Hypothyroidism Detection in Preterm Infants with Serial Newborn Screening. J Pediatr. 2019 Apr 1;207:220–5.

15.  Vigone MC, Caiulo S, Di Frenna M, Ghirardello S, Corbetta C, Mosca F, et al. Evolution of thyroid function in preterm infants detected by screening for congenital hypothyroidism. J Pediatr. 2014;164(6):1296–302.

16.  Hashemipour M, Hovsepian S, Ansari A, Keikha M, Khalighinejad P, Niknam N. Screening of congenital hypothyroidism in preterm, low birth weight and very low birth weight neonates: A systematic review. Pediatr Neonatol. 2018;59(1):3–14.

17.  Van Trotsenburg P, Stoupa A, Léger J, Rohrer T, Peters C, Fugazzola L, et al. Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update - An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology. Thyroid. 2021;31(3):387–419.

18.  McGrath N, Hawkes CP, Mayne P, Murphy NP. Optimal Timing of Repeat Newborn Screening for Congenital Hypothyroidism in Preterm Infants to Detect Delayed Thyroid-Stimulating Hormone Elevation. 2018.



Comments
Name*: Surname*:
E-mail*:
Hospital*:
Address:
C.P.: Country:
Comments*:
(450 Words)
Security code*:
* Required Fields
Send
Send Send Send
Send