Incidence of congenital malformations in congenital hypothyroidism

SCREENING of the lntarnational of Namatal Scraanlng

Journal Society

Screening

3 (1994) 125-130

Incidence of congenital malformations hypothyroidism

in congenital

A. Cassio’, L. Tatbb, C. Colli”, E. Spolettinib, E. Costantinib, E. Cacciari a** “First Pediatric Clinic, University of Bologna, Via Massarenti 11, 40138 Bologna, Italy bPediatric Clinic, University of Verona, Verona, Italy

Received 14 December 1993;accepted 16 September 1994

Introduction: We investigated the frequency and types of congenital malformations in infants with congenital hypothyroidism (CH) detected by neonatal screening in four northeastern regions of Italy. Methods: Newborn dried blood specimens were collected at 3-7 days of age. Thyroid hormone (T4) and thyroid stimulating hormone (TSH) were measured by radioimmunoassay. Results: 235 infants with CH were identified among 745 801 screened infants (1:3174). 22 infants (9.4%) had congenital anomalies, as compared to an incidence of 1.8% for congenital anomalies in the general population. The infants with CH and congenital anomalies had significantly lower values for blood T4, birth weight and gestational age. Discussion: This study confkms other data indicating that congenital malformations are substantially more frequent among infants with CH than expected. The presence of these malformations, which often produce clinical complications in the neonate, should not delay collectioln of the neonatal screening specimen or the start of treatment in infants found to have CH:. Keywords:

Congenital hypothyroidism;

Congenital malformation;

Neonatal screening

1. Introduction Recent reports have described an unusually high incidence of congenital malformations in children with congenital hypothyroidism (CH) diagnosed by neonatal screening [l-7]. We examined 235 infants with CH who were screened in four regions of Italy in order to define the incidence of congenital malformations and their possible relationship to the basic thyroid defect and the effectiveness of screening. ~_ *Corresponding author. 0925-6164/94/$07.00 0 1994 Elsevier Science B.V. All rights reserved SSDZ 0925-6164(94)00019-O

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2. Patients and methods In four northeastern regions of Italy (Veneto, Friuli, Trentino Alto Adige and Emilia Romagna) infants were screened in newborn blood specimens collected between 3 and 7 days of life. The screening method was radioimmunoassay for TSH and T4 on filter paper [ 81. The criteria for requesting repeat specimens, diagnosis and follow-up were uniform for the two centers (Bologna and Verona) participating in the study [8,9]. The malformations were detected or suspected on the basis of clinical signs during the neonatal period and before the diagnosis of CH by the local medical staff. The malformations and CH were later confirmed. Minor congenital anomalies were not considered unless occurring in combination with major abnormalities. The incidence of malformations in the general population was from a population based Congenital Malformations Registry established in Emilia Romagna, a region of northern Italy, which is part of a European study (EUROCAT) [lo]. The diagnosis of CH was confirmed in all patients in this analysis by withdrawing treatment for a few weeks during the second year of life. 15 of the 22 patients with CH and anomalies had a thyroid scan; eight showed athyreosis and seven had an ectopic gland. Student’s t-test and x2 test were used for statistical analysis of results.

3. Results We identified 235 CH patients (74 males and 161 females) among 745 801 infants examined from January 1982 to December 1990. This gave an incidence for CH of one in 3174 live births. 22 infants with CH (9.4%) had additional congenital anomalies, eight of which (36.4% of those with congenital anomalies) were cardiac. This incidence of 9.4% for congenital malformations was significantly higher than the incidence of 1.8% in the newborn control population (PC 0.0001) (Table 1). Among these 22 infants with CH and additional congenital abnormalities were seven males and 15 females and eight premature and 14 full-term infants. Table 2 shows TSH and T4 levels on dried blood spot and some neonatal features in the infants with additional congenital defects (group 1) as compared to the infants with isolated CH (group 2). For each subject in group 1, we examined these parameters in newborns with isolated CH (group 2) who were detected by screening immediately before and after the group 1 subject in the same region. Group 1 patients had significantly lower birth weight and gestational age (P< 0.025) and a higher incidence of respiratory distress syndrome (RDS) than the infants in group 2 (33.3% vs. 11.8%; x2= 3.19; P=O.O7). In subjects with additional congenital malformations, the T4 levels in the dried blood spots were significantly lower (P
A. Cassio et al./Screening

Table 1 Incidence of congenital malformations control infants

3 (1994)

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in 235 infants with congenital hypothyrodism

CH patients n Congenital heart disease Trisomies Digestive system malformations Internal urogenital system malformations Central nervous system rnalfonnations Multiple defects Other Total

127

and in 103484

Control population %

n

%

8

3.40**

416

0.40

3 2

1.28** 0.85*

149 136

0.14 0.13

1

0.43

102

0.11

1

0.43

145

0.14

153 111 1872

0.15 0.75 1.81

0.85 2.13* 9.36**

2 5 22

* Pi 0.05 vs. control population; ** P
Table 2 TSH and T4 spot values and some neonatal features (mean&SD) (group 1) xnd in infants with isolated CH (group 2)

Group 1

in infants with additional defects

‘T4 spot I:mnol/l)

TSH spot (mu/l )

Birth weight (g)

Gestational age (weeks)

Clinical score

27*16.7** ((22)

248.3k113.1 (22)

2880&740* (22)

38.4+3.3* (21)

2.5 f 1.6 10.2& 12.7 (21) (11)

36k33.1 (18)

210.9+118 (44)

3300*445 (44)

40.7+ 1.0 (44)

2.8k1.7 (44)

26k22.5 (42)

Group 2 ~43.8+27 ((44)

Epiphyseal surface (mm?

26.2&44 (33)

Onset of treatment (days)

Values in parentheses represent the number of cases. * P
age at onset of treatment was later in group 1 infants (Table 2). Neither of these differences was significant. The clinical score at diagnosis [8], family history of thyroid disease and the socioeconomic status were essentially the same in the two groups.

4. Discussion Our results are consistent with the high incidence of congenital abnormalities that have been reported in previous studies in CH from newborn screening (Table 3). In

100 493 1538 297 100 243 25 235

malformations

Femhoff et al. (1987) Grant et al. (1988) Lazarus et al. (1988) N Engl Collab (1988) Rosenthal et al. (1988) Siebner et al. (1992) Majeed-Saidan et al. (1993) Our study

of congenital

No. of CH infants examined

data on incidence

Ref.

Table 3 Published hypothyroidism

23 36 123 22 9 38 6 22

CH infants with malformations

in congenital

23.0 7.3 8.0 7.4 9.0 15.6 24.0 9.4

(“W

Prevalence

(CH)

13 6 35 7 3 14 4 8

Cardiac malformations

13.0 1.2 2.3 2.4 3.0 5.8 16.0 3.4

Prevalence of cardiac malformations

(%)

A. Casio

et al.lScreening

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129

our study, we examined a homogeneous and quite numerous sample of population, that was evaluated by means of detailed clinical data and uniform criteria. Furthermore, the Congenital Malformations Registry established in the EmiliaRomagna Region enabled us to compare this sample with a newborn control population from the same area in the same period and examined with the same criteria. Table 3 shows that most studies report similar incidences of abnormalities [2-6, and our study], although differing in the populations examined and in the methodology used. The higher frequencies observed by Majeed-Saidan et al. [7] and Fernhoff et al. [ 1] may be related to the relatively small number of subjects examined and to the incl-usion of preterm infants with isolated patent ductus arteriosus, which many authors consider secondary to prematurity [4]. It is important to emphasize that in all reports the most frequent malformations noted were cardiac. In many reports [ 1,2,4,6] including ours, digestive system malformations (particularly esophageal atresia and cleft palate) were also more frequent. That thlcse anomalies are in tissues derived from embryological or anatomical areas adjacent to the embryonal thyroid gland may be consistent with the hypothesis that the thyroid dysgenesis and the other malformations express a common teratogenic insult in early gestation. Contrary to this hypothesis, however, some authors report the absence of specific or common patterns of extrathyroid abnormalities and a significant number of patients with genetically determined dyshormonogenesis and other congenital conditions [ 1,4,6]. Probably, many pathogenetic mechanisms may be involved. Contrary to the results of Fernhoff et al. [l] and in agreement with Grant et al. [ 111, th’e lower T4 concentrations in patients with congenital anomalies (Table 2) suggests, that the mean severity of fetal hormonal deficiency is greater in patients with associated anomalies. Also, the frequency of RDS appears tendentiously higher in this group of patients and thyroid hormone is known to play an important role in the maturation of the fetal lungs [ 11. In addition, the low birth weight and/or prematurity in our patients represents an atypical feature in CH. Therefore, in our opinion., there should be a greater suspicion of congenital anomalies when these ‘risk factors’ are found. Finally, since the presence of associated anomalies in CH patients are often responsible for neonatal complications that sometimes delay collection of the newborn screening specimen, we urge that particular care be taken to collect the specimen in all neonates without delay so that treatment in those affected by CH can begin promptly.

References [l]

Fem:hoff PM, Brown AL, Elsas LJ. Congenital hypothyroidism: results in delayed treatment. Lancet 1987; i: 490. [2] Grant DB, Smith I. Survey of neonatal screening for primary and Northern Ireland 1982-4. Br Med J 1988; 296: 1355.

increased

risk of neonatal

hypothyroidism

morbility

in England,

Wales

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[3] Lazarus JH, Hunghes IA. Congenital abnormalities and congenital hypothyroidism.

[4] [S] [6] [7] [8]

[9]

[lo]

[ 1I]

Lancet 1988; i: 52. New England Congenital Hypothyroidism Collaborative. Congenital concomitants of infantile hypothyroidism. J Pediatr 1988; 122: 244. Rosenthal M, Addison GM, Price D. Congenital hypothyroidism: increase incidence in Asian families. Arch Dis Child 1988; 63: 790. Siebner R, Merlob P, Kaiserman I, Sack J. Congenital anomalies concomitant with persistent primary congenital hypothyroidism. Am J Med Genet 1992; 44: 57. Majeed-Saidan MA, Joyce B, Khan M, Hamam HD. Congenital hypothyroidism: the Riyadh Military Hospital experience. Clin Endocrinol 1993; 38: 191. Cassio A, Missiroli G, Piazzi S, et al. Rapport0 fra gravita’ dell’ipotiroidismo congenito e sviluppo psicomotorio in un gruppo di soggetti individuati mediante lo screening neonatale. Riv Ital Ped (IJP) 1986; 12: 133. Tato’L, Chiesa M, Zamboni G. Unexpected lesson from Chernobyl. Lancet 1987; i: 803. Calzolari E, Cavazzuti GB, Cocchi G, et al. Congenital malformations in 100 000 consecutive birth in Emilia Romagna Region Northern Italy: comparison with the EUROCAT data. Eur J Epidemiol 1987; 3: 423. Grant DB, Smith I, Fuggle PW, Tokar S, Chapple J. Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features. Arch Dis Child 1992; 67: 87.