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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 2009-2013
Copyright © 2003 by The Endocrine Society

Sex-Specific Impact of Congenital Hypothyroidism due to Thyroid Dysgenesis on Skeletal Maturation in Term Newborns

Guy Van Vliet, Béatrice Larroque, Lida Bubuteishvili, Karine Supernant and Juliane Léger on behalf of the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant

Service d’Endocrinologie Pédiatrique (G.V.V., L.B., J.L.), Hôpital Robert Debré, 75019 Paris, France; and Institut National de la Santé et de la Recherche Médicale U149, Recherche Épidémiologique en Santé Périnatale et Santé des Femmes (B.L., K.S.), 94800 Villejuif, France

Address all correspondence and requests for reprints to: Guy Van Vliet, M.D., Service d’Endocrinologie, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal H3T 1C5, Québec, Canada. E-mail: gvanvliet{at}justine.umontreal.ca.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Newborns with severe congenital hypothyroidism (often defined by the absence of knee epiphyses at diagnosis) are still at risk of loss of intellectual potential despite early treatment. Although there is no significant sexual dimorphism in the age at appearance and size of the knee epiphyses in normal newborns, it was our clinical impression that these epiphyses were more often absent in hypothyroid newborn males than in affected females. Using the large French database of congenital hypothyroidism, we studied the presence or absence of knee epiphyses at diagnosis, as well as the length of gestation and the birth weight of 1827 term newborns with athyreosis or ectopic thyroid. Boys were twice as likely as girls to have absent epiphyses [odds ratio, 2.1 (95% confidence interval, 1.6–2.7), P < 0.001, after adjustment for etiology, plasma free T4 concentration, and presence or absence of clinical signs at diagnosis, gestational age and birth weight]. Compared with the general population of French newborns, those with congenital hypothyroidism were more often born after a prolonged gestation (>=42 wk) and with a high birth weight (9% were above the 95th centile, as opposed to the expected 5%), regardless of sex. We conclude that the impact of congenital hypothyroidism on fetal skeletal maturation is sexually dimorphic. This may result from less efficient conversion of T4 to T3 by growth plate chondrocytes in males.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PERMANENT PRIMARY HYPOTHYROIDISM is the most common congenital endocrine disorder. Its most tragic potential consequence, the irreversible mental deficiency state known as cretinism, is effectively prevented by systematic biochemical screening of newborns, which allows treatment to be started before overt clinical manifestations develop (1, 2). Because biochemical screening of newborns for congenital hypothyroidism (CH) has been such a public health success (3), relatively little attention has been paid in recent years to the other aspects of this condition at the time of presentation, such as its association with prolonged gestation, high birth weight, and delayed bone maturation.

All studies of intellectual outcome since screening began have found that children with severe CH at diagnosis, although their mean IQ is in the normal range, may suffer a loss of intellectual potential compared with siblings or with other appropriate controls (4, 5). A widely used criterion for defining severity of CH at diagnosis in a term newborn is the absence of knee epiphyses on x-ray (6, 7, 8). Indeed, thyroid hormone insufficiency does not retard fetal growth in humans but may lead to delayed bone maturation; the finding of a prenatal bone age at diagnosis of CH is common and indicates that hypothyroidism has started before birth (9).

In normal children, females mature earlier than boys in many body functions, and this difference is classically considered to be already present at the time of birth (10). However, studies of overall skeletal maturation before birth in normal fetuses have generally led to the conclusion that, although girls are indeed ahead of boys, this difference does not reach statistical significance (11). As regards the knee epiphyses in particular, a recent study using ultrasound has confirmed the absence of a significant sexual dimorphism in the age of appearance and in the height of the distal femoral epiphysis in normal newborns (12).

In CH newborns, it was our clinical impression that the absence of radiologically visible knee epiphyses in a term newborn was noted more often in boys than in girls. The purpose of the present study was to validate this impression and to evaluate the impact of CH on length of gestation and birth weight using the large database maintained by the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant (AFDPHE) since neonatal screening for CH began in France.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Screening for CH in France is based on the measurement of TSH on dried blood spots at 3 d of age. After several regional pilot programs, screening became mandated on a nationwide basis in 1979. From the beginning of TSH screening, the AFDPHE has asked all physicians who take care of newborns with CH to complete a form containing the following information: sex, gestational age, birth weight, whole blood TSH at screening and plasma TSH at diagnosis, plasma T4 (total or free T4) at diagnosis, presence or absence of symptoms and signs suggestive of CH (defined as three or more of the following: constipation, physical inactivity, prolonged icterus, mottled skin, macroglossia, umbilical hernia, hypotonia, coarse facies), presence or absence of the epiphyses of the knee, etiological diagnosis on the basis of a nuclear medicine scan (with 99mTechnetium or 123Iodine), and age when treatment was begun. The type of CH was entered as follows: ectopic thyroid, athyreosis, goiter or thyroid dyshormonogenesis, transient hypothyroidism, or unknown.

As of December 31, 2000, the AFDPHE database contained information on 4771 CH newborns. The inclusion criterion for the present study was that complete information about the presence or absence of the distal femoral epiphysis and of the proximal tibial epiphysis and the sex of the baby had been reported by the treating physician. This was the case for 3273 newborns. All individual patient forms were reviewed by two of the investigators (L.B. and G.V.V.). To deal with as homogeneous a group as possible, there were several exclusion criteria: 1) cases with an orthotopic gland of normal (104 girls and 111 boys) or increased (213 girls and 206 boys) size; these were excluded because the severity of CH is generally less in this category with presumed dyshormonogenesis (13) and because, in the vast majority of these, there was no information in the database as to whether the problem was permanent or transient; 2) documented transient CH (43 girls and 51 boys); 3) etiological diagnosis not specified (50 girls and 37 boys); 4) a scintigraphic diagnosis of athyreosis, but with plasma hormone concentrations at diagnosis of less than 50 mIU/liter for TSH and of more than 5 pmol/liter for free T4 (7 girls and 1 boy); 5) gestational age not reported (636 girls and 371 boys) or preterm (<37 wk; 69 girls and 39 boys); the latter criterion was chosen because the distal femoral epiphysis is present in about 75–85% of normal newborns after 37 wk but is frequently absent at younger ages (14, 15); or 6) unusually late age at start of treatment (greater than 40 d; 109 girls and 53 boys). Some patients had more than one exclusion criterion. Thus, 1827 patients with CH due to thyroid dysgenesis (CHTD; athyreosis or ectopy) and complete data remained for analysis.

All plasma T4 values were converted to SI units. During the 1980s, the measurement of total T4 was progressively replaced by that of free T4. Total T4 concentrations were converted to free T4 concentrations by the equation of Tillotson et al. (16). Free T4 values of less than 1 pmol/liter were considered undetectable and assigned a value of 1 pmol/liter. Because plasma free T4 concentrations were not normally distributed, they were log-transformed before statistical analysis.

The hypothesis that the ossification centers of the knee were more frequently absent in CHTD boys than in CHTD girls was explored by {chi}2 analysis. This analysis was next adjusted for severity of CH assessed by etiology (athyreosis vs. ectopy), plasma free T4 at diagnosis (above or below the mean value for the whole cohort), presence or absence of clinical signs, gestational age, and birth weight. The odds ratio and confidence intervals for males having more often than females a severe delay in bone maturation as assessed by absence of both knee epiphyses were calculated and adjusted for severity of CH according to the criteria mentioned above.

The percentage of CH children born at 42 wk gestation or more was compared with that observed in the general population of term children using the data from the French National Perinatal Study, which included 1 wk of births in all maternities in France in 1981 and in 1995 (17). The impact of fetal hypothyroidism on birth weight was evaluated by comparing, by {chi}2 analysis, the observed vs. expected percentages of the CH cohort falling in given centile categories for gestational age and sex calculated for French newborns (18).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Table 1Go shows the clinical and biochemical characteristics of the patients according to etiology of CH and sex. As is known for thyroid dysgenesis in general, there was a predominance of females; in more recent cohorts, this female predominance has been found to be more pronounced for ectopy than for athyreosis (19, 20, 21), but this was not the case for the AFDPHE database. The percentage of CH patients born after a gestation of 42 wk or more was not significantly influenced by sex and etiology, but it appeared higher than in the general population in France; between 1981 and 1995, the percentage of term babies delivered after a gestation of at least 42 wk decreased from 11.4% to 1.6% (17); by contrast, the percentage of term CHTD babies born at 42 wk gestation or more was about 10% over the whole period studied and was still 6.0% for the years 1994–1996. Newborns with athyreosis more often had clinical signs and had higher plasma TSH and lower plasma free T4 at diagnosis than those with ectopic tissue. These differences held true after correction for sex, i.e. the clinical and biochemical severity of hypothyroidism was related to the etiology but not to the sex of the newborn. Lastly, the age at which the knee x-ray was taken did not differ significantly by sex or etiology.


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  		Table 1. Clinical and biochemical characteristics of the 1827 CHTD newborns studied

 
Table 2Go gives the percentage of patients with zero, one, or two visible knee epiphyses by sex and by various estimates of severity of CH. Forty percent of the boys, as opposed to only 28% of the girls, had no visible epiphysis, thus confirming the clinical impression that was the impetus for the present study. The number of knee epiphyses was significantly related to sex, severity of CH assessed by etiology (athyreosis vs. ectopy), level of plasma free T4 (less than vs. equal or greater than the mean values for the whole cohort), and presence or absence of clinical signs (all P < 0.001).


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  		Table 2. Number of knee epiphyses in term CHTD newborns by sex and by estimates of severity of hypothyroidism

 
Table 3Go gives the odds ratio (with 95% confidence intervals) for having absent epiphyses by sex, adjusted for etiology, plasma free T4, and clinical signs at diagnosis, gestational age, and birth weight. Even after adjustment for potential confounders, the odds ratio of having absent epiphyses for boys vs. girls was 2.1 (95% confidence interval, 1.6–2.7; P < 0.001). Having absent epiphyses was also more likely in athyreosis, compared with ectopy, in newborns with lower free T4, clinical signs, shorter length of gestation, or lower birth weight. Figure 1Go shows that the percentage of CHTD boys who had absent epiphyses was greater than that of CHTD girls at all gestational ages. In fact, the percentage of boys with absent knee epiphyses went up after 40 wk.


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  		Table 3. Adjusted odds ratio for having absence of both epiphyses in term CHTD newborns

 


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  		Figure 1. Percentage of CHTD newborns with absent knee epiphyses as a function of gestational age. The number of individuals with absent knee epiphyses is indicated above each bar.

 
Table 4Go shows that, although the lower half of the distribution of the birth weight centiles of the term CH newborns (stratified by sex and gestational age) did not differ from that of the general population (18), the upper half did; overall, 14% of CHTD newborns were above the 90th centile for weight (as opposed to the expected 10%), and 9% were above the 95th centile (as opposed to the expected 5%). Interestingly, in view of the sex-specific impact of CHTD on fetal bone maturation, this tendency toward high birth weight was similar in boys and girls.


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  		Table 4. Distribution of birth weight in CHTD

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our review of a large database of newborns with CHTD has revealed novel findings that have potentially important biological and clinical implications. First, it confirmed our clinical impression that the impact of CHTD on fetal bone maturation is sex-specific; CHTD boys are twice more likely than girls to have absent knee epiphyses at diagnosis. This is not related to different proportions of athyreosis vs. ectopy or to differences in biochemical severity of hypothyroidism at diagnosis. Moreover, the clinical manifestations of CHTD and the impact of CHTD on length of gestation and birth weight did not differ significantly between boys and girls. Lastly, the sex difference in bone maturation was apparent at all gestational ages studied. Thus, the sexual dimorphism of the impact of CHTD is highly specific for fetal bone maturation. Because of this high specificity, a general mechanism such as more efficient transplacental transfer of maternal T4 (22) to a female than to a male fetus with CHTD seems unlikely, and local mechanisms at the level of the fetal growth plate need to be considered.

The effect of the prohormone T4 in tissues is modulated through its local intracellular conversion to either the biologically active T3 by the deiodinase enzymes type I and II or the inactive rT3 by deiodinase type III (23). Interestingly, type II and III deiodinase expression by cultured growth plate chondrocytes has very recently been reported in abstract form (24). In view of our clinical findings, it would be worthwhile to examine whether the expression of these deiodinases is sexually dimorphic in fetal chondrocytes. It is also noteworthy that, in his landmark studies of CH in the prescreening era, Andersen (25) found that diagnosis by clinical signs before the age of 6 months was made more often in boys. We did not find a significant difference in the frequency of clinical signs in the present cohort of CH children diagnosed by screening and examined at a mean age of 16–18 d. Therefore, Andersen’s data may suggest that there is a general delay in the early postnatal maturation of peripheral deiodination of T4 to T3 in boys. Along this line, it would be interesting to evaluate whether hypothyroidism acquired later during childhood has a more profound impact on the bone maturation of affected boys.

The second important finding in our study is that CHTD is associated with prolonged gestation and high birth weight, but not with low birth weight. This confirms the results of our recent study suggesting that permanent CHTD is not more prevalent in low birth weight newborns (26). Thus, the U-shaped curve between birth weight and risk of CH reported by Waller et al. (27) likely reflects cases of transient CH in the low birth weight category; unlike us, Waller et al. had no information on the etiology of the CH cases they studied. The focus of recent research on the endocrine control of parturition and of fetal growth has been on preterm births and low birth weight (28), and the mechanisms underpinning the prolonged gestation and high birth weight of CHTD babies remain elusive. However, regardless of the mechanisms involved, our clinical findings have potential practical implications.

First, studies of developmental outcome of CHTD children using the absence of knee epiphyses as the only criterion of severity of hypothyroidism at diagnosis may result in a disproportionate number of males being labeled severe. The sex ratio in the severe CH group would therefore be different from the CH group as a whole. Given that learning disorders occur with a higher frequency in boys in the general population (29), this may in turn lead to a bias incorrectly ascribing learning problems to CH. This emphasizes the need to adjust for sex in studies of developmental outcome in CH. When this is done, the impact of CH on intellectual development does not appear different in boys and girls (8), suggesting that the mechanisms whereby the fetal brain is somewhat protected against hypothyroidism (such as the up-regulation of brain type II deiodinase) is equally efficient in both sexes, in contrast to those in the growth plate or in other peripheral tissues.

Second, given the importance of starting treatment very early in severe CH (30), we would like to suggest than in a newborn with unexplained postmaturity and high birth weight, it might be worthwhile to perform an ultrasound of the knee, followed by an immediate determination of plasma TSH if the knee epiphyses are absent; this would allow treatment of children with severe CH within 24–48 h of birth and prevent the loss of intellectual potential that can otherwise still be seen in these children. Postmaturity in general is not associated with increased birth weight; rather, birth weight tends to decrease after 42 wk (18). On the other hand, most pathological conditions associated with delayed bone maturation in a neonate are also associated with decreased, rather than increased birth size (14). However, only prospective studies will determine how many cases of severe CH could be detected in newborns with unexplained high birth weight, postmaturity, and delayed bone maturation.

In summary, CHTD boys are twice as likely as CHTD girls to have no visible knee epiphyses at diagnosis. In contrast, the association of CHTD with prolonged pregnancy and with high birth weight is similar in boys and in girls. Further research is needed to understand the biological mechanisms underlying these phenomena.


   Acknowledgments
 
The support of Professors Paul Czernichow and Jean-Pierre Farriaux is gratefully acknowledged. This study was made possible by the contributions of a large number of physicians to the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant database.


   Footnotes
 
G.V.V. was supported by the Conseil National des Universités (France) as Professeur Associé at Université Paris VII-Denis Diderot and by the sabbatical leave program of the European Society for Paediatric Endocrinology (funded by Eli Lilly \|[amp ]\| Co.).

Abbreviations: CH, Congenital hypothyroidism; CHTD, CH due to thyroid dysgenesis.

Received November 6, 2002.

Accepted February 3, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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