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Academic Medical Center, Emma Children’s Hospital, Department of Pediatric Endocrinology, University of Amsterdam, 1100 DE Amsterdam, The Netherlands
Address all correspondence and requests for reprints to: Marlies J. E. Kempers, M.D., Academic Medical Center, University of Amsterdam, G8-205, Emma Children’s Hospital AMC, Department of Pediatric Endocrinology, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: m.j.kempers{at}amc.uva.nl.
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Abstract |
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Introduction |
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In case of maternal gestational autoimmune Graves’ disease, the preservation of a normal fetal thyroid hormone state to ensure normal brain development is a complex issue. Dependent on the presence of antithyroid antibodies, the use of antithyroid drugs, and the maternal thyroid hormone state, the fetal and neonatal thyroid function can be disturbed with high variability in type of effects as well as in severity (7, 8, 9, 10, 11). Remarkably, only a minority of newborns from mothers with gestational autoimmune thyroid disease demonstrates a disturbed thyroid hormone state (8, 12, 13, 14). A probably undervalued risk is the occurrence of central CH, in infants of mothers with Graves’ disease, first described in 1988 by Matsuura et al. (7). The published reports on this condition suggest a rare occurrence (7, 8, 12, 15, 16, 17, 18, 19, 20, 21), but because of its clinical course, we speculate that it often remains unrecognized unless it is given specific attention.
Because the Dutch T4-based neonatal CH screening also detects congenital hypothyroidism of central origin, we explored this issue. The case histories of 18 infants with central CH, born to 17 mothers with untreated or inadequately treated Graves’ disease are presented.
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Materials and Methods |
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The Department of Pediatric Endocrinology in the Emma Children’s Hospital Amsterdam Medical Center functions as a national center for consultation on diagnostics and treatment of children with thyroid diseases. Since the start of the Dutch CH screening, the department has been involved in at least half of all cases of CH. In 1994 the first patient with central CH born to a mother with Graves’ disease was recognized and since 1999, 19 more children were diagnosed. Detailed information could be retrieved from 18 patients.
Neonatal screening
The Dutch screening, performed 4 to 7 d after birth, is based on measurement of T4 in filter paper blood spots. T4 concentrations are compared with the day mean and expressed as SD scores. If heel puncture blood spot concentration of T4 is -0.8 SD or less, TSH is additionally measured in the blood spot. If T4 is -1.6 SD or less, TSH and T4-binding globulin concentration are additionally measured in the blood spot. Depending on T4, and if measured TSH and T4-binding globulin concentrations, the test is interpreted as abnormal, borderline, or normal. Children with borderline tests undergo a second screening. Children with one abnormal test (T4 
-3.0 SD and/or TSH 
50 mU/liter) or two consecutive borderline tests (T4 moderately decreased, not caused by T4-binding globulin deficiency and/or TSH moderately increased) are referred to a pediatrician. This method enables detection of CH of thyroidal origin (decreased T4, elevated TSH concentration) and central origin (decreased T4, not caused by T4-binding globulin deficiency with normal TSH concentration).
Diagnosis of CH of central origin
The criteria for diagnosis of central CH are a free T4 concentration of less than 0.9 ng/dl (<12 pmol/liter) in combination with a TSH concentration of less than 20 mU/liter and at least one other entity that suggests disintegrity of the thyroid’s regulatory system (e.g. abnormal response to TRH administration, multiple pituitary hormone deficiencies, anatomical abnormalities on brain magnetic resonance imaging, mutations in genes involved in embryogenesis, or function of hypothalamus or pituitary).
Diagnosis of maternal thyroid disease
Based on the moment the diagnosis of maternal Graves’ disease is made, three groups were composed: group A, after delivery, group B, during pregnancy, and group C, before pregnancy. Because all mothers were supposedly hyperthyroid during (part of) pregnancy, the maternal condition was defined as gestational hyperthyroidism; the fetal condition was defined as hyperthyroid fetal environment.
Laboratory measurements
The plasma free T4 and plasma TSH concentration were measured by time-resolved fluoroimmunoassays (Delfia Free T4 and Delfia hTSH Ultra, Wallac Oy, Turku, Finland). The free T4 normal range at the age of 2–3 wk is 0.9–2.3 ng/dl (12–29 pmol/liter) (22, 23). The TSH normal range at the age of 0–3 months is 1–10 mU/liter (22, 23), thereafter 0.4–4.0 mU/liter. TSH receptor antibodies were measured using the TRAK assay (Brahms, Berlin, Germany) either with radioactive label or by luminescence.
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Results |
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Group A.
Mothers A1–9 were diagnosed with hyperthyroidism because of Graves’ disease during the first weeks after delivery (Table 1
), seven of them after their children were diagnosed with central CH. Mother A4 was diagnosed a few days after delivery because she experienced tachycardia; simultaneously her daughter was referred to the pediatrician because of an abnormal CH-screening result. Mother A9 was diagnosed 2 wk after delivery, after she encountered problems with breast-feeding. No information was available on maternal thyroid function during pregnancy, except that mother A1 had noticed a neck swelling from the third month of pregnancy.
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) and were treated since then with antithyroid drugs and propranolol. At the time of delivery, plasma free T4 concentrations had normalized, except for those of mother B4. Group C. Mothers C1–5 were diagnosed with Graves’ disease before pregnancy, but none of them was treated adequately. The mothers of children C1and C2 (twin pregnancy) and C3 stopped using antithyroid drugs in the first trimester. Mother C4 stopped using antithyroid drugs a few months before pregnancy. Only mother C5 was treated with antithyroid drugs throughout pregnancy. Plasma free T4 concentrations measured throughout pregnancy were all above 1.7 ng/dl (22 pmol/liter).
Table 1 shows that in the three groups together 44% of the parents (50% of the mothers) were not native Dutch, whereas in group A even 89% of the mothers were not native Dutch.
Table 2 shows that in the majority of the mothers TSH-receptor antibodies were present. In two subjects in whom TSH-receptor antibody measurements in the mothers were lacking, they were detectable in the children.
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Group A.
Children A1–8 were referred to the pediatrician because of abnormal CH-screening results (Table 1); child A9 was referred at the age of 4 wk after disclosure of maternal hyperthyroidism 2 wk earlier. All children had, when measured in venous blood samples, abnormally low plasma free T4 concentrations and plasma TSH concentrations within the age-specific normal range, except for child A6 whose TSH was initially suppressed (Fig. 1). The children A1 and A3–7 underwent a TRH test, demonstrating a blunted TSH response (Fig. 2). CRH tests, performed in three children, revealed normal ACTH and cortisol responses (data not shown). Because maternal hyperthyroidism was diagnosed before the diagnostic work-up was completed, investigation of the other hormonal systems were not performed. Magnetic resonance imaging of the hypothalamic-pituitary region performed in children A4and A6 showed no abnormalities.
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). In child B3 plasma free T4 was initially normal but increased to above the normal range after a few days. Without intervention plasma free T4 decreased to below the normal range within a few weeks although with suppressed TSH. In child B4 plasma free T4 was initially normal, which gradually decreased to below the normal range; plasma TSH was suppressed. TRH tests, performed in the children B2–4, showed blunted TSH responses.
Group C.
Cord blood examination in the children C1–3 and C5 showed normal plasma free T4 concentrations and low TSH concentrations (Fig. 1). Child C4 had low-normal plasma free T4 1 d after birth [1.0 ng/dl (13 pmol/liter)]; TSH was not measured. In the children C3 and C4 plasma free T4 decreased in the first week after birth; in the other children, free T4 increased initially but decreased after a few weeks below the normal range. Children C1–2 and C4–5 underwent a TRH test that showed a blunted TSH response (Fig. 2).
Treatment in children
Child A1 was not treated because his plasma free T4 concentration spontaneously normalized, already during the phase of diagnostic work-up. Although the TSH response after TRH administration was blunted in the neonatal period, the response had become normal when retested at the age of 1 yr (Fig. 2). In all other children, T4 supplementation was initiated. In child A5 T4 supplementation was interrupted at the age of 4 months; she remained euthyroid afterward. In child B1 T4 supplementation was interrupted at the age of 6 months. At the age of 1 yr, his TRH test showed a normal TSH response (Fig. 2). However, because at that time plasma free T4 concentration was below the normal range [0.8 ng/dl (10.7 pmol/liter)] with slightly increased TSH (7.1 mU/liter), T4 supplementation was restarted and has continued to date. In the other patients, the effect of interruption of T4 supplementation was not sorted out because of the potential risk of cerebral damage under the age of 3 yr.
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Discussion |
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All children developed moderately to extremely decreased neonatal free T4 concentrations in combination with normal or suppressed TSH concentrations. Most children were already hypothyroid at the first thyroid function measurements within a few days after birth, although one child became hypothyroid after a short hyperthyroid phase and six children after an initial euthyroxinemic phase. The blunted TSH response on TRH administration confirmed the disturbance of the child’s thyroid regulatory system. As shown in Fig. 1, the initiation of T4 treatment was incidentally delayed for several weeks, presumably as a consequence of the unfamiliarity with this specific thyroid entity in children of mothers with Graves’ disease.
The reported incidence of permanent central CH detected by neonatal screening in The Netherlands is around 1 in 20,000 children, i.e. about 10 patients every year (24, 25), of whom the great majority has permanent deficiency of multiple pituitary hormones. Although the Dutch T4-based screening was introduced in 1981, the first patient with central CH because of maternal gestational hyperthyroidism was detected as late as 1994. The other 17 children presented here were born over a 3-yr period since 1999; they represent an incidence of central CH because of maternal gestational hyperthyroidism of 1:35,000. However, the total number of children with central CH because of maternal gestational hyperthyroidism is probably even higher because not all patients might have come to our attention. Therefore, the total incidence of central CH in The Netherlands is at least 1 in 15,000 newborns.
For the Dutch population, accurate incidence figures of Graves’ disease during pregnancy are not available. International estimations of the incidence of Graves’ disease during gestation of about 1 in 500 (26, 27, 28, 29) indicate that about 1 in 70 women (1.5%) with Graves’ disease gives birth to a child with central CH. However, because all presented children were born to inadequately treated mothers, the risk seems to be restricted to these mothers. This implies that, within the spectrum of neonatal thyroid dysfunction related to maternal Graves’ disease, the occurrence of central CH seems of the same magnitude as that of congenital hyperthyroidism, estimated as 1–5% (26, 27, 30). Neonatal screening appeared to be indispensable in the diagnosis of at least seven mother-child pairs (i.e. 40%). However, also in the Dutch T4-based neonatal screening program, several cases might remain undetected because they became hypothyroid after an initial euthyroid or hyperthyroid phase (40% of the present cohort).
Intriguingly, an impressive percentage (44%) of the parents originated from outside The Netherlands, mostly underdeveloped countries. Especially in group A, 70% of parents (and even 90% of mothers) were not native Dutch; language problems together with the unfamiliarity with the Dutch health care system might have led to insufficient medical care.
The finding that all women with Graves’ disease who gave birth to children with central CH were inadequately treated suggests a causal relationship. We hypothesize that the maternal gestational hyperthyroidism causes a hyperthyroid fetal environment. Because substantial maternal-fetal transfer of T4 occurs in euthyroid mothers pregnant with children with thyroidal CH (3), maternal hyperthyroidism may result in increased T4 transfer. The exposure of the fetal hypothalamic-pituitary-thyroid system to higher-than-normal thyroid hormone concentrations might have impaired its physiologic maturation during intrauterine life. The system was not triggered to produce its own thyroid hormone through TSH and TRH secretion and not prepared to become self-supporting. After birth pituitary TSH secretion in response to dropping plasma (free) T4 concentrations as well as to TRH administration is inadequate; likewise, hypothalamic TRH secretion might be inadequate as well.
Hyporesponsiveness of the pituitary is also observed in adult patients with hyperthyroidism; after initiation of treatment (antithyroid drugs or 131I) and normalization of thyroid hormone concentrations, the reinstitution of adequate TSH secretion, either basal or after TRH administration, takes weeks to months (31, 32).
Other factors (putatively) involved in pituitary hyporesponsiveness during Graves’ disease are e.g. TSH-receptor antibodies occupying the pituitary TSH receptor (33) or pituitary autoantibodies associated with lymphocytic hypophysitis (34), which is especially seen in women during or shortly after pregnancy, sometimes associated with autoimmune thyroid disease. However, these factors fail to explain why central CH is strictly confined to inadequately treated maternal gestational hyperthyroidism. For the fetal thyroid system, the only relevant feature, distinguishing pregnant mothers with overt hyperthyroidism from those mothers with adequately treated Graves’ disease, is the presence of a hyperthyroid fetal environment. Therefore, it is very likely that instituting adequate maternal treatment might have prevented the central CH in the children we studied.
According to reports in literature (8, 15, 17, 18, 19, 20) discussing the course of central congenital hypothyroidism related to maternal Graves’ disease, this type of central CH has a transient expression; thyroid hormone concentrations remain within the normal range after withdrawal of T4 treatment or the TSH response in response to TRH administration normalizes. In one of our patients who demonstrated a spontaneous normalization of free T4 concentration, the TSH response to TRH administration became normal within a year. In two other patients, interruption of T4 supplementation was evaluated: One remained euthyroid and the other became hypothyroid within a few months, despite a normal TRH test result. At the moment we cannot exclude that subtle changes in the thyroid regulatory system may persist. The hypothesized overexposure of the fetal hypothalamic-pituitary-thyroid system to thyroid hormone might have permanently altered the tuning of the pituitary set point of TSH secretion. Consequently, plasma free T4 and TSH concentrations, albeit in the normal range after interruption of T4 supplementation, might differ from those of children prenatally exposed to a euthyroid environment. Animal studies suggest that short-term overexposure of neonatal rats to T4 results in permanent alterations of the hypothalamic-pituitary regulatory system (35, 36, 37). Besides, patients with CH of thyroidal origin, prenatally underexposed to thyroid hormone, need plasma free T4 concentrations in the high normal range to normalize TSH secretion during postnatal thyroxine treatment (38). This suggests that their regulation in the negative feedback system differs from children without CH.
Maternal Graves’ disease during pregnancy carries the risk of a variety of adverse effects for the offspring with a wide spectrum of abnormalities in the thyroid function. All patients presented here experienced a phase of central hypothyroidism, starting before or just after birth, which we explained by postulating a prenatal phase of hyperthyroidism that affected the thyroid’s regulatory system. Especially because both conditions are known to impair brain development (39, 40), preventive action or timely correction is important.
Certainly, the most effective management would be the preservation of euthyroidism in all pregnant women. This, however, would imply routine screening on thyroid function during gestation because at least some of the women with Graves’ disease appear to escape from recognition of this diagnosis. As long as such a preventive maternal screening method is not available, the neonatal CH screening, on the condition that it is T4 based, seems helpful to detect central congenital hypothyroidism. In the diagnostic work-up of patients with central CH, evaluation of maternal thyroid function should be incorporated.
The thyroid function of the offspring of mothers with Graves’ disease, especially those with inadequate treatment throughout pregnancy, should be controlled carefully, at least up to a few weeks after birth. If there is any doubt about the integrity of the child’s thyroid regulatory system [free T4 < 0.9 ng/dl (<12 pmol/liter) and TSH < 20 mU/liter], a TRH test should be performed. In case of a (partly) suppressed TSH response after administration of TRH, the presence of central CH is proven and T4 supplementation should be given for at least several months.
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Acknowledgments |
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Footnotes |
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Received April 16, 2003.
Accepted August 21, 2003.
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References |
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