Neonatal Autoimmune Diseases: Neonatal autoimmune thyroid disease

Neonatal autoimmune diseases are distinctly rare. Most neonatal autoimmune diseases result from the transplacental transfer of maternal antibodies directed against fetal or neonatal antigens in various tissues.

The majority of thyroid diseases in pregnant women can be effectively treated and usually do not pose any risk of a fetal and neonatal thyroid dysfunctions that would be higher as compared to general population. A negative effect of a thyroid disease most commonly occurs when the condition is not properly diagnosed and treated or the mother develops an autoimmune disease. Although thyroid dysfunction in neonates associated with maternal thyroid diseases in pregnancy are not common, they may be life-threatening and associated with a risk of irreversible CNS damage. Therefore, appropriate diagnostic and management of maternal thyroid disease throughout pregnancy followed by appropriate management of a newborn is essential in the prevention of undesirable neonatal outcomes.

Thyroid hormones have been shown to be absolutely necessary for early brain development. During pregnancy, both maternal and foetal thyroid hormones contribute to foetal brain development and maternal supply explains why most of the athyreotic newborns usually do not show any signs of hypothyroidism at birth. Foetal and/or neonatal hypothyroidism is a rare disorder. Its incidence, as indicated by neonatal screening, is about 1:4000. Abnormal thyroid development (i.e. agenesia, ectopic gland, hypoplasia) or inborn errors in thyroid hormone biosynthesis are the most common causes of permanent congenital hypothyroidism. Recent studies reported that mutations involving Thyroid Transcriptor Factors (TTF) such as TTF-1, TTF-2, PAX-8 play an important role in altered foetal thyroid development. Deficiency of transcriptor factor (Pit-1, Prop-1, LHX-3) both in mother and in the foetus represents another rare cause of foetal hypothyroidism. At birth clinical picture may be not always so obvious and typical signs appear only after several weeks but a delayed diagnosis could have severe consequences consisting of delayed physical and mental development. Even if substitutive therapy is promptly started some learning difficulties might still arise suggesting that intrauterine adequate levels of thyroid hormones are absolutely necessary for a normal neurological development. Placental transfer of maternal antithyroid antibodies inhibiting fetal thyroid function can cause transient hypothyroidism at birth. If the mother with thyroid autoimmune disease is also hypothyroid during pregnancy and she doesn’t receive substitutive therapy, a worse neurological outcome may be expected for her foetus. Foetal and/or neonatal hyperthyroidism is a rare condition and its incidence has been estimated around 1:4000-40000, according to various authors.

The most common causes are maternal thyroid autoimmune disorders, such as Graves’ disease and Hashimoto’s thyroiditis. Rarer non autoimmune causes recently identified are represented by TSH receptor mutations leading to constitutively activated TSH receptor. Infants born to mothers with Graves’ history may develop neonatal thyrotoxicosis. Foetal/neonatal disease is due to transplacental thyrotrophin receptor stimulating antibodies (TRAb) passage. It’s extremely important recognizing and treating Graves’ disease in mothers as soon as possible, because a thyrotoxic state may have adverse effects on the outcome of pregnancy and both on the foetus and newborn. Thyrotoxic foetuses may develop goitre, tachycardia, hydrops associated with heart failure, growth retardation, craniosynostosis, increased foetal motility and accelerated bone maturation.

Neonatal Graves’ disease tends to resolve spontaneously within 3-12 weeks as maternal thyroid stimulating immunoglobulins are cleared from the circulation but subsequent development may be impaired by perceptual motor difficulties. Hashimoto’s thyroiditis is a very common autoimmune thyroid disease. In presence of maternal Hashimoto’s thyroiditis, there are usually no consequences on foetal thyroid, even if antiTPO and antiTg antibodies can be found in the newborn due to transplacental passage. However there are some literature reports describing foetal and neonatal hyperthyroidism in the affected mothers’ offspring.

While autoantibodies have been detected in patients with neonatal autoimmune disease, the pathogenic role of autoantibodies has not been well defined. Other mechanisms may play a role in the development of neonatal autoimmunity, including fetal/maternal microchimerism and aberrant apoptosis of fetal cells.

The pathophysiologic basis for the development of neonatal autoimmunity is not entirely clear, but differences in the neonatal immune system compared with the adult immune system, as well as unique characteristics of target antigens in the newborn period may be important factors.

The autoinflammatory syndromes are a completely different category, but are also included in discussion of neonatal autoimmune diseases. The autoinflammatory syndromes include which all share a common pathophysiologic mechanism.

Neonatal autoimmune diseases involving the interaction between maternal antibodies and fetal/neonatal antigens include neonatal lupus, neonatal anti-phospholipid syndrome, Behcet’s disease, neonatal autoimmune thyroid disease, neonatal polymyositis and dermatomyositis, neonatal scleroderma and neonatal type I diabetes mellitus.

The autoinflammatory syndromes include :

1. The cryopyrin associated periodic syndromes (CAPS)
2, Familial cold autoinflammatory syndrome (FCAS)
3. Neonatal onset multisystem inflammatory disease (NOMID)
4. Muckle-Wells syndrome, which all share a common pathophysiologic mechanism.

Neonatal autoimmune thyroid disease
Neonatal autoimmune diseases are distinctly rare. Most neonatal autoimmune diseases result from the transplacental transfer of maternal antibodies directed against fetal or neonatal antigens in various tissues. In neonatal lupus, the heart seems to be particularly susceptible. Primary autoimmunity in newborns, with the exception of familial autoinflammatory diseases, is virtually non-existent. The pathophysiologic basis for the development of neonatal autoimmunity is not entirely clear, but differences in the neonatal immune system compared with the adult immune system, as well as unique characteristics of target antigens in the newborn period may be important factors. Neonatal lupus is the most common presentation of autoimmunity in the newborn. But the characteristics defining neonatal lupus are not well defined and the presentation of neonatal lupus differs from that of classical lupus. Other neonatal autoimmune diseases involving the interaction between maternal antibodies and fetal/neonatal antigens include neonatal anti-phospholipid syndrome, Behcet’s disease, neonatal autoimmune thyroid disease, neonatal polymyositis and dermatomyositis, neonatal scleroderma and neonatal type I diabetes mellitus. While autoantibodies have been detected in patients with neonatal autoimmune disease, the pathogenic role of autoantibodies has not been well defined. Other mechanisms may play a role in the development of neonatal autoimmunity, including fetal/maternal microchimerism and aberrant apoptosis of fetal cells.

The autoinflammatory syndromes are a completely different category, but are also included in discussion of neonatal autoimmune diseases. The autoinflammatory syndromes include the cryopyrin associated periodic syndromes (CAPS) – familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID) and Muckle-Wells syndrome, which all share a common pathophysiologic mechanism.

Mothers affected by autoimmune thyroiditis

During pregnancy there are many physiological changes of maternal thyroid function. Hypothyroidism has been reported in around 2.5% of otherwise normal pregnancies. Hypothyroidism, if undiagnosed and untreated, could cause not only obstetric complications, such as hypertension, placental abruption, preterm delivery, low birth weight, but also exposes fetus to low thyroid hormone levels. The lack of maternal thyroid hormone during early pregnancy might have some irreversible effects on fetal development. It is now clear that there is a close relationship between maternal thyroid deficiencies and the neuropsychological development of her child. Several studies demonstrated that maternal hypothyroidism was associated with impaired psychomotor and intellectual development of the child . In order to reproduce the physiologic changes of thyroid function during gestation, women with known hypothyroidism and receiving L-thyroxine before pregnancy should increase their dosage by 30% to 60% during pregnancy .

The most common cause of hypothyroidism during gestation is autoimmune thyroiditis, which is characterised by the presence of specific thyroid autoantibodies. The presence of thyroid peroxidase antibodies (TPOAb) is frequent associated to thyroiditis in women of childbearing age; TPOAb have been found in 10% of women during or shortly after pregnancy. Dussault et al reported that there is no correlation between the presence of maternal antimicrosomal antibodies and congenital hypothyroidism; a further study conducted in Quebec in 1999 demonstrated an increased prevalence of transient congenital hypothyroidism associated with maternal autoimmune thyroid disease, particularly antimicrosomal autoantibodies were found in 77% of mothers of infants with transient congenital hypothyroidism. Furthermore, the presence of maternal TPOAb with normal maternal thyroid function has been described in association with impaired neuropsychological development during early childhood.

Autoimmune thyroiditis characterised by the presence of TSH receptor antibodies is a less frequent disorder and its incidence in pregnancy is not well known. Maternal-to-fetal transfer of TSH receptor-blocking antibodies can lead to a rare condition of transient congenital hypothyroidism. The incidence of this disorder in North America is 1 in 180.000 normal infants, or approximately 2% of babies with congenital hypothyroidism[; Prospective studies about thyroid function in neonates born from mothers affected by autoimmune thyroiditis are not available in literature; in particular is not yet known if maternal thyroiditis could influence thyroid hormone levels of the neonate in the first period of life. Even if cases of CH related to the presence of maternal TSH-receptor antibodies are well documented in literature as noted above, data about the exact impact of maternal TPO-antibodies on neonatal thyroid function are not available.

The importance of thyroid function monitoring in the first months of life.

Evaluation of thyroid function in neonates born from mothers affected by autoimmune thyroiditis in order to define if a precise follow-up is necessary for these children. The influence of maternal thyroid peroxidase antibody (TPOAb) and L-thyroxine therapy during pregnancy on neonatal thyroid function was also investigated.

Transient mild elevation of serum TSH above the normal reference value for age is frequently observed in the first month of life in infants born from mothers affected by autoimmune thyroiditis. Persistent hyperthyrotropinemia requiring replacement therapy is observed in 2.2% of these neonates. According to our experience, follow-up is recommended in these newborns; the most accurate and not invasive way to carefully monitor these infants after neonatal screening for CH seems to be serum-testing TSH between 2nd and 4th week of life.

Intractable neonatal seizures: an unusual presentation of congenital hypothyroidism.

Congenital hypothyroidism is the most common treatable cause of mental retardation. Sutsko reported an unusual case of congenital hypothyroidism presenting as intractable seizures in an infant delivered to a mother known to have autoimmune hypothyroidism and who was noncompliant with therapy. This rare presentation of congenital hypothyroidism has not been reported previously.

References:

  • Chang C. Neonatal autoimmune diseases: A critical review. J Autoimmun. 2012 May;38(2-3):J223-38.
  • Radetti G, Zavallone A, Gentili L, Beck-Peccoz P, Bona G. Foetal and neonatal thyroid disorders. Minerva Pediatr. 2002 Oct;54(5):383-400.
  • Kumorowicz-Czoch M, Starzyk J. A neonate born to a mother with thyroid disease–safe or at risk?. Przegl Lek. 2010;67(11):1205-9.
  • Rovelli R, Vigone MC, Giovanettoni C, Passoni A, Maina L, Corrias A, Corbetta C, Mosca F, Chiumello G, Weber G. Newborn of mothers affected by autoimmune thyroiditis: the importance of thyroid function monitoring in the first months of life. Ital J Pediatr. 2010 Mar 10;36:24.

 

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