2157 Hyperthyroidism and thyrostatics

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An uncontrolled hyperthyroidism of a pregnant woman is a risk for the outcome of pregnancy and the fetus: fetal growth retardation, pre-eclampsia, prematurity, and intrauterine death or stillbirths occur more often (Glinoer 1997). In cases of Graves' disease or Hashimoto thyroiditis - the latter usually results in hypothyroidism - the maternal auto-antibodies should be tested at the beginning of pregnancy and early in the third trimester. A high concentration, especially of TSH-receptor antibodies (TRAb), is often correlated with a diaplacental transfer of these antibodies. It is estimated that 1-2% of pregnancies with Graves' disease result in a transient hyperthyroidism of the fetus or newborn, respectively (Carrol 2005). A recently published prospective study on 115 pregnant women reports a much higher rate of 12.6% of fetal/neonatal hyperthyroidism (Rosenfeld 2005).

Pharmacology and toxicology

Propylthiouracil (PTU), carbimazole, and thiamazole (methimazole) (an active metabolite of carbimazole) arc drugs with antithyroid (thyrostatic) activity. They inhibit the synthesis of T3 and T4 by blocking the organification of iodine and the coupling of iodothyro-nine residues. All of these agents can reach the fetus.

Propylthiouracil has a higher protein-binding than the other thyrostatic substances, and presumably a lower placental transfer. However, no significant differences in neonatal thyroid function were found by several authors. With maternal daily doses up to 100 mg PTU or up to 10 mg methimazol, 21% and 14% respectively of the neonates had increased values of TSH (not significantly different) (Momotani 1997). In the study by Rosenfeld (2005) mentioned above,

9.5% of in utero PTU-exposcd children developed hypothyroidism and 5.4% also developed goiter. Not all hypothyroid neonates demonstrated goiter directly after birth: some were noted only at the screening control 2 weeks later.

Individual case descriptions led to the hypothesis that methima-zole could cause skin defects (aplasia cutis) in the fetus and other teratogenic effects like choanal atresia, esophagus atresia, tracheal esophageal fistula, hypoplastic nipples, facial dysmorphism, and psychomotoric developmental delay (Nakamura 2005, Barbcro 2004, Karg 2004. Ferraris 2003, Karlsson 2002, Clementi 1999, Wilson 1998, Hall 1997, Johnsson 1997, Vogt 1995). Foulds (2005) reviewed all the published cases and concluded that there are 16 reports regarding infants or fetuses exposed to methimazol/thiama-zol in first trimester, showing a similar pattern of malformations. He concluded that there exists a rare embryopathy.

However, multiple case collections have indicated neither morphologic developmental disturbances (Wing 1994) nor effects on the size or function of the thyroid or on the physical and intellectual development of children as a result of prenatal exposure to propylthiouracil or methimazole (Eisenstein 1992, Messer 1990). In a prospective multicenter case-control study on the outcome of 204 methimazole-exposed pregnancies, no significant total major malformation rate was reported. However, among the eight reported birth defects, there was one case of choanal atresia and one case of esophagus atresia (di Gianantonio 2001).

To date, thyrostatic drugs during pregnancy do not appear to induce a significant increase in the rate of major malformation. However, methimazole can cause a rare embryopathy with a frequency of 1:1000 to 1:10000 exposed fetuses (Cooper 2002, Diav-Citrin 2002).

Carefully adjusted thyrostatic therapy with antithyroid medications is unlikely to lead to fetal goiter in pregnancy. Earlier goiter-caused obstructions of the airways and interference with the birth process were described as a result of therapy with thyrostatics, in combination, to some degree, with high levels of iodine or with thyroid hormones.

Perchlorate is indicated only in the rare case of excessive iodine intake. Used in pregnancy, it could impair iodine transfer to the fetus.

Recommendation. Hyperthyroidism has to be treated in pregnancy. Propylthiouracil is the thyrostatic drug of choice in pregnancy, especially in the first trimester.Thiamazole (methimazole) and Carbimazole are to be considered second-choice drugs. The dose can be kept to a minimum by maintaining maternal thyroid status a little above normal. Thyrostatic therapy should not be combined with thyroxine supplementation, because this co-therapy increases the mother's thyrostatic needs. Fetal hypothyroidisms as a consequence of maternal antithyroid therapy as well as hyperthyroidism as a consequence of placental transfer of auto-antibodies In case of Graves' disease have been described. Therefore, the thyroid gland of the fetus should be monitored by ultrasound scan. The screening of thyroid parameters of the newborn is absolutely necessary, and this Is compulsory in many countries. A second evaluation of the thyroid status should be performed 2 weeks after birth in the case of Intrauterine exposure. Mild symptoms of hyperthyroidism with borderline laboratory parameters can be treated symptomatically without thyrostatics, for example with i-receptor blockers such as propranolol or metoprolol. If thiamazole (methlmazole) or carbimazole has been used during organogenesis, a detailed anatomical ultrasound examination is recommended. In cases of severe thyrotoxicosis, thyroidectomy may be indicated - even during pregnancy.

For information regarding hyperthyroidism and radioiodine therapy, see Chapter 2.20.

2.15.8 Glucocorticoids

(See also Chapter 2.3.) Pharmacology

The adrenal cortex synthesizes two classes of steroids: the corticosteroids (glucocorticoids and mineralocorticoids) and the androgens. Corticosteroids act on the carbohydrate, protein, and lipid metabolism; the maintenance of fluid and electrolyte balance; and the preservation of the normal function of the cardiovascular and immune systems, the kidneys, the skeletal muscle, and the endocrine and nervous systems. In addition, corticosteroids allow the organism to resist stressful circumstances such as noxious stimuli and environmental changes. The effects of glucocorticoids are mediated by genomic and non-genomic mechanisms (Czock 2005). Corticosteroids interact with specific receptor proteins in target tissues to regulate the expression of the corticosteroid-rcsponsive genes, modifying the levels of proteins synthesized by these target tissues. The genomic mechanism includes activation of the cytosolic glucocorticoid receptors that lead to activation or repression of protein synthesis, including cytokines, chemokines, inflammatory enzymes, and adhesion molecules, which modify the inflammation and immune response mechanisms (Czock 2005). The therapeutic effects of glucocorticoids are predominantly mediated through the repression of genes encoding inflammatory mediators. However, inhibition of other transcription factors may account for the deleterious effects of glucocorticoids, such as adrenal suppression and osteoporosis (Roumestan 2004). In contrast with these genomic effects, some actions of corticosteroids can be immediate and mediated by membrane-bound receptors (Christ 1999). Pharmacokinetic parameters such as the elimination half-life, and pharmacodynamic parameters like the concentration producing the half-maximal effect, determine the duration and intensity of glucocorticoids' effects.

The corticosteroids arc grouped according to their capacity for Na+ retention, their effects on carbohydrate metabolism, and their anti-inflammatory effects. Thus, glucocorticoids have pleoiotropic effects and arc used in clinical practice in (as well as replacement therapy in cases of adrenal insufficiency) treating diverse diseases such as inflammatory rheumatic disorders, asthma, autoimmune diseases (systemic lupus erythematosus and others), acute kidney transplant rejection, and allergic and skin diseases. In pregnant women at risk for preterm birth, corticosteroids are also used for the induction of lung maturity. High doses of daily glucocorticoids are usually required in patients with severe diseases involving major organs, whereas alternate-day regimens may be used in patients with less aggressive disease. Intravenous glucocorticoids (pulse therapy) are frequently used to initiate therapy in patients with rapidly progressive, inmunologically mediated diseases (Rournpas 1993).

All systemic glucocorticoids cross the placenta to some degree after administration to the mother (Levitz 1978), but the fetal serum concentrations can vary according to the glucocorticoid used. Betamethasone and dexamethasone cross the placenta well (this is the reason why they have been traditionally used by obstetricians to enhance fetal lung maturation), whereas prednisone, methylprednisolone, and prednisolone appear to cross the placenta only to a small extent, and may for Lhis reason be preferred for the treatment of maternal illness.

Teratogenic effects

The maternal treatment with glucocorticosteroids during the first trimester of pregnancy does not seem to represent a major teratogenic risk in humans. In spite of children with congenital dcfects being described in several case reports of women treated during the first trimester of pregnancy for a wide variety of maternal diseases, there has been no consistent pattern of defects leading to the suggestion of a causal drug effect, Likewise, some prospective epidemiological studies have been published in which there was no evidence to suggest a significant increased risk of congenital malformations

(Gur 2004, Park-Wyllie 2000). Nevertheless, several epidemiological studies have associated maternal treatment with glucocorticoids with an increased risk of oral clefts (Kallcn 2003, Pradat 2003, Carmichael 1999, Rodriguez-Pinilla 1998). Moreover, in one prospective negative study the authors include a meta-analysis of the epidemiological studies published so far that concludes that therapeutic doses of corticosteroids in humans increase the risk of oral clefts by an order of 3.4-fold, which is consistent with existing animal studies (Park-Wyllie 2000).

The association between glucocorticoids and oral clefts has also been discussed following maternal use of topical corticosteroid during pregnancy {Edwards 2003, Czcizel 1997), although Czeizel discounted this finding because the mothers stopped the medication after the first month of gestation. The results of Edwards (2003) should be interpreted with caution because, although statistically significant, the confidence interval was extremely wide (1.67-586!) due to the small sample size.

Regarding the use of inhaled glucocorticoids {e.g. budesonide or beclomethasone) in pregnant women who have asthma or other allergie process (such a rhinitis), the available data show no evidence of an apparent fetal risk (Dcmoly 2003, Kallén 1999; see also Chapter 2.3).

Thus, taking into consideration the existing data, it is reasonable to conclude that there is no evidence of a significant increase in the basal risk for congenital anomalies, although a possible association with clefts cannot be excluded.

Fetal toxicity

There is still concern regarding intrauterine glucocorticoid exposure as the origin of some adult diseases. Conditions that are suspected of having been programmed before birth include hypertension, diabetes, coronary heart disease, and stroke (Rennick 2006. Newnham 2001. Challis 1999). Thus, the long-term effects of fetal glucocorticoids (especially dexamethasone) in humans are unclear, and whether they have a role in programming the individual for adult degenerative diseases remains to be studied.

Some clinical studies have suggested a possible relationship between antenatal exposure to prednisone and other corticosteroids as a treatment for maternal diseases, and an increased incidence of fetal growth restriction. Nevertheless, the effect of the corticosteroids in these cases of intrauterine growth retardation is uncertain, and the underlying maternal disease (often autoimmunity diseases, renal transplantation, asthma) as well as the concomitance medications {such as immunosuppressant drugs) could be playing a predominant role.

Depending on dose and the treatment interval, adrenal cortical insufficiency in the newborn babies may occur.

Fetal effects of betamethasone or dexamethasone for Induction of lung maturity

The administration, between 24 and 34 weeks' gestation, of betamethasone (12mg i.m. every 24 hours for two doses) or dexamethasone (6mg i.m. every 12 hours for four doses) is a well-established intervention to promote fetal lung maturation and prevent neonatal respiratory distress syndrome, neonatal mortality, and ventricular hemorrhage. Antenatal exposure to betamethasone but not dexamethasone has been associated with a decreased risk of cystic periventricular leukomalacia among very premature infants (Baud 1999).

Nevertheless, multiple works have been published showing adverse effects on the fetus after the administration of two or more complete courses, such as decreased fetal growth (Thorp 2002), reduction in birth head circumference (Thorp 2002), transient hypertrophic cardiomyopathy (Yunis 1999), increased mortality (Banks 1999), prolonged adrenal suppression, increased risk of early-onset neonatal sepsis, and increased perinatal mortality. Also, adverse cffects have been described in the pregnant woman exposed to multiple courses, such as a higher incidence of postpartum endometritis (Abbasi 2000).

Recently, a work has been published which analyzed a sample of 29 557 singleton live-born infants without congenital defects to study the effects on fetal growth of antenatal corticosteroid treatment used to promote fetal lung maturation (Rodriguez-Pinilla 2006). In this work, and controlling for potential confounder factors (year of birth, maternal age, gestational age, parity, maternal smoking and/or alcohol consumption, gestational diabetes, non-gestational diabetes, and other maternal chronic diseases), the exposure to more than one course of antenatal corticosteroids resulted in a significant reduction in birth weight, length, and head circumference in singleton preterm infants. The birth weight decreased by 22% (p < 0.0001), the length by 5% (p = 0.002), and the head circumference by 6% (p = 0.0005). Exposure to just one course of antenatal corticosteroids also significantly reduced the weight (by 17%; p < 0.0001) and the length (by 5%; p = 0.0001), but not the head circumference. This correlation between the administered dose and the weight of the newborn children had been previously proven in animal experiments (lkegami 1997). In addition, the significant interaction found between the treatment and the gestational age at birth indicated that the effect of corticosteroids Is enhanced in the most premature babies (Rodriguez-Pinilla 2006).

It is important to note the potential negative repercussions on the programming of the developing CNS of antenatal exposure to dexa/betamethasone. This has been demonstrated by comparing magnetic resonance indices of brain maturation in infants exposed to repeat antenatal glucocorticoid (GC) therapy and born at or close to term, with non-GC exposed control infants. GC-exposed infants had a significantly lower whole cortex convolution index (a measure of the complexity of cortical folding) and smaller surface area (Modi 2001). Nevertheless, at present there is no conclusive information to prove a significant decrease in the head circumference after the exposure to a single course of GC (Rodriguez-Pinilla 2006). Also, exposure to a single course has not been associated with later obvious adverse effects on growth, intellectual and motor development, school achievement, social-emotional functioning, and lung function in the 10-14-year-olds studied (Doyle 2000, Schmand 1990). Dalziel (2005) followed up, at age 30 years, 534 individuals whose mothers had participated in a double-blind, placebo-controlled, randomized trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. There were no differences between the two groups in body size, blood lipids, blood pressure, plasma Cortisol, prevalence of diabetes, or history of cardiovascular disease. Only after a glucose tolerance test were the prenatally betamethasone-exposcd identified as having higher plasma insulin concentrations. These facts, together with the evidence that the administration of a single course is effective to prevent the neonatal respiratory distress syndrome, justify its administration in the pregnant woman at risk of preterm delivery. Nevertheless, a recently published randomized controlled trial supported the use of repeat doses of corticosteroids (betamethasone), 7 or more days after the initial course, in women who remain at risk of very preterm birth (Crowther 2006). Beyond the thirty-fourth week of pregnancy, support of lung maturation is usually not necessary.

On the other hand, placebo-controlled studies with mice exposed to corticosteroids during pregnancy have shown that betamethasone has less detrimental effects than does dexamethasone on the neurobehavioral development of the offspring, and is more potent in accelerating fetal lung maturity (Christensen 1997, Rayburn 1997). These experimental results, together with clinical studies in premature infants, suggest that betamethasone must be the preferred corticosteroid for use in women at risk of preterm delivery (Groneck 2001, Baud 1999).

Recommendation. Replacement therapy can and should be conducted throughout pregnancy.

In maternal inflammatory diseases, the benefits of glucocorticoid therapy on the maternal health can be offset by the low risk to the fetus, as long as there is a sufficient indication for maternal treatment and no safer alternative is available. Beyond its use during the first trimester, a high-resolution echocardiography could be recommended, especially for the diagnosis of oral clefts.

In maternal asthma and allergic diseases, pregnancy Is not considered to be a contraindication for the continuation of corticosteroids therapy. Severe asthma may compromise maternal and/or fetal oxygenation. Therefore, risk-benefit consideration still favors the use of oral or inhaled corticosteroids during pregnancy when indicated for the treatment for asthma.

In pregnant women at risk of preterm delivery, single course of GC treatment before preterm delivery is recommended until week 34. The use of betamethasone for this indication may be of advantage compared to dexamethasone.

For adrenal medulla hormones, see Chapter 2.3.

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