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Effects of Propylthiouracil and Methimazole on Fetal Thyroid Status in Mothers with Graves' Hyperthyroidism
... Postmortem olarak over kistleri, tiroid ve adrenal bezde multinodüler hiperplazi saptanmıştır (45). (28, 30,(48)(49)(50)). Bu durum postnatal erken dönemde gözlenebilir, kısa süreli hipertiroidi ya da ötiroidi tablosunun peşinden ortaya çıkabilir ya da hipotiroidi tablosu hipertiroidi aşamasına geçmeden önce görülebilir (8, 30). ...
Fetal and neonatal hyperthyroidism may occur in mothers with Graves’ disease. Fetal thyrotoxicosis manifestation is observed with the transition of TSH receptor stimulating antibodies to the fetus from the 17th- 20th weeks of pregnancy and with the fetal TSH receptors becoming responsive after 20 weeks. The diagnosis is confirmed by fetal tachycardia, goiter and bone age advancement in pregnancy and maternal treatment is conducted in accordance. The probability of neonatal hyperthyroidism is high in the babies of mothers that have ongoing antithyroid requirement and higher antibody levels in the last months of pregnancy. Clinical manifestation may be delayed by 7-17 days because of the antithyroid drugs taken by the mother. Neonatal hyperthyroidism symptoms can be confused with sepsis and congenital viral infections. Herein, the diagnosis and therapeutic approach are reviewed in cases of fetal neonatal hyperthyroidism.
Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, e.g iodine deficiency and excess, anti- TSHR antibodies and exposure to anti-thyroid or iodine-rich medications may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.
This chapter includes clinical cases, background, evidence-based practical management options, preventive measures, key-point summaries of thyroid disease and answers to questions patients ask. The management of women with thyroid disease preconceptually and during pregnancy is a clinical area that is advancing rapidly. In iodine replete countries, the incidence of hypothyroidism diagnosed before pregnancy is about 1%, the commonest cause being primary thyroidal failure due to autoimmune thyroiditis. Over 90% of hyperthyroidism in pregnancy is secondary to Graves’ disease. Adequate treatment and control of both hypothyroid and hyperthyroid disease in pregnancy is associated with good obstetric outcome. As there has been no evidence that subclinical or mild hyperthyroidism is associated with any adverse outcome the balance of risk is in favor of thyroxine dose increases in maternal hypothyroidism. Dose change recommendations should be made promptly, and thyroid function checks made 4–6 weeks later on every occasion.
Graves’ disease is an autoimmune organ specific disease characterized by excessive production of hormones from the thyroid gland and by its diffuse enlargement. The growth and function of the thyroid gland are stimulated by autoantibodies directed against the thyroid-stimulating hormone receptor. Pregnancies complicated by Graves’ disease are characterized with higher incidence of abortion, preterm delivery, low-birth- weight infants and neonatal mortality, as well as maternal complications such as heart failure, eclampsia and rarely thyroid storm. When fully controlled hyperthyroidism have excellent outcomes. Different therapeutic approaches are used in women with Graves’ planning pregnancy and in those when the disease is diagnosed after they became pregnant. Thionamides are the first choice for treatment, with Propylthyouracil being preferred for the first trimester and Methimazole for the second and third trimester. Aplasia cutis and some other malformations were associated with methimazole use during pregnancy. Monitoring the effect of treatment should ensure keeping maternal FT4 in the high normal range. Block-and replace regimen is not recommended and rdioiodine therapy is absolutely contraindicated. Thyroidectomy may be considered before pregnancy or in rare cases in the second trimester. Iodine is avoided because of the risk of fetal hypothyroidism and goiter. The use of beta-blockers is controversial. Noenatal thyrotoxicosis may occur in association with maternal Graves’ disease due to maternal TSAbs cross through the placenta.
Thyroid disease is common in women of childbearing age and can have significant effects on the development of the fetus and perinatal outcomes. Maternal thyroid hormone is critical for proper fetal neurodevelopment and the fetus relies on thyroid hormone from it's mother for the first half of pregnancy. Both overt maternal hypothyroidism and overt maternal hyperthyroidism have been shown to be associated with adverse effects on central nervous system grey matter and neurocognitive development of offspring as well as increased obstetrical risks. Treatment of overt thyroid conditions improves outcomes. Subclinical maternal hypothyroidism may increase adverse neurocognitive and obstetrical outcomes although data is conflicting. To date, treatment of subclinical hypothyroidism has not shown benefit. Subclinical hyperthyroidism is well tolerated in pregnancy. Thyroid autoantibodies alone may also affect neurodevelopment and obstetrical outcomes however recent data has shown no improvement with levothyroxine treatment. Several rare maternal genetic thyroid conditions can affect the fetus including a TSH receptor mutation leading to hypersensitivity to hCG and thyroid hormone resistance. The thyroid plays a crucial role in fetal health and understanding it is important for optimal care. This article is protected by copyright. All rights reserved.
This chapter presents two clinical scenarios concerning thyroid disease. The first involved a 29‐year old woman, experiencing significant nausea and some vomiting and confirming taking her synthroid, but noting that she could not tolerate her prenatal vitamins. The clinical issues involved were adjustment of the dosage of T4 in pregnant women with hypothyroidism and the thyroid function and antibody tests to be performed in pregnant women being treated for hypothyroid disease. In the second scenario, a 37‐year‐old woman was having Grave's disease and being currently on propoth‐iouricil. The clinical questions to be resolved included the risks to the fetus and the pregnancy with inadequately treated hyperthyroidism or Graves' disease, the treatment options for a pregnant woman with Graves' disease, and the thyroid function and antibody tests to be followed to manage her Graves' disease in pregnancy.
Physiological and endocrine adaptations occur in the mother in response to the demands of pregnancy. These demands include support of the fetus (volume support, nutritional and oxygen supply, and clearance of fetal waste), protection of the fetus (from starvation, drugs, toxins), preparation of the uterus for labor, and protection of the mother from potential cardiovascular injury at delivery. The presence of a preexisting endocrine disorder is likely to affect the ability of the mother to adapt to the demands of pregnancy and, as a result, may influence fetal growth and development. Drugs used to treat such disorders may also affect perinatal outcome. The most common preexisting endocrine disorders that can complicate pregnancy are diabetes mellitus, thyroid dysfunction, and obesity. Less common preexisting maternal endocrine disorders include pituitary tumors, diabetes insipidus, and hyperparathyroidism.
The physiological and endocrine adaptations that characterize pregnancy can also lead to the development of pregnancy-specific diseases in previously healthy women, the most common of which are gestational diabetes and disorders of the endocrine and sympathetic nervous systems associated with preeclampsia and preterm labor. This chapter is designed to review in detail the underlying pathophysiology of these pregnancy-specific diseases, as well as the effects of pregnancy on preexisting endocrine disorders. A better understanding of these conditions will improve the ability of clinicians to optimize maternal and perinatal outcome in such pregnancies.
Discuss the management of a 23 year old primiparous woman with a metal Starr-Edwards mitral valve replacement who is receiving maintenance therapy with warfarin and who presents at 5 weeks’ gestation.
Autoimmune thyroid diseases (AITD), the most common endocrine disorders affecting humans, cause cellular damage and alter the thyroid gland function by humoral and cell-mediated mechanisms. Three principal thyroid autoantigens are involved in the development of AITD: thyroperoxidase (TPO), thyroglobulin (TG) and thyroid stimulating hormone receptor (TSH-R). Other autoantigens have also been described, but as yet their diagnostic role in thyroid autoimmunity has not been established. Laboratory tests that determine the cell-mediated aspects of the autoimmune process are not currently available. However, tests of the humoral response, i.e. thyroid autoantibodies, can be assessed in most clinical laboratories. Thyroid autoantibodies are valuable for classification and reflect disease activity and progression. Lately, TPO antibodies assays have been used for the assessment of risk for developing AITD. Thyroid autoantibodies measurement is hampered by method specificity and sensitivity problems, as well as suboptimal standardization. Despite that, autoantibody tests have inherent clinical utility in a number of clinical situations.
Background:
Thyroid disease in pregnancy is a common clinical problem. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were first published in 2011, significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid disease in women during pregnancy, preconception and the postpartum period.
Methods:
The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English-language articles were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. The guideline task force had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.
Results:
The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research.
Conclusions:
We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid disease in pregnant and postpartum women. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with these disorders.
Introduction: Graves’ hyperthyroidism is associated with significant morbidity and mortality risk. The thionamides, methimazole, its pro-drug derivative carbimazole, and propylthiouracil, remain a cornerstone of management. Yet despite decades of use, optimal strategies for maximising treatment response and curtailing adverse effect risk remains uncertain.
Areas covered: We reviewed the current literature on the evidence based medical management of Graves’ disease. Specifically, we evaluated current approaches to the use of thionamides, adjunctive therapies, and potential novel agents for controlling Graves’ hyperthyroidism.
Expert opinion: Primary medical therapy is successful in less than 50% of cases and so careful selection of patients for medical treatment based on a combination of pathological and pragmatic considerations is essential. Carbimazole or methimazole is the treatment of choice in the non-pregnant population driven by its more favourable pharmacokinetic and adverse effect profile over propylthiouracil. In pregnancy the choice of treatment is less straightforward and an approach that minimises undue fetal exposure to all thionamides should be adopted. Additional data is needed on the value of adjunctive therapies including potassium perchlorate, iodides, glucocorticoids, lithium, and cholestyramine. Novel agents directed against pathogenetic targets including TSH receptor blocking monoclonal antibodies and small molecule antagonists may hold promise for the future.
Background:
Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This article describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition.
Methods:
The American Thyroid Association (ATA) previously co-sponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since 2011, the ATA felt updated-evidence-based guidelines were needed, and assembled a task force of expert clinicians who authored this report. The task force examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group.
Results:
Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded.
Conclusions:
One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.
The prevalence of Graves’ disease is approximately 3.0/1000 with an incidence of about 0.5/1000/year. The prevalence and incidence in women during child bearing years is not known but thyrotoxicosis is said to occur in 2/1000 pregnancies and Graves’ disease would be expected to account for at least 80% of these cases. While these figures are low, Graves’ hyperthyroidism can have a dramatic effect on the mother as well as the fetus. The thyroid hormone changes and immunological effects of normal pregnancy will be reviewed as a background to the discussion of Graves’ disease in pregnancy and the postpartum period. The subject has been reviewed (1–4)
Fetal thyroid metabolism depends on normal fetal thyroid development and hormonogenesis as well as normal maternal thyroid physiology. Thyroid hormone production has been detected in the fetus as early as 10 wk gestation, and thyroid follicles have been identified histologically by 12 wk (1,2) From the 13th wk of gestation until the third trimester, there are increases in fetal serum concentrations of thyroxine (T4), thyroxine-binding globulin (TBG), and thyroid-stimulating hormone (TSH), independent of maternal serum concentrations (3,4), indicating maturation of the fetal thyroid gland. Tri-iodothyroinine (T3) does not rise significantly until the third trimester (3), a finding that is explained by the late appearance of type I deiodinase, which catalyses the synthesis of T3 from T4.
The management of Graves’ hyperthyroidism has evolved in recent years chiefly due to a better understanding of the underlying molecular immunology and an “evidence-based” approach to clinical controversies. Since patients with Graves’ disease can present with signs and symptoms of orbitopathy, the ophthalmologist must recognize the signs and symptoms of, as well as the treatment options for, the associated thyrotoxicosis. In this chapter, an evidence-based algorithmic approach to the medical management of Graves’ hyperthyroidism is discussed.
Thyroid function abnormalities during pregnancy can affect up to 10 % of all women. The mother's thyroid dysfunctions have an influence on fetal development, not only iodine deficiency, but also hyperthyroidism, hypothyroidism, and immunological disorders or inappropriate production of hCG. This review focuses on all thyroid dysfunctions during pregnancy.
The aim of our study was to investigate if the thyroid axis of newborn calves is
affected by prenatal application of propylthyouracil (PTU). The study included 20
late pregnant Holstein cows. One group (n=10) was treated with PTU (4 mg/kg of
BW daily) from day 20 before expected calving until the day of calving. The other
group (n=10) was non-treated. Placental samples of dams were obtained for measuring
mRNA expression of iodothyronine deiodinases type I (D1), type II (D2) and type
III (D3). After parturition calves were separated from the dams and included in the
study. Blood samples were taken daily from each calf starting on the day of birth until
day 7 of age. Blood T3, T4 and TSH concentrations were measured. PCR analysis of
the placental tissue revealed an abundance of all three types of placental deiodinases
in non-treated cows, and a signifi cant elevation of mRNA levels for all three types of
deiodinases after PTU treatment. Calves that originated from dams treated with PTU
had signifi cantly lower T3 and T4 and signifi cantly higher TSH concentrations compared
to non-treated calves during the fi rst 2 days of life. Starting from day 4 until day 6 of
life the opposite effect was observed meaning that calves prenatally exposed to PTU
had signifi cantly higher T3 and T4 and slightly lower TSH. Our study, for the fi rst time,
provides information related to iodothyronine deiodinases mRNA expression in bovine
placenta, and confi rm that PTU treatment of pregnant dams provokes depression of
thyroid function in newborns during the fi rst days of life.
First cause of hyperthyroidism among women of childbearing age, Graves' disease raises the risk of maternal and fetal complications, including eclampsia, cardiac failure, abortion, prematurity, fetal death, all of which can be avoided if maternal hyperthyroidism is closely controlled. The risk of transplacental hyperthyroidism has been shown to correlate to the titre of anti-TSH receptor antibodies and has to be evaluated not only in women treated for Graves' disease during pregnancy, but also in women who have previously received radio iodine treatment or undergone surgery for Graves' disease: TSH-receptor antibodies may indeed remain at a high level several years after initial treatment. Both methimazole and propylthiouracil are equally effective to restore maternal euthyroidism. Accumulation of case-reports relating congenital malformations (mostly aplasia cutis, but in some cases, severe malformations) among the offspring of methimazole-treated women suggests the possibility of a teratogenic effect of methimazole. Despite the fact that the link between severe congenital, defects and methimazole exposure during pregnancy is not formally established, propylthiouracil should be preferred to methimazole for the treatment of young hyperthyroid women.
Hyperthyroidism is one of the most common endocrine disorders in pregnant women, and it can severely complicate the course and outcome of pregnancy. Methimazole (MMI) and propylthiouracil (PTU) are the standard anti-thyroid drugs used in the treatment of hyperthyroidism in pregnancy. Traditionally, MMI has been considered to have clearer evidence of teratogenicity than PTU. Recent studies suggest that PTU can be hepatotoxic, leading to a United States Food and Drug Administration “black box alert.” We wished to systematically review the effects of PTU and MMI during pregnancy, and to compare maternal and fetal safety.
The case of a pregnant woman with highly active Graves' disease and high levels of TSH-receptor-autoantibodies (TRAK) is presented. Because of the known diaplocental transit of TRAK (who stimulate the fetal thyroid to thyroxicosis) the mother was treated with high doses of Methimazol in order to treat the fetal thyrotoxicosis. After delivery umbilical cord blood T4 and T3 values of the newborn were normal, but 5 days later (after wash-out of maternal Methimazol) the child was clearly thyrotoxic and was treated with Methimazol. 6 weeks later the therapy was ceased, because the maternal TRAK (according to its halflife-time) had decreased in the newborn. It is concluded, that pregnant women with high titres of TRAK should be treated in specialised endocrine units.
Recommendations for the management of women with hypothyroid and hyperthyroid disorders pre-conceptually and during pregnancy are constantly being refined as new evidence continues to emerge. Abnormal thyroid function, particularly during the first trimester of pregnancy, is associated with increased obstetric risk and can impact on the neurodvelopment of the child. Thus, treatments should ideally be optimised prior to conception with clear management plans in place for when pregnancy is first confirmed. Adequate treatment and control of both hypothyroid and hyperthyroid disease in pregnancy is associated with good obstetric outcome.
IntroductionNormal physiologic changes in pregnancyAutoimmune thyroid diseaseHyperthyroidismHypothyroidismPostpartum thyroiditisReferences
Gender-based differences in the evaluation and management of thyroid disorders principally stem from considerations that arise in the setting of pregnancy. Interactions may be viewed from different perspectives. On one hand, it must be recognized that thyroid autoimmunity and functional disorders that persist as untreated conditions may have a significant impact on fertility, fetal development, and maternal outcomes. At the same time due consideration must be given to the extent to which approaches to the evaluation and management of functional disorders and neoplastic changes identified during pregnancy must be guided by an understanding of (a) physiologic adaptations in thyroid function that occur during the course of gestation, and (b) limitations imposed by the potential teratogenicity of agents commonly used to diagnose and treat thyroid disorders. An informed appreciation of these interactions is particularly important in light of the estimated prevalence of readily diagnosed thyroid disorders in women of reproductive age. During the course of gestation, increased renal blood flow and glomerular filtration act to increase clearance and excretion of iodide. The net effect is to increase dietary iodine requirements. Current recommendations specify that pregnant women maintain an average iodine intake of 250 μg daily. Women who live in iodine-sufficient regions are usually able to achieve this goal through a combination of dietary supplementation and daily ingestion of specifically formulated prenatal vitamins.
Thyreostats are thioamid antithyroid drugs. The activity of these compounds consists in inhibiting the synthesis of thyroid hormones: triiodothyronine (T3) and thyroxine (T4), which favors the processes of fattening animals. The weight gain of animals is mainly due to water retention in their tissues and gastrointestinal tract. Because of the cancerogenic and teratogenic properties of thyreostatic drugs, their use for animal fattening has been banned in Europe since 1981. Control studies conducted in Poland show that thyreostats are not used in farm animals. Several cases of endogenous thiouracil content in the urine of cattle and pigs have been reported over recent years. This article presents the properties of thyreostatic compounds, discusses a possible cause of endogenous thiouracil occurrence, and provides an overview of methods used in the analysis of thyreostatic residues.
Purpose of review:
Recognition and management of thyroid disease during pregnancy is challenging with conflicting recommendations from various professional organizations.
Recent findings:
We review the literature related to the diagnosis and management of gestational hypothyroidism and hyperthyroidism. We also discuss postpartum thyroiditis, thyroid nodules and thyroid cancer. The evidence clearly demonstrates that both overt hypothyroidism and hyperthyroidism should be treated, but controversy exists regarding the treatment of subclinical hypothyroidism and thyroid antibody positive euthyroidism, and whether pregnant women should be screened for thyroid disease.
Summary:
Appropriate management of thyroid disease during pregnancy is important for maternal and fetal health, particularly the recognition and management of hypothyroidism and thyrotoxicosis.
Maternal physiologyFetal thyroid functionTransient hyperthyroidism of hyperemesis gravidarumHyperthyroidismHypothyroidismPostpartum thyroiditisThyroid nodules and cancer in pregnancy
Thyroid hormones are essential development factors and maternal thyroid dysfunction may cause pregnancy complications and diseases in the fetus/child. In the present review we discuss new data on the incidence of Graves'-Basedow disease (GBD) in and around pregnancy, and how hyperthyroidism may affect the risk of spontaneous abortion and stillbirth.
A special concern in pregnant women is the potential side effects from the use of antithyroid drugs (ATDs). One type of side effects is the allergic/toxic reactions to the drugs, which seem to be similar in and outside pregnancy, and another is that ATDs tend to over treat the fetus when the mother with GBD is made euthyroid. To avoid fetal hypothyroidism, the lowest possible ATD dose should be used to keep maternal thyroid function at the upper limit of normality with low serum TSH. Birth defects after the use of methimazole (MMI) (or its prodrug carbimazole) have been considered to be very rare, and no risk has previously been associated with the use of propylthiouracil (PTU). However, a recent Danish national study found that 1/30 of children exposed to MMI in early pregnancy had birth defects associated with this, and many defects were severe. PTU exposure was associated with defects in 1/40, and these defects were less severe. Proposals are given on how to reduce the risk of ATD associated birth defects.
Pregnancies in women with renal disease, undergoing dialysis treatment or with kidney transplants are increasingly observed. Serious problems with drug dose adjustment may arise in pregnant women with renal impairment. This review gives a practical overview on the risks of drug use during gestation, the recommended drugs of choice (e.g. methyldopa, cyclosporin), and provides some proposals for dosage adjustments in pregnant women with renal impairment.
In normal pregnancy, the glomerular filtration rate and plasma volume increase, whereas plasma protein binding and liver function may be impaired. An increase in dosage is needed for cyclosporin and for methadone because of increased hepatic clearance. The dosage of erythropoetin must be increased because of lower potency in pregnant women. Little more is known on the impact of gestation on drug dose, since pharmacokinetic studies are rarely done in pregnant women.
The dosages of magnesium, lithium and morphine must be reduced in renal impairment. Dose adjustment to renal function is critical and is essential for anti-infective agents (e.g. ceftazidime, ganciclovir). Basing drug dose on estimated creatinine clearance might be the most practical solution in pregnant women with renal impairment.
Graves’ disease is an autoimmune disorder in which autoantibodies to the thyroid-stimulating hormone receptor cause hyperthyroidism through unregulated stimulation of the thyroid-stimulating hormone receptor. Effective management of Graves’ disease in pregnancy must address the competing fetal and maternal priorities of controlling hyperthyroidism in the mother on the one hand, and on the other, minimizing the impact of maternal disease and antithyroid drugs on the well-being of the fetus. Optimal strategies for achieving this intricate balance are currently a source of continued debate among thyroid experts and studies in recent decades are now providing greater clarity into the risk posed to the unborn baby by the combination of biochemical, immunological and pharmacological hazards arising from Graves’ disease and its therapy. This review summarizes the current best practice and highlights important considerations and areas of uncertainty in the management of Graves’ disease in pregnant women.
Control of thyroid function in hyperthyroid women during pregnancy is based on antithyroid drugs (ATD) [propylthiouracil (PTU) and methimazole (MMI)]. While a teratogenic effect has been suggested for MMI and, more recently, for PTU, a clear demonstration is still lacking. Aim of this study was to assess the safety of ATD during pregnancy.
A total of 379 pregnancies were retrospectively recruited in eight Italian Departments of Endocrinology and divided in five groups: (1) MMI-treated and euthyroid throughout pregnancy (n = 89); (2) MMI-treated and hyperthyroid on at least two occasions (n = 35); (3) PTU-treated women and euthyroid throughout pregnancy (n = 32); (4) PTU-treated women and hyperthyroid on at least two occasions (n = 20); and (5) non-ATD-treated (n = 203). Data on maternal thyroid function, miscarriages, type of delivery, neonatal weight, length and TSH, perinatal complications and congenital malformation were analyzed.
The gestational age at delivery, the rate of vaginal delivery, neonatal weight, length and neonatal TSH did not significantly differ among groups. In all groups, the rates of spontaneous miscarriage and of major congenital malformations were not higher than in the general population. No newborns were born with a phenotype similar to those described in the "MMI embryopathy".
While a clear demonstration of a teratogenic effect of MMI is currently lacking, it seems reasonable to follow the current guidelines and advice for PTU treatment in hyperthyroid women during the first trimester of pregnancy. Further, large and prospective worldwide studies will be needed to fully clarify the issue of ATD safety during pregnancy.
To evaluate the maternal and neonatal outcomes of pregnancies complicated with hyperthyroidism, according to the maternal treatment and thyroid function status during pregnancy.
The abundance of published data on the neonatal effects of maternal Graves' disease (GD) contrasts with the paucity of information on fetal effects. In our yet unpublished study, we prospectively studied 72 pregnant women with a history of Graves' disease. Fetal ultrasonography was done at 22 and 32 weeks of gestational age. Fetal goiter was found at 32 weeks in 11 of the fetuses of the 41 mothers with positive TSH-receptor antibodies and/or antithyroid treatment and in none of the fetuses of the 31 other mothers. In the 11 fetuses with goiter, ultrasound findings (thyroid Doppler and bone maturation), fetal heart rate, and maternal antibody and antithyroid drug status effectively discriminated between hypothyroidism (n=7) and hyperthyroidism (n=4). One fetus with hyperthyroidism died in utero at 35 weeks from heart failure. Treatment was successful in the ten other fetuses. One fetus without goiter had moderate hypothyroidism at birth.This study showed that it is of the utmost importance to have the fetal thyroid scrutinized by an expert ultrasonographist and to have team work with obstetricians and paediatric endocrinologists in pregnant mothers with GD. This allowed us to accurately determine fetal thyroid status and to adapt the treatment in mothers successfully. Fetal hyperthyroidism does exist and needs an appropriate aggressive treatment.
Over the last century, much has been learned about the pathogenesis, manifestations, and management of Graves' disease leading to the establishment of evidence-based clinical practice guidelines. The joint clinical practice guidelines from the American Thyroid Association and the American Association of Clinical Endocrinologists give recommendations on both the diagnosis and treatment of hyperthyroidism. A survey of clinicians performed that same year, however, revealed that current practices diverge from these recently published guidelines in multiple areas. These differences will need to be assessed serially to determine the impact of the guidelines on future clinical practice and perhaps vice versa.
Thyroid disorders are frequent in women of reproductive age. However, they are often overlooked because their manifestations may be confused with those of the hypermetabolic state that is characteristic of pregnancy. To the physiological changes that occur during pregnancy -cardiovascular, pulmonary, hematological, immunological, etc., it is necessary to add modifications in the thyroid axis that presents different situations during pregnancy; those variations make it difficult to correctly diagnose and treat pathological situations. Disorders of thyroid axis have negative consequences on both mother and fetus, among them: preeclampsia, abortion, premature delivery and disorders of the fetal central nervous system. Treatment must be oriented to counteract the effects of either increased or diminished thyroid function; for that purpose, differences concerning requirements and safety of medicines must be taken into account. Presently there is controversy concerning routine screening of pregnant women for thyroid disorders; so far, the available tests are usually performed only in high-risk women.
Hyperthyroidism in pregnancy is a serious condition and its management is complex. Whilst carbimazole/methimazole (CBZ/MMI) and propylthiouracil (PTU) have similar efficacies in controlling hyperthyroidism, their risk of side effects such as major congenital abnormalities and hepatotoxicity are different.
Various combinations of the terms 'anti-thyroid drugs', 'thionamide', 'carbimazole', 'methimazole', 'propylthiouracil', 'pregnancy', 'side effects', 'agranulocytosis', 'birth defects', 'congenital malformations', 'embryopathy', 'aplasia cutis', 'hepatotoxicity', 'hepatic failure', 'maternal' and 'fetus' were used to search MEDLINE and the Cochrane library. The references of retrieved papers were also reviewed.
There is increasing evidence for a CBZ/MMI embryopathy, whilst data remain lacking for major congenital abnormalities with PTU. In contrast, PTU is associated with increased risk of severe liver injury. Management strategies to reduce these risks by using PTU in the first trimester and CBZ/MMI in the later trimesters remain untested.
More evidence is still needed in defining the relative risks between CBZ/MMI and PTU of major congenital abnormalities and severe liver injury in pregnancy. Studies are also needed to establish the suitability of recent management suggestions in switching from PTU to CBZ/MMI after the first trimester. Major adverse outcomes secondary to CBZ/MMI and PTU are rare, and inadequately treated hyperthyroidism poses a far greater risk.
Objective
To determine the factors related to adverse pregnancy outcomes and neonatal thyroid dysfunction in pregnancies complicated by Graves’ disease.
Study Design
Thirty-five pregnancies complicated by Graves’ disease were divided into two groups: adverse pregnancy outcome (n = 15) and no adverse pregnancy outcome (n = 20). Adverse pregnancy outcomes included spontaneous abortion, stillbirth, premature delivery, fetal growth restriction, and pregnancy-induced hypertension. The 31 pregnancies resulting in live births were also divided into two groups: neonatal thyroid dysfunction (n = 9) and normal neonatal thyroid function (n = 22). Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), TSH-receptor antibody (TRAb), the duration of hyperthyroidism in pregnancy, doses of antithyroid medication, and the duration of maternal antithyroid medication throughout pregnancy were compared.
Results
There were no significant differences in these factors between pregnancies with an adverse pregnancy outcome and those with no adverse pregnancy outcome. However, serum levels of FT4, TRAb, the duration of hyperthyroidism in pregnancy, the maximum daily dose of antithyroid medication, and the total dose of antithyroid medication were significantly different between pregnancies with neonatal thyroid dysfunction and those with normal neonatal thyroid function. Multivariate logistic regression analysis showed that the FT4 level in mothers was a significant factor related to the development of neonatal thyroid dysfunction (odds ratio 28.84, 95% confidence interval 1.65–503.62, p < 0.05).
Conclusion
Graves’ disease activity in women of childbearing age should be well controlled prior to conception.
Background:
Fetal/neonatal hyperthyroidism is a well-known complication of maternal Graves' disease with high concentrations of TSH-receptor antibodies (TRAb). Few data are available on the management of fetal hyperthyroidism in surgically treated Graves' disease.
Methods:
Clinical, ultrasound and biochemical data are reported in a fetus/neonate whose mother underwent a thyroidectomy > 10 years before and whose sibling was thin and hyperthyroid at birth.
Results:
Maternal TRAb were persistently > 40 U/l; unequivocal signs of fetal hyperthyroidism were identified at 29 weeks gestational age (GA). The fetus was treated through maternal antithyroid drug (ATD) administration; the dose was reduced gradually once fetal tachycardia and valve dysfunction disappeared and normal T4 was confirmed by fetal blood sampling. Maternal euthyroidism was maintained. The neonate showed normal growth for GA and T4 concentration at birth but severe hyperthyroidism relapsed from day 13 until day 58. TSH remained strongly suppressed throughout the pre- and postnatal course.
Conclusions:
Prenatal ATD in a taper-off regime allowed normal T4 and growth in a hyperthyroid fetus from a thyroidectomised Graves' mother. Fetal TSH cannot be used to adjust the ATD dose. Prenatal ATD appears to postpone the onset but does not affect the severity or duration of the neonatal hyperthyroid flare.
Objective:
To evaluate the peer-reviewed literature on hypothyroidism, hyperthyroidism, and thyroid autoimmunity in pregnancy.
Methods:
We review published studies on thyroid autoimmunity and dysfunction in pregnancy, the impact of thyroid disease on pregnancy, and discuss implications for screening.
Results:
Overt hyperthyroidism and hypothyroidism are responsible for adverse obstetric and neonatal events. Several studies of association suggest that either subclinical hypothyroidism or thyroid autoimmunity increase the risk of complications. One randomized controlled trial showed that pregnant women with subclinical hypothyroidism benefit from treatment in terms of obstetric and neonatal complications, whereas another study demonstrated no benefit in the intelligence quotient of babies born to women with subclinical hypothyroidism. Thyroid autoimmunity has been associated with increased rate of pregnancy loss, recurrent miscarriage, and preterm delivery.
Conclusion:
Current guidelines agree that overt hyperthyroidism and hypothyroidism need to be promptly treated and that as potential benefits outweigh potential harm, subclinical hypothyroidism also requires substitutive treatment. The chance that women with thyroid autoimmunity may benefit from levothyroxine treatment to improve obstetric outcome is intriguing, but adequately powered randomized controlled trials are needed. The issue of universal thyroid screening at the beginning of pregnancy is still a matter of debate, and aggressive case-finding is supported.
Introduction:
Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications, but teratogenic effects of antithyroid drug (ATD) treatment have been described. Evidence is still lacking in regard to the safety and choice of ATD in early pregnancy.
Objective:
Our objective was to determine to which degree the use of methimazole (MMI)/carbimazole (CMZ) and propylthiouracil (PTU) in early pregnancy is associated with an increased prevalence of birth defects.
Methods:
This Danish nationwide register-based cohort study included 817 093 children live-born from 1996 to 2008. Exposure groups were assigned according to maternal ATD use in early pregnancy: PTU (n = 564); MMI/CMZ (n = 1097); MMI/CMZ and PTU (shifted in early pregnancy [n = 159]); no ATD (ATD use, but not in pregnancy [n = 3543]); and nonexposed (never ATD use [n = 811 730]). Multivariate logistic regression was used to estimate adjusted odds ratio (OR) with 95% confidence interval (95% CI) for diagnosis of a birth defect before 2 years of age in exposed versus nonexposed children.
Results:
The prevalence of birth defects was high in children exposed to ATD in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%; P < .001). Both maternal use of MMI/CMZ (adjusted OR = 1.66 [95% CI 1.35-2.04]) and PTU (1.41 [1.03-1.92]) and maternal shift between MMI/CMZ and PTU in early pregnancy (1.82 [1.08-3.07]) were associated with an increased OR of birth defects. MMI/CMZ and PTU were associated with urinary system malformation, and PTU with malformations in the face and neck region. Choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, and aplasia cutis were common in MMI/CMZ-exposed children (combined, adjusted OR = 21.8 [13.4-35.4]).
Conclusions:
Both MMI/CMZ and PTU were associated with birth defects, but the spectrum of malformations differed. More studies are needed to corroborate results in regard to early pregnancy shift from MMI/CMZ to PTU. New ATD with fewer side effects should be developed.
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