Joana Patricia Rodrigues Félix Thyroid (dys)function: a burning issue in pregnancy
2011/2012
Joana Patrícia Rodrigues Félix
Thyroid (dys)function: a burning issue in pregnancy
Mestrado Integrado em Medicina
Área: Ginecologia/obstetrícia
Trabalho efetuado sob a Orientação de: Professora Doutora Alexandra Matias
Trabalho organizado de acordo com as normas da revista: Journal of Neonatal-Perinatal Medicine
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Eu, Joana Patrícia Rodrigues Félix, abaixo assinado, nº mecanográfico 060801248, estudante do 6º ano do Mestrado Integrado em Medicina, na Faculdade de Medicina da Universidade do Porto, declaro ter atuado com absoluta integridade na elaboração deste projeto de opção.
Neste sentido, confirmo que NÃO incorri em plágio (ato pelo qual um indivíduo, mesmo por omissão, assume a autoria de um determinado trabalho intelectual, ou partes dele). Mais declaro que todas as frases que retirei de trabalhos anteriores pertencentes a outros autores, foram referenciadas, ou redigidas com novas palavras, tendo colocado, neste caso, a citação da fonte bibliográfica.
Faculdade de Medicina da Universidade do Porto,
Assinatura:
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Projecto de Opção do 6º ano – DECLARAÇÃO DE REPRODUÇÃO
Nome: Joana Patrícia Rodrigues Félix
Endereço electrónico: med06248@med.up.pt Telefone ou Telemóvel: 913497266
Número do Bilhete de Identidade: 13320163
Título da Monografia:
Thyroid (dys)function: a burning issue in pregnancy
Orientador:
Professora Doutora Alexandra Matias Pereira da Cunha Coelho de Macedo
Ano de conclusão: 2012
Designação da área do projecto:
Ginecologia/obstetrícia
É autorizada a reprodução integral desta Monografia para efeitos de investigação e de divulgação pedagógica, em programas e projectos coordenados pela FMUP.
Faculdade de Medicina da Universidade do Porto,
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Resumo
Já há muito tempo que a humanidade reconhece a importância da interação
materno-fetal e que as alterações na saúde materna podem ter grande um impacto no desenvolvimento do feto.
Conforme o nosso conhecimento sobre esta interação aumenta, novas patologias maternas vão sendo consideradas como maléfica, passando a ser corrigidas, se possível, de forma a minimizar os danos no novo ser.
Nos últimos anos, vários estudos têm provado uma associação clara entre as disfunções tiroideias da mãe e alterações no desenvolvimento fetal, principalmente no primeiro trimestre da gravidez, quando o feto é totalmente dependência de hormona tiroideia materna.
O maior relevo tem sido dado para as alterações do sistema nervoso central fetal, mas a disfunção desta glândula também se associa a subfertilidade, abortamentos de repetição, complicações durante a gestação (descolamento da placenta ou pré-eclampsia tardia) e complicações após o parto, como tiroidite pós-parto.
Estas provas irrefutáveis, fizeram a comunidade científica ponderar se a intervenção actual (rastrear grávidas com risco aumentado de disfunção tiroideia) será
suficiente, uma vez que estas patologias são frequentes na população e muitas vezes assintomáticas.
Este trabalho tem como objectivo fazer uma compilação de publicações recentes, no sentido de compreender se é necessários alargar a população alvo a ser testada e se o rastreio universal é viável e vantajoso.
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Monografia
Thyroid (dys)function: a burning issue in
pregnancy
Author:
Joana Félix MD, Alexandra Matias MD, PhD
Contact: Dpt. Ob & Gyn of Hospital de S. João
Al. Prof. Hernâni Monteiro Porto
Portugal almatias@mail.telepac.pt
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1) Abstract:
Background: As maternal thyroid hormone plays an important role in the fetal development, thyroid dysfunction is associated with an increased risk of adverse obstetrical outcomes. Therefore, it is of utmost importance that we detect and treat the pregnant women with thyroid anomalies in order to prevent an undesired outcome.
Methods: Using article databases such as PubMed and Google academic, books of endocrinology and obstetrics and some web sites of medical journals and
organizations of the last ten years, we collected, synthesized and integrated
information about the embryology, physiology, histology and imaging of fetal thyroid, maternal thyroid disease and their impact on the fetus, the treatment that can be offered, the guidelines and the impact of this screening on the course of pregnancy. Conclusions: Universal screening for thyroid dysfunction during pregnancy is a desirable end point, but more studies are needed to support its implementation.
Key words: Pregnancy screening, thyroid function, hypothyroidism, hyperthyroidism, thyroid antibodies.
Word count:
- Abstract: 147
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2) Introduction
Since ancient times that we recognize the impact of maternal health in the fetal development. As knowledge of maternal-fetal interactions increases, new topics are brought up for debate by the scientific community.
Nowadays, thyroid (dys)function in pregnancy is a new and mediatic topic intensively under debate, because there are several and reliable clinical trials that demonstrate the negative impact of maternal dysfunction in the development of the fetus.
For this reason it is mandatory to assess the true impact of thyroid disorders in pregnancy and the need to timely screen, diagnose and treat those women at risk.
This paper compiles the most recent published articles on the impact of thyroid (dys)function and the advantages and cost-effectiveness of screening thyroid disorders during pregnancy.
3) Methods:
Using article databases such as PubMed and Google academic, books of endocrinology and obstetrics and some web sites of medical journals and organizations of the last ten years, we collected, synthesized and integrated information about the embryology, physiology, histology and imaging of fetal thyroid, maternal thyroid disease and their impact on the fetus, the treatment that can be offered, the guidelines and the impact of this screening on the course of pregnancy.
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4) Thyroid gland of the fetus and the mother
4.1) Fetal thyroid embryology
The thyroid gland is the first endocrine glands to develop. It originates from a proliferation of endodermal epithelial cells of the pharyngeal floor, between the tuberculum impar and the copula, at a point called the foramen cecum, approximately on the 24th day after conception. [1] [2] [3]
The initial thyroid precursor is the thyroid primordium, which proliferates into thyroid diverticulum. This structure is initially hollow, but then it becomes a solid mass that divides into two lobes connected by an isthmus. [1]
As the embryo and tongue grow, the gland descends in the neck, passing anterior to the hyoid bone and laryngeal cartilages. At this point, the thyroid is still connected to the tongue by the thyroglossal duct, which will obliterate entirely between the 7th and 10th gestational weeks. As the thyroid gland descends, it develops its adult shape, with two lobes connected by an isthmus. By the 7th gestational week, the thyroid gland has assumed its definitive form and location immediately anterior to the trachea. [1] [2] [3]
4.2) Fetal thyroid physiology
A normal thyroid function during the intra-uterine period is essential for the balanced development of the fetus.
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During the first trimester, fetal thyroid hormone depends on the maternal circulation. [4] Evidence has demonstrated that T4 values in celomic fluid vary directly with the maternal serum T4 concentrations, proving the important role of transplacental passage of maternal thyroid hormone. [4] [5]
The beginning of fetal thyroid function, at 10th week of gestation, is marked by thyroxine (T4) detection. T4 production will gradually rise until reaching the adult concentration at approximately 36 weeks. [4] [5] [6]
Thyroxine-binding globulin (TBG) concentration also increases progressively, reflecting the functional maturation of the fetal liver and its increasing capacity to synthesize proteins. [4]
The detection of Triiodothyronine (T3) is also possible early in pregnancy, but the concentration levels in the fetal serum are low. These findings suggest that the process that converts T4 in T3 is either immature or not activated, since the major source of Free T3 results from the peripheral conversion of T4. [4]
Thyroid-stimulating hormone (TSH) is measurable around the 12th weeks, and its concentration will increase during pregnancy, despite the high serum free T4 concentrations. This is caused by the immaturity of the negative-feedback system until after birth. [4] [5] [6] (Figure 1)
Since the pituitary-thyroid axis is not yet functioning, the regulation of thyroid hormones depends on deiodinase enzymes. For example, in a fetus with
hypothyroidism, the type II deiodinase increase and type I and III decrease, allowing a decline in T3 degradation and a shunting of T4 to the brain. [4] [5] [6]
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The placenta is also important in thyroid fetal function. This organ is responsible for the passage and metabolism of mother’s thyroid hormones. Type II and type III deiodinase are present in placental tissue, and their function is to regulate fetal exposure to maternal thyroid hormones, converting T4 to T3 (deiodinase II) and T4 and T3 to reverse T3 and T2 (deiodinase III). For example, the activity of type II deiodinase increases when the availability of T4 decreases, maintaining T3
production in the placenta when maternal serum T4 concentrations are reduced. [5] [6] [7] (Figure 2)
Because of the highly active placental type III deiodinase, the beneficial effects of T3 are restricted to the placental cells. Some experts even think that the purpose of type III deiodinase is to maintain low T3 concentrations in the fetus and to protect
decidual cells from hypothyroidism. [5] [6]
Lastly, amniotic fluid is also important in thyroid metabolism. Its pattern reflects the maternal and fetal metabolisms. Reverse T3 and T4 (and their sulfatate conjugates) account for 95% of thyroid hormones. During the course of gestation RT3 will
decrease while T4 will increase. [6]
4.3) Fetal thyroid histology
As mentioned before, the initial thyroid precursor is hollow. [1] Then it becomes a solid mass composed of follicular cells, parafollicular or C cells and stroma.
The gland has a follicular structure with a peripheral line of rest follicular cells (with round to oval nucleus) attached to a basement membrane cells, followed by a
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variable number of active thyroid hormone-producing follicular cells packed around the central colloid deposit. [8]
This follicular appearance is similar to the adult thyroid gland, but with more cells, smaller follicles and less eosinophilic colloid. [8] As the pregnancy advances, the number of follicular cells decreases and their appearance become more cuboidal, with eosinophilic and apical cytoplasm. Their secretory activity increases and
although the hormone synthesis starts early at the 11th week, colloid storage is only seen after the start of second trimester. [8] Going into more detail, thyroid histology at 12 weeks show small follicular structures with little amount of colloid and round to oval cell with few cytoplasm (Figure 3A); on the 17th week there is an increase of the eosinophilic colloid inside the follicles and of the cells cytoplasm (Figure 3B). On the 36th week of gestation the gland presents histology similar to the adult thyroid with large eosinophilic follicles, surrounded by cuboidal cells with an apical cytoplasm (Figure 3C).
C cells are distributed between follicular cells and their function is to secrete
calcitonin, a hormone that regulates calcium. [9] Their identification with hematoxylin-eosin is very difficult in the fetal thyroid. Therefore, immunohistochemic and
grimelius silver methods are used to identify them. [8]
The stoma is the fibrous tissue and blood vessels that surrounds the follicular structures and its function is to support and nurture the thyroid cells. [8]
Fetal thyroid has also a fibrous capsule that limits the gland as the adult thyroid, but unlike the latter, fetal thyroid does not have lipofusion pigment. This is an important characteristic since the presence of pigments represents a thyroid anomaly. [8]
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4.4) Maternal thyroid disease and it impact on the fetus
Pregnancy represents a challenge for the thyroid gland. During this period major changes like the enlargement of the thyroid, the increase of thyroid blood flow, hormones and binding proteins and alterations in iodine handling are noticed. [10]
These hormones contribute to the correct development of the fetus and any maternal thyroid dysfunction can result in an adverse outcome.
The presence of thyroid antibodies occurs in 10% of women at 14 weeks of gestation and it is associated with a poor pregnancy prognosis. Their presence increases the risk of developing hypothyroidism. A pregnant woman with normal thyroid function but positive antibodies must be followed during pregnancy. [11]
The presence of antibodies is a risk factor of complications, independent of hypo or hyperthyroidism, like miscarriage, premature delivery, placenta abruption and subfertility. [11] [12] [13] [14] Their presence might even serve as a marker for other autoimmune conditions that can also increase the risk of fetal death. [15]
The antibodies are also associated with an increase in maternal complications like post-partum thyroiditis. [13]
Hypothyroidism is another maternal disorder that can affect the fetus. It occurs in 2.5% of women and can be caused by autoimmune disease or suboptimal iodine intake. [11] [16]
Early detection of hypothyroidism is crucial because the increase in TSH has been associated with impaired neuropsychological development of children [17] [18] and several other adverse outcomes, including spontaneous early preterm delivery [19],
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late-preeclampsia, miscarriage [20], fetal death and recurrent pregnancy loss [21] [22] [23].
The biggest problem is that this dysfunction is particularly difficult to diagnose because it can be subclinical and even when the pregnant woman has symptoms, the clinical manifestations are quite similar to normal pregnancy complaints (drowsiness, fatigue, extreme weight gain, constipation, hair loss, dry skin, general malaise).
Hyperthyroidism is found in 0.2% of all pregnancies and is usually due to Graves’ disease (which improves in the pregnancy). [11] [16] This dysfunction has been related to preterm delivery, miscarriage and placenta abruption. It also increases maternal morbidity due to the risk of congestive heart failure, thyroid storm and preeclampsia in women with uncontrolled hyperthyroidism. [11] [16].
Unlike hypothyroidism, sub-clinical or mild hyperthyroidism does not increase fetal or maternal morbidity. It is more readily diagnosed by a careful history, physical exam and laboratory testing. I 123 is very useful for thyroid scanning but it is contraindicated in the pregnancy due to its radioactivity that can be concentrated in fetal thyroid. [24]
5) Thyroid disease
5.1) Thyroid function screening
Screening comprises the systematic application of a test or inquiry for a disease, to the general population, to detect those individuals at high risk of being affected by
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the disease. Since thyroid dysfunction has a negative impact on the mother and fetus, universal screening of this hormonal dysfunction has been under debate. Currently, the American College of Obstetricians and Gynecologists (ACOG) recommends thyroid testing only in high-risk pregnant women who are symptomatic or have a personal history of thyroid disorders, type 1 diabetes or other autoimmune disorders. [25] As ACOG, the American Thyroid Association and the American Association of Clinical Endocrinologists also recommend aggressive case finding instead of universal screening. [26]
Not only who should be tested should be under debate, but also methods and cut-offs of the screening because there are no reliable population studies with reference intervals.
Guidelines recommend serum TSH as the initial test [25] because of its high sensitivity and specificity in the diagnosis of thyroid dysfunction [11] [27]. However, due to the thyroid-pituitary instability during pregnancy it is clearly insufficient alone. [28]
As total and free thyroid hormones measurement can be influenced by the elevation of TGB and very likely can lead to a wrong diagnosis, they cannot be used alone. [29] But some studies report that the combination of TSH and FT4 (free thyroxine) is the most sensitive method of screening [28] and this association seems particularly useful in low iodine countries where the prevalence of isolated hypothyroxinemia (low FT4 and normal TSH) is higher. [18] [30]
Thyroid antibodies like Thyroid peroxidase antibody (TPO-ab) can also be used in the screening to detect and treat early thyroid autoimmune disease. Their
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measurement allows us to predict the risk of thyroid dysfunction and obstetric complications during the pregnancy. [28] Some authors advocate that this test must be associated with TSH determination in high-risk women for autoimmune diseases [30]. TSH plus TPO can also be very beneficial if performed before conception. [31] In order to make all these measurements meaningful there is still an unsolved problem: the heterogeneity of both methods and population. Population based reference ranges need to be established, as well as remove several confounding factors such population composition, iodine intake, laboratory methods and the individual and genetic set point. [28]
5.2) Imaging of fetal thyroid
The prenatal scan is used to detect fetal goiter, enlargement and/or different coloring patterns of fetal thyroid gland, in situations of thyroid dysfunction.
Fetal goiter can be associated with fetal hyperthyroidism in cases in which maternal thyroid-stimulating antibodies cross the placenta stimulating the fetal thyroid (Figure 4), [32] or more rarely, with fetal hypothyroidism. The latter is usually caused by a primary metabolic thyroid disorder, transplacental passage of thyroid-inhibiting antibodies or the excessive treatment of hyperthyroidism. [32]
By adding the Doppler technique to the ultrasound examination we are able to
differentiate fetal hyper from hypo-function of thyroid gland, because hyperthyroidism causes an increase in central blood flow, while hypothyroidism presents more
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Fetal thyroid control in the womb is very important when we are treating a maternal thyroid disease like Graves disease. This allows the stricter control of mother dysfunction avoiding fetal hypothyroidism. [33] [34]
MRI (magnetic resonance imaging) is another way of studying the fetal thyroid, but is a more expensive method (Figure 6).
The presence of fetal thyroid changes as observed by imaging requires the evaluation of both mother and fetus thyroid status. [32]
6) Treatment
Once thyroid dysfunction is proved to be harmful, its prevention and treatment are very important.
As a start, all pregnant women should be prescribed additional iodine intake (150µg/day) to avoid iodine deficiency. [35] Another important measure is to treat every woman of childbearing age with known thyroid dysfunction, because it is well recognized that if they get pregnant while euthyroid the risk of fetal adverse outcome is equal to the general population [35].
The treatment of hypothyroidism is based on replacing the hormone with levothyroxine. The dose needed depends on several factors and has to be adjusted periodically, by monitoring thyroid function every 4/6 weeks, until 16/20 weeks and then less frequently. This monitoring scheme is based on the fact that levothyroxine dosage needs to be increased until 16 to 20 weeks and then they reach a plateau [35] [36].
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To those women who are already taking levothyroxine it should be explained that they have to increase their standard dose each week by 29%. [36]
Apart from its use in hypothyroidism, levothyroxine can also be useful in reducing the risk of miscarriage and premature birth in euthyroid women with autoimmune thyroid disease. [37]
Hyperthyroidism has several forms of treatment but not all can be used in pregnant woman. The pharmacologic treatment is one of the most common choices and it is based on the use of antithyroid drugs like methimazole (MMI) and propylthiouracil (PTU). [38]
Because MMI is associated with embryologic defects like aplasia cutis, atresias (choanal and esophageal) and PTU with liver disease, [34] [35] [38] some authors advocate that PTU should be used in the first trimester and, once embryogenesis has been completed, switched to MMI. [35] Both drugs can cause agranulocytosis, which is the most serious complication and requires immediate cessation of therapy. [35] [38] The dose used must be the lowest possible to repair the mother’s normal function, because these drugs can cross the placenta causing fetal hypothyroidism. [35]
β-Blockers, like propanolol, can also be use temporarily to reduce the symptoms associated with overachieving function (tachycardia, anxiety, weight loss), but because these drugs can be harmful to the uterine blood flow and can cross the placenta affecting the fetus development, they must be discontinued as soon as the symptoms improve. [35] [39]. The dose of β-Blockers must be adjusted to keep the maternal heart rate between 70 to 90 beats per minute. [38]
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Finally, thyroidectomy can also be considered in pregnant woman in who medical control cannot be achieved. [35] Surgery must be delayed until after the first trimester. [38]
7) Discussion
Thyroid dysfunction, a common anomaly in reproductive age women [16], increase the risk of obstetric complications such as impaired neuropsychological development, early preterm delivery, preeclampsia, fetal death and recurrent pregnancy loss. [40] [12] [20] [17] [41] [19] [42] [43]
It is therefore important that we answer three questions: WHO should we test? WHEN would it be soon enough? And HOW can we detect this dysfunction?
WHO?
Vaida et al. conclude in one of their studies that testing only high risk women would miss one third of pregnant women affected by thyroid anomalies. [18] A posterior study obtained an even higher percentage, claiming that 55% pregnant women would be missed if we use the current guidelines. [13]
It seems no longer acceptable to leave one third of women under diagnosed, when the negative impact can be so great and the diagnosis and treatment so easily accessible. [44]
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Another important fact about case finding instead of universal screening is that it cannot ensure equal care to all pregnant woman. Some studies prove that women were more likely to be detected if they were evaluated by an obstetric urban practitioner than by a family rural one. [45] This idea was reinforced by the Chang et al. study that focused on women with socioeconomically disadvantaged backgrounds. They obtained even more dramatic results than Vaida et al., who had 80% undiagnosed pregnant women with increased TSH. [46]
On the other hand, Negro et al. conclude that universal screening does not decrease the negative outcomes compared to case finding because adverse outcomes are less likely to occur in low risk women.
Cost-effectiveness studies have demonstrated that screening is economically beneficial [47] or even cost saving compared to no screening. [48] [26] But the true cost-effectiveness of the universal screening can only be proved by a randomized controlled trial. [26]
Some experts say that universal screening is not yet proven as the best solution [49] and, based on this absence of evidence, the American Thyroid Association, the American Association of Clinical Endocrinologists, the Endocrine Society and the American and College of Obstetrics and Gynecology recommend aggressive case finding instead of universal screening. [50] [24]
Hossein et al. reinforces the idea that their guidelines are based on a “lack of evidence for benefit rather than on evidence for a lack of benefit” and for the author this is an inadequate decision. [51]
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WHEN?
Most of the trials tend to test the thyroid function on the first trimester (first antenatal visit) [18] [13] [48] but is it soon enough?
The answer is maybe not because the fetus is most dependent on maternal thyroid in the first half of pregnancy (mainly on the first 13 weeks) [18] and nervous system development is already achieved by the first antenatal visit, so diagnosis and treatment of the thyroid dysfunction at this time may not prevent the total damage of this organ [11]
For this reason, it is generally agreed that screening should be done as early as possible, [52] even at the pre-conception visit so women can correct their thyroid dysfunction before getting pregnant. [31]
Another important point is that first trimester or pre-conception screening alone only allows the detection of disorders that occurred prior to pregnancy, missing those that appear later. [52] It is now relevant to establish if late dysfunction that appears in a less dependent fetus has also a negative impact and if it is worthwhile to test them.
HOW?
Serum TSH determination is the test approved by the guidelines. It is regarded as the most sensitive and specific method to screen pregnant and no pregnant women, [29] but it still has not appropriate reference values to the pregnant population. [13] Serum Free T4 is also useful to establish thyroid function, particularly in countries with low iodine consumption because they have a greater prevalence of isolated
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hypothyroxinemia. [18] The problem of this test is that the increase of TBG will hinder the correct interpretation of its value. Some authors suggest using Total T4 (TT4) with 100nmol cut-off instead. [29]
TPO antibodies can also give important information about pregnancy outcome. Besides increasing the risk of hypothyroidism, TPO-ab are also associated with adverse outcome by themselves. [13]
Expert opinions on which further tests to use are still mixed. Some think that serum TSH alone is enough to screen [30] but others disagree [28]. On low iodine countries, the TSH plus FT4 association seems very important, once the TSH determination alone would miss 40% of the dysfunction. This association seems to have the greater number of followers, even in countries without iodine deficits. [30] [29]
Some defend that TSH-TPO association would be ideal, particularly in the pre-conception period. [31]
In the midst of disagreement, all seem to agree that we need randomized controlled trials that prove the impact of treating these maternal dysfunctions. [18] But this trial can take a long time to be implemented because we can only evaluate correctly the negative impact on neuropsychological development and QI during childhood.
Until then, aggressive case finding is going to prevail. So it is very relevant alert the pregnant caregivers to the importance of thyroid dysfunction so they can diagnose and treat more often this kind of dysfunction.
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8) Guidelines
The American College of Obstetricians and Gynecologists guidelines [24]: Screening of all pregnant women with a personal history, physical examination, or symptoms of a thyroid disorder.
The Endocrine Society Clinical Practice Guideline [50]: case finding should be recommended among the following groups of women at high risk for thyroid disease by measuring TSH:
a) Women with a history of hyperthyroid or hypothyroid disease, premature delivery or thyroid lobectomy.
b) Women with a family history of thyroid disease.
c) Women with a goiter.
d) Women with thyroid antibodies (when known).
e) Women with symptoms or clinical signs suggestive of thyroid underfunction or overfunction, including anemia, elevated cholesterol, and hyponatremia.
f) Women with type I diabetes.
g) Women with other autoimmune disorders.
h) Women with infertility who should have screening with TSH as part of their infertility work-out.
i) Women with previous therapeutic head or neck irradiation.
j) Women with a history of miscarriage or preterm delivery. USPSTF recommendation level is B; evidence is fair (GRADE 1)”
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9) Conclusions:
A universal screening of thyroid dysfunction in the pregnancy is a desirable end point, but more studies need to be done to support its implementation and clinical justification.
10) Acknowledgements:
We would like to thank to Gerard N. Burrow and Otilia Brandão for giving permission to use their images in our paper.
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[32] E. Merz, Ultrasound in obstetrics and gynecology. s.l. : Thieme, 2007.
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12) Legends to the figures
Figure 1 - Relative changes in maternal and fetal thyroid hormones during
pregnancy. (Adapted from N Gerard et al, 1994)
Figure 2 - Interrelations of maternal, placental, and fetal pathways in thyroid function
during pregnancy. (Adapted from N. Gerard et al, 1994)
Figure 3 - Thyroid histology at 12 weeks (3A) shows small follicular structures with
little amount of colloid and follicular cells with few cytoplasm; on the 17 th
week (3B) there is an increase of the eosinophilic colloid inside the follicles and of the cells cytoplasm. On the 36th week of gestation (3C) the gland presents histology similar to the adult thyroid with large eosinophilic follicles, surrounded by cuboidal cells with an apical cytoplasm (courtesy of O. Brandão).
Figure 4 – Ultrasound bidimensional image from a fetal goiter presenting as a
voluminous mass in the fetal neck. (Courtesy of A. Matias)
Figure 5 – Fetal hypothyroidism is evidenced by Doppler ultrasound as presenting
with a more peripheral vascularization pattern in the fetal thyroid. (Courtesy of A. Matias)
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Anexos
Autorização de reprodução de imagens:
Imagens 1 e 2: confirmação por email: gerard.burrow@yale.edu
“Assunto - Permission to reproduce copyrighted materials: Joana,
You have my permission to use Figures 1&3 from my article "Fetal and Maternal Function.
Good Luck with your thesis and in Medicine. Gerard N. Burrow,M.D.”
Imagens 3A, 3B e 3C: confirmação por email: o.brandao@portugalmail.pt
“Assunto - :
É com muito gosto que cedo as imagens acima referidas com o objectivo de serem utilizadas na sua tese de mestrado.
Esperando, também, ter sido útil, desejo que tudo corra bem. Até sempre e com os melhores cumprimentos,
Otilia Brandao”
Imagens 4, 5 e 6: confirmação por email: almatias@mail.telepac.pt
“Assunto - Pedido de permissão para utilizar material já publicado: Estimada Joana Félix,
“As imagens contidas na sua monografia correspondentes ao caso clínico "Tiroxina intra-amniótica no tratamento do bócio fetal hipotiróideu" podem ser usadas na tese de mestrado e qualquer publicação que daí decorra. Cumprimentos
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Methods:
Using article databases such as PubMed and Google academic, books of endocrinology and obstetrics and some web sites of medical journals and organization of the last ten years, we collected, synthesized and integrated
information about the embryology, physiology, histology and imaging of fetal thyroid, maternal thyroid disease and their impact on the fetus, the treatment that can be offered, the guidelines and the impact of this screening on the course of pregnancy.
Fetal Thyroid embryology:
The Developing Human: clinically oriented embryology (8th ed.) – (1) Langman's Medical Embryology – (2)
Medscape: key Word: “thyroid embryology” – (3)
Fetal thyroid physiology:
PubMed: key word “fetal thyroid function” – (4) PMID: 1422233, (5) PMID: 19901830, (6) PMID: 8090169
Google academic: key word “fetal thyroid function” – (7)
Fetal thyroid histology
Google books: KEY WORD: “Histology of thyroid gland” – (8) AND (9)
Maternal thyroid disease and it impact on the fetus:
Pubmed: key words “physiology of thyroid function in pregnancy”, “thyroid disease in pregnancy”, “Maternal Thyroid Function at 11 to 13 Weeks” – (10) PMID: 382166, (11) PMID: 15858112, (12) PMID:20718684, (14) PMID:21857181, (15) – PMID: 11126160, (16) – 12487768, (17) PMID: 10451459, (18) PMID: 17032713, (19) PMID: 18984665, (20) PMID: 20865794 and (22) PMID: 18923214
Google academic: “maternal thyroid and pregnancy complications”, “epidemiology of thyroid disease in pregnancy”, “maternal thyroid disease”, “TSH pregnancy miscarriage, pregnancy loss, fetal death” – (13), (21)
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Thyroid function screening:
Pubmed: key words “universal screening thyroid in pregnancy”, “thyroid disorders to obstetrician”. – (23) PMID: 199273570, (26) PMID: 19114278, (27) PMID: 20531379, (28) PMID: 21512584 and (29) PMID:15687823
American college of obstetricians and gynecologist: thyroid guidelines - (25) American thyroid association (www.thyroid.org) – key word “thyroid disease and
pregnancy). – (24) Images of fetal thyroid:
PubMed: key word “fetal thyroid ultrasound” and “ultrasound in obstetrics” – (30) PMID: 21411022, (31) PMID: 20375219
Google academic: key word “fetal thyroid ultrasound”, “ultrasound in obstetrics” – (32)
Thyroid disease manager – chapter 6 ultrasonography of the thyroid – (33)
Treatment
PubMed: Key words: “levothyroxine during pregnancy”, “hyperthyroidism in pregnancy treatment” and “intervention for hypothyroidism in pregnancy” – (34) PMID:16118343, (36) PMID: 15254282, (37) PMID: 16621910
Book: Management of Common Problems in Obstetrics and Gynecology fifth edition (35) Chapter 23 - Thyroid Disease in Pregnancy: Hyperthyroidism and chapter 24 - Thyroid Disease in Pregnancy: Hypothyroidism
Discussion:
PubMed: “maternal thyroid function at 11-13 weeks”, “hyperthyroidism and hypothyroidism in pregnancy”, “thyroid and pregnancy” and
“cost-effectiveness screening pregnant thyroid function” - (38) PMID: 10447008, (40) PMID: 21252742, (41) PMID: 11397821, (42) PMID: 21687610, (43) PMID: 15142372, (44) PMID: 17209222, (45) PMID: 16458648, (46) PMID: 21715539, (47) PMID: 18762789, (48) PMID: 18505905 and (49) PMID: 14722150
The Journal of clinical Endocrinology and Metabolism: “thyroid and pregnancy”- (51) Google academic: – “thyroid dysfunction during pregnancy” and “screening thyroid
status in pregnancy” – (52)
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Apêndice
Normas de submissão da revista: Journal of Neonatal-Perinatal Medicine
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Tables: Submit tables within the word processing manuscript document but at the end in its own section.
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[2] T.N. Raju, R.D. Higgins, A.R. Stark and K.J. Leveno, Optimizing care and outcome for late-preterm (near-term) infants: a
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