ppt referat obgyn

Diagnosis and Management Thyroid Autoantibodies in Miscarriage and Preterm Birth COUNSELOR : DR ARIE A. POLIM, SP OG-KFER, D. MAS

PRESENTANT :

PAULINE OCTAVIANI 2011-061-147

CINDY AGUSTIANI 2011-061-150

FUJIYANTO 2012-061-082

INEZ AYUWIBOWO S 2012-061-083

Contents

Session 1 : Preterm Birth and Miscarriage

Session 2 : Anatomy, Physiology, and Disorder of Thyroid

Session 3 : Thyroid Function in Pregnancy

Session 4 : Association between Thyroid Autoantibodies and Misscariage and Preterm Birth

Introduction

Misscariege : affects up to 1:5 women who conceive

Preterm delivery : occurs in 6-10% of pregnancies

There is evidence thyroid autoimmunity is an important risk factor for miscarriage and preterm birth

the prevalence ranges from 6-20%, being even higher in women with a history of recurrent pregnancy loss at around 17-30% and in women with a history of subfertility at around 10-31%.

Session 1 : Preterm Birth and Miscarriage

Preterm birth

Preterm Birth

Epidemiology

Prematurity a major public health concern and the leading cause of neonatal mortality

USA preterm delivery rate is 12–13%. The preterm birth rate has risen in most industrialised countries, with the USA rate increasing from 9,5% in 1981 to 12,7% in 2005.

Preterm births account for 75% of perinatal mortality and more than half the long-term morbidity. Although most preterm babies survive, they are at increased risk of neurodevelopmental impairments and respiratory and gastrointestinal complications.1

Preterm birth

Figure 1: Major causes of death in children younger than age

5 years and in neonates (yearly average for 2000–03)1

Preterm birth

The obstetric precursors leading to preterm birth

1. delivery for maternal or fetal indications, in labouris either induced or the infant is delivered by prelabour caesarean section

2. spontaneous preterm labour with intact membranes

3. preterm premature rupture of the membranes (PPROM), irrespective of whetherdelivery is vaginal or by caesarean section

Preterm birth

Risk Factors

patients who experience a preterm birth recurrence risk is 2x higher. In addition, the gestational age of the initial preterm birth is predictive of the gestational age of the subsequent preterm birth.

Of all women with a prior preterm birth who deliver preterm in a subsequent pregnancy, 50% of deliveries occur within 1 week and 70% of deliveries occur within 2 weeks of the gestational age of the prior preterm delivery.

Preterm birth

In an observational study performed by the National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units (MFMU) women with a history of at least one previous preterm birth at <32 weeks, women underwent endovaginal ultrasounds between 16 and 18 weeks and then every 2 weeks until 24 completed weeks gestation.

Closed cervical length measurements as well as the presence or absence of dynamic changes of the cervix were assessed. The primary endpoint was spontaneous preterm birth at <35 weeks gestation.

Results cervical length between 16 and 18 weeks was most predictive of recurrent preterm birth. Cervical length measurements <25 mm had a positive predictive value of 75%, and cervical length measurements <15 mm had a positive predictive value of recurrent preterm birth at 35 weeks gestation of 100%.2

Preterm birth

Pathophysiology of Preterm Birth

The process that results in labor and birth involves a cascade of events that is incompletely understood.

Myometrial and amniotic membrane overdistention, decidual hemorrhage, premature fetal endocrine activation (through the hypothalamic-pituitaryadrenal axis), and intrauterine infection/inflammation have all been implicated in the pathophysiology of preterm labor.

Progesterone withdrawal and estrogen activation have also been thought to play a role in parturition.

Preterm birth

As gestation progresses to term, the myometrial sensitivity to progesterone changes.

There is an increased expression of progesterone receptors in the myometrium decreased progesterone availability to suppress the expression of estrogen. The myometrium becomes more sensitive to estrogen,and myometrial contractility increases.

This pathway accounts for the role of progesterone administration in the prevention of preterm birth.1

Preterm birth

Management and Prevention of Spontaneous Preterm Birth :

Fetal fibronectin testing a tool to help triage patients presenting with preterm contractions.

Fetal fibronectin is found normally in vaginal secretions in the first and late third trimesters and should be virtually undetectable between 22 and 35 weeks gestation, and its presence during this period is believed to be pathologic.

studies to evaluate the role of progesterone in the prevention of spontaneous preterm birth.

Progesterone inhibits the formation of gap junctions and inhibits myometrial contractions. Its use has also been shown to prevent spontaneous abortion in women in whom the corpus luteum has been excised.

Miscarriage

Miscarriage

Miscarriage spontaneous loss of the conceptus before 20 weeks’ gestation may also called a "spontaneous abortion."

A majority of miscarriages that occur <10 weeks’ gestation are due to chromosomal aneuploidies arising from noninherited, new nondisjunctional events; these events are more frequent in very early miscarriages.

The rate is increases with a maternal age <18 years or ≥35 years, an increasing number of previous miscarriages, and increasing parity.

The sharp increase in the rate of miscarriage in women ≥ 35 years is due in part to increasing rates of aneuploidy in association with older oocytes.3

Recurrent miscarriage, defined as the loss >3 consecutive pregnancies, occurs in approximately 1% of couples attempting to bear children.

Session 2 : Anatomy, Physiology, and Disorder of Thyroid

Anatomy of Thyroid

Thyroid anatomy : it is located in the neck just below the larynx, anterior to the trachea between the cricoid cartilage and the suprasternal notch.

The thyroid consists of two lobes that are connected by an isthmus

Normally, the size is 12-20 g, highly vascular, and soft in consistency.

The gland consists of numerous spherical follicles secreting a proteinaceous fluid containing large amounts of thyroglobulin, the protein precursor of thyroid hormones.

Thyroid Physiology

Thyroid Physiology

Thyroid hormone regulated through a negative-feedback loop involving the hypothalamus, the anterior pituitary, and the thyroid gland.

Hypothalamic TRH (Thyrotropin-releasing hormone) stimulates pituitary production of TSH (Thyroid Stimulating Hormone), which in turn stimulates thyroid hormone synthesis and secretion (T3 and T4). Thyroid hormones negative feedback to inhibit TRH and TSH production.

Thyroxine (T4) is the main hormone released from the thyroid gland and it is transformed into biologicaly active triiodothyronine (T3), which has the greatest metabolic effect

Disorder of Thyroid

Disorder of thyroid may develop primarily (dysfunction of thyroid gland) or secondarily (alterations in pituitary or hypothalamic)

Hyperthyroidism is an excessive thyroid function. Primary hyperthyroidism is a form of thyrotoxicosis. Secondary hyperthyroidism is caused by TSH-secreting pituitary adenomas.

major etiologies of thyrotoxicosis are hyperthyroidism caused by Grave’s disease, toxic multi nodular goiter, and toxic adenomas.

The clinical features are attributable to the metabolic effects of increased circulating levels of thyroid hormone. This results in an increased tissue sensitivity to stimulation by the sympathetic nervous system.

Disorder of Thyroid

Grave’s disease is an autoimmune disease that results in stimulation of the thyroid gland and resultant hyperthyroidism.

The hyperthyroidism is caused by thyroid stimulating immunoglobulin (TSI) synthesized in the thyroid gland, bone marrow, and lymph nodes.

TSI binds to TSH receptors in the thyroid gland and stimulate the synthesis and secretion of excess thyroid hormone. The hyperfunction of the thyroid gland is reflected in an increase rate of thyroid gland metabolism, which may contribute to hypervascularity and enlargement of the gland.

Disorder of Thyroid

hypothyroidism is caused by a deficient production of thyroid hormone. Primary hypothyroidism causes :

defective hormone synthesis resulting from autoimmune thyroiditis

endemic iodine deficiency, or

iatrogenic loss of thyroid tisuue after surgical or radioactive treatment for hyperthyroidism, also conginetal defects.

Secondary hypothyroidism is a conditions that cause either pituitary or hypothalamic failure to stimulate normal thyroid function.

Disorder of Thyroid

Autoimmune thyroiditis, called Hashimoto disease gradual inflammatory destruction of thyroid tissue caused by infiltration of lymphocytes

circulating thyroid autoantibodies (antithyroid peroxidase and antithyroglobulin antibodies).

Cytokines

induction of apoptosis also involved in tissue destruction

the thyroid lymphocytic is composed of activated CD4+ and CD8+ T cells and B cells.

CD8+ cytotoxic T cells, which destroy thyroid cells by either necrosis or apoptosis. Local T cells production of cytokines thyroid cells more susceptible to apoptosis. These cytokines also impair thyroid cell function directly and induce the expression of other proinflammatory molecules by the thyroid cells themselves, such as nitric oxide.

Antibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO) are clinically useful markers of thyroid autoimmunity

Session 3 : Thyroid Function in Pregnancy

Inez Ayuwibowo

Thyroid Hormone Physiology Changes in Normal Pregnancy

Thyroid gland volume may enlarge Thyroid hormone production increases about 50%

Total T4 = approximately 1.5 times the non-pregnant value (due to the relatively high circulating hCG concentration)

Free triiodothyronine (FT3) concentration ~ FT4

Adequate concentrations of T4 maternally derived from= neural development during the first trimester.

Thyroid Hormone Physiology Changes in Normal Pregnancy

The placenta secretes hCG, unique beta subunit = TSH agonist elevated levels gestational transient hyperthyroxinaemia (0.3% of pregnancies)

Estrogen increase the amount of thyroid hormone binding proteins in the serum increases the total thyroid hormone levels in the blood

“Free” thyroid hormone = usually remain normal

Metabolically controlled by the placental deiodinase enzymes and the thyroid hormone cell transporters thyroid hormone from maternal to fetus

Fetus starts to produce thyroid hormones by the end of the first trimester (10-12 weeks of pregnancy)

Essential Tests of Thyroid Function in Pregnancy

Ultrasound to detect an increase in thyroid volume

The interpretation of thyroid function during gestation needs to be adjusted according to pregnancy-specific ranges

It is essential therefore to have reliable accurate tests of thyroid function in pregnancy as maternal thyroid dysfunction may affect maternal health, foetal health and obstetric outcome.

Ultrasound to detect an increase in thyroid volume

The interpretation of thyroid function during gestation needs to be adjusted according to pregnancy-specific ranges


It is essential therefore to have reliable accurate tests of thyroid function in pregnancy as maternal thyroid dysfunction may affect maternal health, foetal health and obstetric outcome.

Serum TSH concentrations = first clinical indicator for thyroid dysfunction in the non-pregnant patient

Early gestation – TSH is suppressed does not provide a good indicator

T4 and T3 (either bound or free) concentration to assess thyroid status

Later in gestation (from about16 weeks on) TSH is more reflective of thyroid status.


Trimester-specific reference ranges for TSH

first trimester, 0.1–2.5 mIU/L

second trimester, 0.2–3.0 mIU/L

third trimester, 0.3–3.0 mIU/L

Thyroid antibodies (Thyroid Peroxidize Antibodies, TPOAbs and TSH receptor antibodies, TSHRAbs) indication of thyroid status = important implications for the pregnancy

Thyroid Dysfunction in Pregnancy

Iodine deficiency during pregnancy - maternal goitre

Most common maternal hyperthyroidism during pregnancy = Graves’ disease

due to thyroid stimulation by thyrotropin receptor antibodies

1 in 1500 pregnant patients

Occur first trimester, often third trimester

Inadequately treated maternal hyperthyroidism early labor and pre-eclampsia.


The aim of treating hyperthyroidism in pregnancy with antithyroid drugs is to maintain serum thyroxine (T4) in the upper normal range of the assay used with the lowest possible dose of drug.

The thionamide drugs CMI, MMI, and PTU (preferred drug in the first trimester) are all effective in inhibiting thyroidal biosynthesis of thyroxine during pregnancy.

CMI or MMI should be given in the second and third trimesters

Radioiodine is contraindicated to treat hyperthyroidism during pregnancy

Surgery is an acceptable alternative but very rarely

Beta-blockers can be used during pregnancy to help treat significant palpitations and tremor due to hyperthyroidism


Hypothyroidism is quite common in pregnancy

Subclinical hypothyroidism 2.5%

Asymptomatic

50–60% will have evidence of autoimmune thyroid disease (TPOAbs, TgAbs)

Overt hypothyroidism 5% of all women who have a high TSH.

The aim of treating hypothyroidism is to return serum TSH to the range between 0.5 and 2.5mU/L.

Adequate replacement of thyroid hormone in the form of synthetic levothyroxine, frequently increase during pregnancy

Prenatal vitamins contain iron and calcium that can impair the absorption of thyroid hormone from the gastrointestinal tract

Session 4 - Association Between Thyroid Autoantibodies and Miscarriage and Preterm Birth

Preface

1990 :

Stagnaro-Green : euthyroid women with TA (+) more liable to have a spontaneous abortion.

Patients who were positive for thyroid antibodies (TPO and Tg) had a twofold increase in the risk of pregnancy loss (17% vs. 8,4%, p=0,011).

Since then, numerous studies on the association between TAI and miscarriage have been published.10,11

Preface

Although many types of antithyroid antibodies have been described, the most common : thyroid peroxidase.

The prevalence of thyroid peroxidase antibodies is increased almost 10-fold in women compared with men, it increases with age, and it has been reported in 5–10% of pregnant women

Overt and subclinical hypothyroidism are the two disorders most commonly associated with adverse outcomes, and together, they are thought to represent a continuum of autoimmune thyroiditis.

Thyroid autoimmunity is an important risk factor for miscarriage and preterm birth.

The odds of miscarriage more than tripled and that of preterm birth doubled in women with thyroid autoantibodies

TPO are present in 10% of women at 14 weeks’ gestations.

The exact mechanisms of these associations are unknown, though two have been proposed:

1. The presence of thyroid autoantibodies in women with normal thyroid function could be associated with a subtle deficiency in the availability of thyroid hormones (a fall in circulating free thyroid hormones within the reference range) or a lower capacity of the thyroid gland to adequately rise to the demand for augmented synthesis of thyroid hormones required in pregnancy.

2. Thyroid autoantibodies might be an indicator of an underlying enhanced global autoimmune state.

This itself can have a direct adverse effect on placental or fetal development.

Diagnosis of Thyroid Autoantibodies in Preterm Birth and Miscarriage

TPOAb levels are associated with a high risk of miscarriage and failure to conceive with in-vitro fertilization

Universal screening for thyroid disorders in pregnancy not recommended

Women to be screened for TPO antibodies before or during pregnancy not recommended

TPOab assay = immunoenzymatic "sandwich" assay

blood serum, hemolyzed not acceptable

be separated from the cells within 2 hours of collection

refrigerated and stable for 7 days

sample volume for the assay is 1 mL, min 0.3 mL

Reference range for TPOab is less than 35 IU/mL



TPO antibodies are found in the majority of patients with Hashimoto's and Grave's disease, myxodema,pernicious anemia without overt thyroid disease, treated with lithium, amiodarone, interleukin-2 or interferon-alpha

Recommend that all pregnant women should have TSH and TPOAb levels measured in the first trimester of their pregnancy


Management

Levothyroxine (LT4) correct any relative deficiency of thyroid hormones and impact

on both systemic immune regulation and the local placental-decidual environment.13

effective when given during the early stages of pregnancy.14 At early gestational stages, the presence of thyroid hormones in fetal

structures can only be explained by transfer of maternal thyroid hormones to the fetal compartment, because fetal production of thyroid hormones does not become efficient until mid-gestation.20

Whether thyroid hormones should be given prior to or during pregnancy in euthyroid women with thyroid autoantibodies remains controversial.14

Management

OH :

elevated TSH (>2.5 mIU/L) in conjunction with a decreased FT4 concentration.

TSH levels of 10.0 mIU/L or above, irrespective of their FT4 levels.

SCH is defined as a serum TSH between 2.5 and 10 mIU/L with a normal FT4 concentration.

Women who are TPOAb (+) and have subclinical hypothyroid should be treated with LT4.

Dose : 50 - 100 microgram daily. Max dose is 200 microgram daily.

LT4 dose often needs to be incremented by 4–6 weeks gestation and may require a 30–50% increment in dosage.

Management

OH normalized as soon as possible.

Target TSH :

< 2.5mIU/L in the first trimester, < 3mIU/L in second and third trimesters or to trimester-specific normal TSH ranges (first trimester: 0.1-2.5 mIU/L; second trimester: 0.2-3.0 mIU/L; third trimester 0.3-3.0 mIU/L).

Thyroid function tests should be remeasured within 30–40 day.

After delivery, most hypothyroid women need to decrease the thyroxine dosage they received during pregnancy.

Management

Varying degrees of adjustment dosage based upon the underlying cause of their thyroid dysfunction. Ex. : Loh et al. who observed that patients with a history of thyroid cancer on doses of

LT4 sufficient to suppress preconception TSH required smaller and less frequent incremental adjustments of LT4 during the pregnancy in order to keep TSH within the normal range than did patients suffering from other causes of hypothyroidism.

Negro et al 115 women who were TPO-positive were divided into two groups: Group A (n = 57) included TPO+ women treated with levo-thyroxine

Group B (n = 58) included TPO women who received no levothyroxine intervention

Group C (n = 869) consisted of all TPO antibody negative women, none of whom received levothyroxine.

The miscarriage rate was significantly higher in Group B (13.8%) than in Group A (3.5%) or C (2.4%) (P < 0.05). Similarly, the preterm delivery rate was higher in Group B (22.4%) than in Group A (7%) or C (8.2%) (P < 0.05).21

Management

Selenium. Se exerts multiple actions on endocrine systems by modifying the expression

of at least 30 selenoproteins.

Well-characterized selenoenzyme families include the glutathione peroxidases (GPx), thioredoxin reductases, & iodothyronine deiodinases acting as antioxidants, and modifying redox status and thyroid hormone metabolism.

• Se supplementation may decrease inflammatory activity in patients with autoimmune thyroiditis, especially in those with high activity, and ameliorates the thyroid echogenicity pattern.

• Se administration in the dosage of 200µg/d during pregnancy and the postpartum period exerted an antiinflammatory action, reduced TPOAb titers, and ameliorated the US echogenicity pattern with respect to controls.

Management

Women who had had an miscarriage had significantly lower selenium hair content than control.

Selenium concentration varies during pregnancy but tends to be lower in the third trimester.

Study (Italy) :

supplementing Se-Met in pregnant women with AIT resulted in lower incidence of Post Partum Thyroid Disease (PPTD) and of permanent hypothyroidism by comparison with two other study groups, one placebo and one control.

the reduction in anti-TPO was greater in the SeMet group than the decreased titer induced by the gestational immunosuppression in the control group

Conclusion

The maternal physiological changes that occur in normal pregnancy induce complex endocrine and immune responses reliable accurate tests of thyroid function in pregnancy as maternal thyroid dysfunction may affect maternal health, fetal health and obstetric outcome. including preterm delivery, placental abruption, and abnormal neuropsychologic development.

There is evidence that thyroid autoimmunity is an important risk factor for miscarriage and preterm birth. The odds of miscarriage more than tripled and that of preterm birth doubled in women with thyroid autoantibodies, especially thyroid peroxidase antibodies (TPOAb).

Conclusion

Detection of IgG autoantibodies against thyroid peroxidase enzyme is a useful aid in the diagnosis of autoimmune thyroid diseases. Recent reports have suggested that all pregnant women should have TSH and TPOAb levels measured in the first trimester of their pregnancy.

Treatment with levothyroxine might correct any relative deficiency of thyroid hormones . This thyroxine treatment may be effective in reducing number of miscarriages when given during the early stages of pregnancy.

Selenium is effective in reducing TPOAb titers in patients affected by thyroid autoimmune diseases, probably due to its modification of the inflammatory and immune responses

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