Thyroid Disorders

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Thyroid Disorders Pregnancy & Fertility

Overactive or underactive thyroid function is more common in women and can occur during pregnancy, after pregnancy (often resulting in post partum depression), or may be the cause of infertility, fetal abnormalities, stillbirth and premature labor. Although pregnancy causes the thyroid gland to enlarge, thyroid function usually remains stable. Therefore, pregnancy itself does not cause abnormal thyroid function, but rather hypothyroidism and hyperthyroidism may be found in pregnant and non-pregnant women alike. In addition, babies who are born to mothers with thyroid disease may also have hypothyroidism or hyperthyroidism, which may impair their future intellectual, emotional and physical development, if unrecognized.

Hyperthyroidism and Pregnancy
Hyperthyroidism affects less than 1% of all pregnancies, but it has important consequences for both the mother and fetus. Although many women with hyperthyroidism experience changes in their menstrual cycle, such as irregular periods and lack of ovulation, these changes do not necessarily into infertility problems in a women with only mild hyperthyroidism. However, once a woman with hyperthyroidism becomes pregnant, there is an increased risk of miscarriage, spontaneous abortion, fetal growth retardation, premature labor and delivery, congenital malformations and possibly pre-eclampsia. Fetal death may occur as a result of chromosomal abnormalities such as Down's syndrome. These risks are decreased in women where the hyperthyroidism is recognized early and treated appropriately. Diagnosis Often it is difficult to distinguish the symptoms of hyperthyroidism from those of normal pregnancy. The symptoms of both conditions may overlap. For example, feeling hot, excessive sweating, emotional excitement, nervousness, vomiting or a racing heart beat may be common to both normal pregnancy as well as hyperthyroidism. However, two common symptoms exclusive to hyperthyroidism are: a very rapid heart rate above 100 beats per minute, and weight loss. If

you are pregnant and are experiencing these symptoms, you should be tested for hyperthyroidism so that it can be treated in order to prevent problems with your pregnancy. Once the diagnosis of hyperthyroidism has been made, it is important to determine the cause of your overactive thyroid in order to choose the most effective treatment. (see the section on hyperthyroidism.) It is important to note that the cause must be diagnosed from physical exam and blood tests. Nuclear scanning can not be performed if you are pregnant because it uses radioactive materials that are taken up by the thyroid gland of both the mother and fetus. The fetal thyroid can be destroyed by this radioactive material, resulting in an underactive thyroid gland, which can cause severe mental, as well as physical, retardation. Always tell your physician if you are pregnant or think you might be pregnant in order to avoid tests that are potentially harmful to your baby. One type of blood test called thyroid-stimulating immunoglobulins may be elevated if you have a particular type of hyperthyroidism called Graves' disease (see the section on hyperthyroidism). This test may be elevated even if you are not currently experiencing any symptoms of hyperthyroidism. It is important to follow these levels of thyroid-stimulating immunoglobulins with blood tests every few months if you are pregnant because elevated levels may have a profound effect on the newborn baby (see section on newborn hyperthyroidism below). Treatment Hyperthyroidism may affect the mother as well as the developing fetus. The most serious complication from untreated hyperthyroidism is heart disease, specifically heart failure as a result of the heart beating faster than normal and working overtime in response to the increased levels of thyroid hormone. Patients may potentially develop a more serious complication of untreated hyperthyroidism called thyroid storm. Usually a stressful triggering event such as labor, caesarean section or untreated infection can cause the hyperthyroidism to spiral out of control. This excess of thyroid hormone can cause death if not diagnosed and treated promptly. Many of the treatments that are typically used for hyperthyroidism can be harmful to the developing fetus or can be passed to the newborn baby via the breast milk. For example, beta blockers (to control heart rate) and iodides can not be used because they may cause problems with your placenta, growth retardation of the fetus or an underactive fetal thyroid. Therefore these drugs are only used in extreme circumstances when the mother's life is in danger or when thyroid surgery is required. Radioactive iodine also can not be used because the radioactive iodine may destroy the fetal thyroid as well as the mother's thyroid gland, resulting in a hypothyroid baby. In this case, not only is the baby at risk for intellectual and physical growth retardation, but the hypothyroidism may cause severe enlargement of the baby's thyroid gland. The gland may be so large that it interferes with normal vaginal delivery, necessitating caesarean section. Therefore, the goal for the treatment of hyperthyroid women is twofold 1) to protect the mother and 2) to protect the developing fetus. Propylthiouracil (PTU) is the most commonly used drug to treat hyperthyroidism during pregnancy. However, it is important to note that the fetal thyroid is vulnerable to anti-thyroid medications taken by the mother such as methimazole, PTU or radioactive iodine. If the fetal

thyroid is affected by these medications, the developing baby may not produce enough thyroid hormone to sustain normal development. However, the risk of harm to the fetus is minimal if the mother is given the lowest possible dose necessary (which is often all that is needed since pregnancy itself can often improve the course of Graves' disease due to natural suppression of the mother's immune system during this period). Without treatment, the baby is at risk for spontaneous abortion and premature delivery. Therefore, the risks and benefits of each individual situation must be carefully measured whenever starting drug therapy in a pregnant woman. No long term ill effects have been noted in intellectual development of those children born to mothers taking PTU for hyperthyroidism during their pregnancy. Surgery Surgery is reserved for those pregnant women who can not take anti-thyroid medication, for example due to allergy or if the mother requires very high doses to control the disease. Thyroid surgery may be performed safely during pregnancy if you are properly prepared with anti-thyroid drugs in order to avoid "thyroid storm" (see above). The safest time to operate is during the second trimester because the risks of miscarriage (during the first trimester) or premature labor and delivery (third trimester) are minimized. Effects on Your Baby Even if you are taking the appropriate medicine during your pregnancy to successfully treat your hyperthyroidism, your baby is still at risk for the development of hyperthyroidism called neonatal thyrotoxicosis. Even with proper medication or surgery, thyroid stimulating antibodies may remain in your bloodstream and may be passed to your newborn baby. Therefore, your baby must be tested (with a simple blood test) immediately after birth for a possible overactive thyroid gland. In addition, anti-thyroid drugs taken by you during your pregnancy may pass through the bloodstream and placenta to your baby and mask your newborn baby's hyperthyroidism for 7 to 10 days until these medications have worn off. Careful follow-up by the baby's pediatrician is essential. Although less than 2% of babies who are born to mothers with Graves' disease suffer from newborn hyperthyroidism, the mortality rate of this disease if not recognized and properly treated is as high as 20%. Both of the commonly used anti-thyroid drugs, methimazole and PTU are passed through the breast milk into your new born baby. In high doses, these medications may block the baby's thyroid gland, causing hypothyroidism. This underactive thyroid may result in severe intellectual and growth retardation. PTU passes into the breast milk less readily than methimazole does, and therefore PTU is preferred in mothers who are breast feeding. However, because of the risk of hypothyroidism for the baby, only mothers who are on extremely low doses of PTU should be allowed to breast feed. The children of these mothers should be followed closely by their pediatricians. If the dose of PTU needs to be increased, the mothers should bottle feed rather than nurse their baby.

Hypothyroidism and Pregnancy
Because many of the symptoms of normal pregnancy such as weight gain, fatigue and swelling overlap with the symptoms of hypothyroidism, it may be difficult to make this diagnosis if you are pregnant. Standard thyroid function blood tests will make this diagnosis with certainty, allowing for successful treatment. Hypothyroidism is treated with thyroid hormone medication in pregnant and non-pregnant persons alike. This treatment is safe for the developing baby because it can not cross the placenta into the baby's bloodstream. Although the causes of hypothyroidism include several different types of thyroid illnesses, the treatment with thyroid hormone medication is the same. Only tiny amounts of thyroid hormone medication are excreted in breast milk. Therefore there is no danger to the newborn baby if you are breast feeding. In addition, it is important to have normal thyroid function in order to produce an adequate supply of breast milk. If you have an underactive thyroid you must be treated with thyroid hormone medication in order to breast feed successfully.

Thyroid Disease After Pregnancy
Post Partum depression is usually due to fatigue, hormonal fluctuations and emotional changes. However, if these symptoms are prolonged, the depression may be due to thyroid disease. Thyroid illnesses are estimated to occur in up to 10% of women after childbirth and may occur up to one year after delivery. It is even more common in women with autoimmune diseases, such as diabetes, Graves' disease, premature graying of the hair, rheumatoid arthritis and vitiligo (see the section on hyperthyroidism). In addition, some forms of postpartum thyroid disease may place you at increased risk to develop this illness again with subsequent pregnancies. Postpartum thyroid disease can be an overactive thyroid, an underactive thyroid or both. Since many of the symptoms of thyroid disease are subtle and often overlap with the postpartum experiences of healthy women, the diagnosis of thyroid disease is often not considered. Symptoms include anxiety, insomnia, difficulty concentrating, irritability, weight changes or fatigue, which are common after delivery, even when thyroid disease is not present. The most common cause of postpartum thyroid disease is thyroiditis, which is usually due to an autoimmune process. Thyroiditis occurs when the body produces antibodies against its own thyroid cells, either causing excess thyroid hormone to be released into the bloodstream (hyperthyroidism) or destroying so much thyroid tissue that the remaining thyroid cannot produce enough thyroid hormone (hypothyroidism). Within the first one to four months after delivery, the hyperthyroid or overactive phase is most common. You may have a slight enlargement of the thyroid gland and you may notice increased anxiety, restlessness, insomnia, weight loss, and difficulty concentrating.

The second phase of postpartum thyroiditis is an underactive or hypothyroid period and usually occurs 3 to 8 months postpartum. This phase can be characterized by a slight enlargement of the thyroid gland and symptoms of weight gain, fatigue, lack of energy and often depression. In fact, many cases of so called postpartum depression have actually been linked to postpartum thyroid disease and are readily treatable (see the section on painless thyroiditis for details). Graves' disease is another cause of postpartum hyperthyroidism. The long-term treatment of Graves' disease versus postpartum thyroiditis is quite different, so it is important to determine which disease you have before starting treatment. A 24 hour radioactive iodine test will be able to tell these two conditions apart. However, you can not take radioactive iodine if you are pregnant or if you are breast feeding, because the radioactive material will damage your baby's thyroid gland.

Infertility
Hypothyroidism and hyperthyroidism are among the many different causes of infertility by preventing ovulation, or the release of an egg. Despite the absence of ovulation, menses may appear normally, so infertility may be the only symptom of an underlying thyroid problem. If you are hypothyroid, you may not ovulate, and it may be difficult for you to become pregnant. Hypothyroidism has also been associated with an increased risk of having cysts forming on the ovaries, or polycystic ovaries, which is also associated with decreased fertility. In women with severe hypothyroidism, the level of a pituitary hormone called prolactin may also be increased, causing milk production (galactorrhea) unrelated to pregnancy and childbirth. The high prolactin level may prevent normal ovulation, causing decreased fertility, sometimes with irregular or absent menses. In addition, some researchers believe that women with untreated hypothyroidism who do conceive are at increased risk for their children to be born with physical abnormalities as well as mental retardation. Spontaneous abortion and fetal death are two other potentially serious complications of untreated hypothyroidism. Diagnosing your hypothyroidism and treating you with thyroid hormone medication will cure you of your thyroid disease. Taking thyroid hormone medication, however, will only improve fertility if you or your spouse is suffering from an underactive thyroid gland. Do not take thyroid hormone medication unless your doctor has diagnosed you as having hypothyroidism and has prescribed this medication for you. Taking unnecessary medication (if you do not have hypothyroidism) could be dangerous, because if you did conceive, the overabundance of thyroid hormone medication in your blood stream may cause miscarriage, premature labor or other problems in carrying the pregnancy to term.
http://www.cumc.columbia.edu/dept/thyroid/pregnant.html

Thyroid Disorders
Thyroid diseases are among the most common endocrine disorders encountered during pregnancy. They are challenging because of the potential complications of the disease itself and of the side effects of the medications used to treat mother and fetus. Thyroid Function during Normal Pregnancy: Introduction Both total thyroxine (T4) and triiodothyronine (T3) levels increase because the level of their carrier, thyroxine-binding globulin (TBG), becomes elevated. Estrogen causes increased TBG synthesis and decreased TBG clearance. The concentrations of free thyroxine (FT4) and free triiodothyronine (FT3) fluctuate but are within the normal range. The thyrotropin-stimulating hormone (TSH) level decreases and may even be low in some patients: 13% in the first trimester, 4.5% in the second trimester, and 1.2% in the third trimester. The TSH level is lowest and FT4 level highest when the human chorionic gonadotropin (hCG) level peaks. Serum thyroglobulin level increases, more toward the end of pregnancy, because of increased thyroid mass. The larger thyroid size is rarely detectable by physical examination, but it has been documented by serial ultrasound measurements. The average increase is 18% but may be much greater in areas of iodine deficiency. Overall, the demand for T4 increases by an estimated 1–3% above daily nonpregnant needs. The increased demand starts very early, reaching a plateau at 16–20 weeks. The fetal hypothalamic-pituitary-thyroid axis becomes functional toward the end of the first trimester. Until then, the fetus is dependent on local monodeiodination of transferred maternal T4 to T3. The small but effective transfer of T4 from mother to fetus seems to be important for fetal growth, particularly early brain development. TSH does not cross the placenta. Thyrotropinreleasing hormone (TRH) crosses the placenta, but it does not have a known effect on fetal thyroid function. Iodine also crosses the placenta, and the fetal thyroid starts concentrating it by weeks 10–12. Excess iodine causes fetal goiter and hypothyroidism. At birth, dramatic changes occur; in the full-term neonate, the thyroid hormone profile reaches normal values after a few hours. Normal thyroid hormones levels in the newborn are crucial for subsequent brain maturation and intellectual development. Hyperthyroidism The reported incidence of hyperthyroidism is 0.2–0.9%. Hyperthyroidism rarely starts during pregnancy; in the majority of patients it antedates pregnancy. In most cases (> 85%) the etiology is Graves' disease. Other causes include toxic nodular goiters, iatrogenic (excess exogenous thyroid), iodine induced, subacute thyroiditis, hyperemesis gravidarum, and hydatidiform mole or choriocarcinoma. Potential complications of hyperthyroidism in the mother include spontaneous abortion, pregnancy-induced hypertension, preterm delivery, anemia, higher susceptibility to infections, placental abruption, and, in severe, untreated cases, cardiac arrhythmias, congestive heart failure, and thyroid storm. In the fetus, possible complications include fetal and neonatal hyperthyroidism, intrauterine growth restriction (IUGR), stillbirth, prematurity, and morbidity related to antithyroid medications. Most maternal and neonatal complications are seen in cases of uncontrolled or untreated hyperthyroidism.

Graves' disease is caused by thyroid-stimulating antibody (TSAb) belonging to the immunoglobulin (Ig)G class, which binds with high affinity to the TSH receptor. TSAb may cross the placenta, bind to fetal TSH receptors, and cause fetal or neonatal hyperthyroidism. However, the placental acts as a partial barrier, so usually only those with high titers are likely to be affected. The diagnosis may not be easy, particularly in mild cases, because normal pregnant women may experience symptoms resembling thyrotoxicosis, such as heat intolerance, warm and moist skin, tachycardia, and a systolic flow murmur on cardiac auscultation. More reliable findings include a goiter, a resting pulse > 100 bpm, onycholysis, eye involvement, and weight loss or failure to gain despite a good appetite. The thyroid enlargement usually is diffuse with a firm consistency. A bruit may be audible over the thyroid but disappears after effective treatment. The eyes (Grave's ophthalmopathy) may be affected in up to half of patients, but pretibial myxedema is found in only 6–10% of cases. Hand tremor, proximal muscle weakness, hyperkinesis, and a hyperdynamic cardiovascular system may be present. Laboratory tests will confirm elevated T4, FT4, T3, and FT3 levels and a suppressed or undetectable TSH level. TSAb titers will be elevated in a significant number of patients. Treatment during pregnancy almost always consists of antithyroid medications. Surgery is performed in exceptional situations, such as allergic reactions to all drugs available or lack of response to very large doses ("drug resistance"), which in most cases has been the result of noncompliance. The goals of treatment are to rapidly achieve and maintain euthyroidism with the minimum but effective amount of medication, provide symptomatic relief, and keep FT4 levels in the upper third of normal. The medications available are propylthiouracil (PTU) and methimazole. Some physicians prefer PTU, but reports of large number of patients indicate that the two drugs are equally effective and have similar side effects. PTU is shorter acting, meaning more pills are required more often; therefore, methimazole may be preferable when compliance is a problem. The initial methimazole dose is 20–40 mg/d and the initial PTU dose is 200–400 mg/d. The dose is gradually reduced as improvement occurs. Most women can be effectively treated on an outpatient basis; however, hospitalization may be considered in severe, uncontrolled cases in the third trimester because of increased risk for complications. Women who have remained euthyroid while taking small amounts of PTU ( 100 mg/d) or

methimazole ( 10 mg/d) for 4 weeks or longer can stop taking the medication altogether by 32–34 weeks' gestation under close surveillance. The purpose is to minimize the risk of fetal/neonatal hypothyroidism, which is otherwise uncommon with PTU doses 200 mg/d or

methimazole 20 mg/d. The therapy is resumed if symptoms recur. Women with large goiters, long-standing hyperthyroidism, or significant eye involvement should remain on treatment throughout pregnancy. Other potential side effects of antithyroid medications are pruritus, skin rash, urticaria, fever, arthralgias, cholestatic jaundice, lupuslike syndrome, and migratory polyarthritis. Leukopenia may be a medication effect but is also seen in untreated Graves' disease; therefore, a white blood cell (WBC) count should be obtained before treatment

is started. Agranulocytosis is the most severe complication, but fortunately it is uncommon. Blockers (propanolol 20–40 mg every 6–8 hours) can be used for symptomatic relief in severe cases but only for short periods (few weeks) and before 34–36 weeks' gestation. Tests of fetal well-being are recommended for poorly controlled cases and for patients with high TSAb titers, even if they are euthyroid. Serial ultrasounds are useful for dating and fetal growth evaluation. Breastfeeding is allowed if the total daily dose of PTU is 150 mg or methimazole 10 mg. The medication should be given immediately after each feeding and the infant monitored periodically. Fetal and neonatal thyrotoxicosis are rare because placental transfer of IgG is limited. Usually only those with high titers are at risk. Fetal tachycardia and IUGR are the most common signs. A fetal goiter has occasionally been detected by ultrasound. High levels of fetal thyroid hormone detected by cordocentesis have been confirmed in a few cases. Treatment consists of administering to the mother antithyroid medication, which effectively crosses the placenta. If untreated, the mortality rate may reach 50%. The clinical manifestations of neonatal hyperthyroidism may appear at the time of birth or may be delayed several weeks if the mother was taking antithyroid medication until delivery. The disease will subside after several weeks or months when the maternal TSAb titer disappears, but infants require treatment in the meantime because, if untreated, the mortality rate may reach 30%. Transient Hyperthyroidism of Hyperemesis Gravidarum Biochemical hyperthyroidism is seen in most women (66%) with this condition. Women in early pregnancy with weight loss, tachycardia, vomiting, and laboratory evidence of hyperthyroidism may be difficult to differentiate from early, true thyrotoxicosis. Women with transient hyperthyroidism of hyperemesis gravidarum have no previous history of thyroid disease, no palpable goiter, and, except for tachycardia, no other symptoms or signs of hyperthyroidism. Test results for thyroid antibodies are negative. TSH level may be suppressed and T4 and T3 levels elevated, but the T3 level is lower than in true hyperthyroidism. The degree of thyroid function abnormalities correlates with the severity of vomiting. The time to resolution is widely variable (1–10 weeks). Treatment is symptomatic, and antithyroid medication is not recommended. The most likely etiology is thyroid stimulation by hCG (or perhaps certain hCG subfractions). Hypothyroidism Hypothyroidism was considered rare because of menstrual disturbances and frequent anovulatory cycles in hypothyroid women but recently has been reported to be much more common. Overt hypothyroidism (elevated TSH, low T4) has been reported in 1 in 1000 to 1 in 1600 deliveries and subclinical hypothyroidism (elevated TSH, normal T4) in 0.19–2.5% of pregnancies. The most common cause of hypothyroidism is autoimmune thyroid disease, with the goitrous form more frequent than the atrophic form with nonpalpable thyroid. Most other cases are

secondary to previous treatment with radioactive iodine or thyroidectomy. Less common causes are transient hypothyroidism in silent (painless) and subacute thyroiditis, drug induced, highdose external neck radiation, congenital hypothyroidism, inherited metabolic disorders, and thyroid hormone resistance syndromes. Secondary hypothyroidism may occur in pituitary or hypothalamic disease. Drugs that may cause hypothyroidism by interfering with thyroid hormone synthesis and/or its release include antithyroid drugs (PTU, methimazole), iodine, and lithium. Increased T4 clearance is caused by carbamazepine, phenytoin, and rifampin. Amiodarone decreases T4 to T3 conversion and inhibition of T3 action. Interference with intestinal absorption is seen with aluminum hydroxide, cholestyramine, ferrous sulfate, calcium, vitamins, soy, and sucralfate. Many pregnant women take ferrous sulfate, and it is important to ensure that thyroxine is taken at least 2 hours before (even 4 hours sometimes recommended) because insoluble ferric–thyroxine complexes may form, resulting in reduced thyroxine absorption. The clinical diagnosis is difficult and frequently unsuspected except in advanced cases. Symptoms may include fatigue, sleepiness, lethargy, mental slowing, depression, cold intolerance (very unusual in normal pregnancy), decreased perspiration, hair loss, dry skin, deeper voice or frank hoarseness, weight gain despite poor appetite, constipation, arthralgias, muscle aching, stiffness, and paresthesias. Signs include general slowing of speech and movements, dry and pale or yellowish skin, sparse thin hair, hoarseness, bradycardia (also unusual in pregnancy), myxedema, hyporeflexia, prolonged relaxation of reflexes, carpal tunnel syndrome, and a diffuse or a nodular goiter. The best laboratory test is the TSH level; current sensitive assays allow very early diagnosis and accurate treatment monitoring. Other useful tests include FT4 and antibody titers. Anemia occurs in 30–40%. It usually results from decreased erythropoiesis, but it may result from vitamin B12, folic acid, or iron deficiency. Levels of lipids and creatine phosphokinase ([CPK] of muscle origin) may be elevated. Implications of Hypothyroidism during Pregnancy Some studies have reported a twofold increased rate of spontaneous abortion in women with elevated levels of thyroid antibodies, even if they are euthyroid, but this finding is not universally confirmed. These antibodies (antiperoxidase-TPO, antimicrosomal-AMA, and antithyroglobulin-ATG) may cross the placenta and cause neonatal hypothyroidism, which, if untreated, may lead to serious cognitive deficiencies. Lower IQs in infants of even very mild hypothyroid women have been reported. None of the most recent reports indicate an increased frequency of congenital anomalies. The main complication found in practically all studies is a high risk of preeclampsia, which often leads to premature delivery with its related morbidity, mortality, and high cost. Placental abruption and postpartum hemorrhage may occur. The severity of the hypertension and other perinatal complications is greater in the more severely hypothyroid woman. Early treatment and close monitoring to ensure euthyroidism will prevent or decrease perinatal complications. Hypothyroidism is frequently associated with other illnesses, particularly type 1 diabetes, chronic hypertension, and anemia; these conditions should be properly monitored and treated as well. Why hypertension occurs more frequently in hypothyroidism is unclear. Reduced cardiac output and increased peripheral resistance have been

found and attributed to increased sympathetic nervous tone and

-adrenergic response.

There is no consensus on whether or not universal screening for hypothyroidism during pregnancy should be performed. We strongly recommend that certain high-risk women undergo routine screening for hypothyroidism: previous therapy for hyperthyroidism, high-dose neck irradiation, previous postpartum thyroiditis, presence of a goiter, family history of thyroid disease, treatment with amiodarone, suspected hypopituitarism, and type 1 diabetes mellitus. Because thyroxine requirements increase very early in pregnancy, hypothyroid women should be seen early and frequently during the first half of pregnancy and less often afterward in the second half.
L-Thyroxine

has long been the treatment drug of choice. The hormonal content of the synthetic drugs is more reliably standardized, and they have replaced desiccated thyroid as the mainstay of therapy. Administration of T4 alone is recommended. In the normal physiologic process, T4 is deiodinated to T3 in the extrathyroidal tissues. In addition, during early pregnancy the fetal brain is unable to use maternal T3. A combination of T4 and T3, approximating the ratio secreted by the thyroid, was sometimes recommended but its usefulness has not been confirmed. The best time to take L-thyroxine is early in the morning, on an empty stomach. Women experiencing nausea and vomiting should be allowed to take it later in the day until they improve. Numerous reports indicate that thyroxine requirements increase during pregnancy. The initial dose should be 2 g per kilogram of actual body weight. Further adjustments are made according to the TSH level. If the TSH level is elevated but < 10 U/mL, add 25–50 g/d; if the TSH level is

>10 but < 20, add 50–75 g/d; and if the TSH level is > 20, add 75–100 g/d. Changes made at less than 4-week intervals may lead to overtreatment. Up to 85% of women receiving thyroxine replacement before pregnancy will require higher doses while they are pregnant. The levels should be checked early in pregnancy and then periodically thereafter to maintain euthyroidism. After delivery, the dosage is reduced to the prepregnancy amount, and a TSH level measured 4–8 weeks postpartum. In women with pituitary disease, the TSH level cannot be used to guide therapy. In these cases, the FT4 level should be kept in the upper third of normal. Postpartum Thyroid Dysfunction Postpartum thyroid dysfunction reportedly occurs in between 2% and 5% of all women. It occurs in autoimmune thyroid disease (usually lymphocytic thyroiditis, less frequently in Graves' disease) and often recurs in subsequent pregnancies. In general the condition resolves spontaneously immediately after delivery, but a high rate of hypothyroidism has been observed after long-term follow-up. The clinical course is characterized by mild hyperthyroid symptoms occurring 4–8 weeks postpartum and sometimes later. The TSH level is suppressed, and T4, T3, and antibody titers are elevated. The thyroid gland may enlarge but is painless to palpation. A needle biopsy, if performed, shows lymphocytic infiltration. A radioactive iodine uptake test, if performed, shows little or no uptake, but the test should not be performed if the patient is breastfeeding. A high uptake would be more consistent with Graves' disease. The symptoms resolve and the results of thyroid tests return to normal after a few weeks or months. However, most patients subsequently develop a hypothyroid phase with clinical symptoms, low T4 level,

elevated TSH level, and further elevation of antibody titers. Spontaneous resolution occurs in most patients after another several weeks or months. The clinical course may vary, with some patients experiencing only the hyperthyroid phase and others only the hypothyroid phase. Treatment in the immediate postpartum is limited to symptomatic patients only ( blockers for the hyperthyroid phase and low-dose levothyroxine or triiodothyronine for the hypothyroid phase, which is enough to alleviate symptoms and allows recovery of thyroid function when discontinued). Solitary Thyroid Nodule during Pregnancy Thyroid nodules are frequently first detected during pregnancy when many women see a doctor for the first time. Little information on the management of these patients is available. The recommended approach in our institution is shown in Figure 24–1. The effect of pregnancy on the natural history of thyroid cancer is not completely known, but the present consensus is that pregnancy does not affect the cancer growth rate or the long-term prognosis. The risk of malignancy for a solitary nodule varies between 5% and 43%, depending on various factors including previous radiation, rate of growth, and patient age. Surgery during pregnancy carries a higher risk if it is performed during the first and the third trimesters (miscarriage, premature delivery, and fetal death); surgery during the second trimester reportedly has a lower complication rate. Radioactive iodine should never be given during pregnancy. Figure 24–1.

Evaluation of single thyroid nodules in pregnancy. Calcium Metabolism in Normal Pregnancy Both, calcium (Ca) and phosphorus (P) have many metabolic functions, including maintenance of the skeletal system, neuromuscular excitability, cell membrane permeability, high-energy phosphate bonds, and blood coagulation. The daily Ca requirements are 1200 mg (400 mg more than outside of pregnancy) and the total accumulation by term is 30 g (> 25 g in the fetus). It is linearly related to fetal weight, and > 80% accumulates in late pregnancy. Of the circulating Ca, 46% is bound to albumin, 7% to other complexes (phosphate, citrate, and other anions), and 47% is free (or ionized). The protein-bound fraction decreases because of increased extracellular volume, transfer to the fetus, and, perhaps, increased renal clearance. The free fraction remains the same, although some studies have reported a slight decrease leading to increased parathyroid hormone (PTH) levels. Urinary Ca excretion increases early in gestation and decreases in late pregnancy but does not exceed the normal range. The P level falls slightly in early pregnancy and rises to normal by 30 weeks. The PTH level remains unchanged during the first half of pregnancy and then rises gradually until term, coinciding with the time of greatest fetal skeletal calcification. PTH promotes Ca transport from mother to fetus. The most potent factor affecting PTH secretion is the free Ca

level (inverse correlation), but calcitonin, vitamin D, and magnesium (Mg) also play a role. Calcitonin is secreted by C-cells inside the thyroid, but these cells actually are of neural crest origin and migrate to the thyroid. Calcitonin is a Ca-lowering hormone whose secretion is also mainly affected by free Ca levels, but in this case the correlation is direct. Its action is antagonistic to that of PTH, and it plays a role in Ca homeostasis and bone remodeling. Vitamin D increases the efficiency of intestinal Ca absorption, plays a role in the maintenance of Ca and P levels, and has a role in the mineralization of bone matrix. In order to exert its action, vitamin D must be transformed into active metabolites [1,25-(OH)2D3] in the kidney, and PTH is needed for the process. The requirements are 400 IU/d, the same as outside of pregnancy. Vitamin D crosses the placenta readily. Whether Ca metabolism during pregnancy is influenced by other hormones, such as estrogen, progesterone, or hCG, is not known. The placenta plays a major role in transporting Ca against a gradient. PTH facilitates this transport, although neither PTH nor calcitonin crosses the placenta. The fetal Ca concentration (both total and free) increases gradually from 5.5–11.0 mg/dL from the second trimester to term. In the fetus, the PTH level is suppressed but detectable, and cord levels are 25% lower than in the mother. Calcitonin in cord is higher than in the mother, a combination favoring skeletal growth, which also causes Ca levels in the newborn to fall to normal. Given these findings, all the observed changes in normal pregnancy favor mineralization of the fetal skeleton. Hyperparathyroidism Hyperthyroidism is a frequently occurring disease but has been uncommonly reported to occur during pregnancy. Just over 120 cases have been reported since 1931, with the first successful surgery performed in 1947. The etiology is an adenoma in 89–90% of cases, hyperplasia (of all the glands) in 9%, and carcinoma in 1–2%. The latter should be suspected in severe hyperparathyroidism, particularly if a palpable neck mass is present (palpable neck masses are reported in < 5% of parathyroid adenomas). Rarely it occurs in a familial pattern with or without other endocrine abnormalities (eg, multiple endocrine adenomatosis). Other causes of hypercalcemia during pregnancy are uncommon and include vitamin D toxicity, sarcoidosis, various malignancies, milk-alkali syndrome, thyrotoxicosis, adrenal insufficiency, and secondary hyperparathyroidism in those undergoing chronic hemodialysis or after renal transplantation. Reported complications include 27.5% fetal mortality and 19% neonatal tetany. Neonatal hypocalcemia is often the initial clue to the presence of maternal hyperparathyroidism. The condition occurs because the high levels of maternal Ca inhibit the activity or the proper development of the infant's parathyroid glands. It develops between days 2 and 14 after delivery, depending on the severity of the maternal hypercalcemia, and usually resolves with appropriate therapy. One case of hypocalcemia persisting for 3 months and another case of hypocalcemia that became permanent have been reported. Complications in the mother include 36% nephrolithiasis, 19% bone disease, 13% pancreatitis, 13% urinary tract infections and pyelonephritis, 10% hypertension (100% in all cases of carcinoma thus far reported), and 8% hypercalcemic crisis. Maternal deaths have occurred among those with complications of pancreatitis or hypercalcemic crisis. Women who developed hypercalcemic crisis had a 30% maternal death rate and 40% fetal demises. Pancreatitis is

reported in only 1.5% of nonpregnant hyperparathyroid patients and in < 1% of normal pregnancies. Most pregnant women with hyperparathyroidism (76%) are symptomatic, whereas 50–80% of nonpregnant hyperparathyroid patients are asymptomatic at the time of diagnosis. Common symptoms include anorexia, nausea and vomiting, thirst, weakness, fatigue, lethargy, headaches, emotional lability, inappropriate behavior, confusion, and even delirium. A persistently elevated serum Ca level and a normal or elevated PTH level, despite hypercalcemia, confirm the diagnosis. Hypercalciuria is commonly seen. The serum levels of P, Mg, and bicarbonate usually are low, and chloride and citrate levels often are elevated. The chloride/P ratio is sometimes used as a diagnostic clue because the ratio usually is > 30 in hyperparathyroidism but is < 30 in hypercalcemia from other causes. The levels of serum alkaline phosphatase (of bone origin) and urinary hydroxyproline will be elevated in cases with significant bone involvement. Surgery is the treatment of choice for confirmed hyperparathyroidism. In pregnancy, the optimal time for surgery is the second trimester, when the complication risks (abortion or premature labor) are reduced. An experienced surgeon performing the neck exploration will be able to proceed appropriately in case of parathyroid hyperplasia (removal of all glands with parathyroid tissue transplantation). In addition, the complication rate should be reduced when an experienced surgeon performs the procedure. Postoperatively, hypocalcemia may occur in patients with significant osteitis fibrosa or if injury occurs to the normal parathyroid glands during surgery. When surgery is not possible, maintaining adequate hydration and administering oral phosphates may be temporary measures until surgery can be safely performed. Preventing hypercalcemic crisis is of utmost importance; if it develops, aggressive treatment is recommended. Hypoparathyroidism The most common cause of hypoparathyroidism is surgical removal or damage to the parathyroid glands, or their vascular supply, during thyroid surgery. Hypoparathyroidism reportedly occurs in 0.2–3.5% of cases after thyroid surgery. Idiopathic hypoparathyroidism is relatively rare and is seldom seen in pregnancy. It may be isolated or occur in association with agenesis of the thymus or as part of a familial disorder, which includes deficiencies of thyroid, adrenal and ovarian function, pernicious anemia, and mucocutaneous candidiasis. Pseudohypoparathyroidism (deficient end-organ response to PTH in bone and kidney) is a rare hereditary disorder infrequently encountered during pregnancy. The severity of symptoms depends on the degree of hypocalcemia and range from clumsiness (fingers), mental changes (mainly depression), muscle stiffness, parkinsonism, acral and perioral paresthesias, to laryngeal stridor, tetany, and convulsions. Clinical signs include dry, scaly skin, brittle nails, coarse hair, and positive Chvostek's (present in 10% of normals) and Trousseau' signs. Ectopic soft tissue calcifications and a prolonged QT interval on the electrocardiogram may be observed. Pseudohypoparathyroidism is more likely if the patient has unusual skeletal or developmental defects and if other family members affected. The diagnosis usually is evident from the history and confirmed by a "normal" or low PTH level in the presence of hypocalcemia, hyperphosphatemia, and normal renal function. Before the availability of specific therapy, maternal morbidity and mortality rates were high, and termination of pregnancy was frequently recommended. Currently the prognosis is much

improved provided the mother is kept eucalcemic. From 1–4 g/d of elemental calcium and 50,000–100,000 U/d of vitamin D usually are recommended. The synthetic vitamin D analogue 1 ,25-(OH)2D3 at doses of 0.25–2 g/d is considered safer by some authors. The therapeutic margin is narrow in these patients, who experience frequent episodes of hypercalcemia or hypocalcemia. Hypercalcemia, when it develops, may be long-lasting. The synthetic analogues are more active and shorter-acting, and they might be safer. In hypercalcemia, the vitamin D therapy is stopped, hydration is provided, and a course of corticosteroids is given (prednisone, or equivalent, 40–100 mg/d). If convulsions and tetany result from hypocalcemia, Ca gluconate 10–20 mg is given intravenously, followed by infusion of 15 mg of Ca gluconate per kilogram of actual body weight administered over 4–8 hours, according to the serum Ca level. Replace Mg if the serum level is low. Once the acute episode resolves, the daily oral therapy is readjusted to prevent recurrences. These patients require frequent serum Ca determinations, and the therapy should be readjusted as often as necessary to prevent acute decompensation. If the mother is hypercalcemic, the newborn may develop hypocalcemia and tetany, the same as when the mother has hyperparathyroidism. If the mother is hypocalcemic, hyperplasia of the fetal parathyroid glands, mobilization of calcium from the skeleton and generalized demineralization, subperiosteal resorption, and even osteitis fibrosa with very high perinatal mortality will occur. With proper treatment, symptoms in surviving infants will subside by age 4–7 months. After delivery, hypoparathyroid women may develop hypercalcemia with the same dose of calcium and vitamin D that was effective during pregnancy. Hypersensitivity to vitamin D in lactating women may result from the effect of prolactin (PRL) on 1 -hydroxylase vitamin D activity. Serum calcium levels should be monitored closely and the doses readjusted as necessary. Vitamin D travels into breast milk, even when low doses are taken, so many physicians discourage breastfeeding in these women.

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