THYROID DISEASES IN PREGNANCY

INTRODUCTION

► The evaluation and treatment of pregnant women with thyroid disease parallels that of nonpregnant women and men, but presents some unique problems. 

THYROID FUNCTION DURING NORMAL PREGNANCY 

The major changes in thyroid function during pregnancy are an increase in serum thyroxine-binding globulin (TBG) concentrations and stimulation of the thyrotropin (TSH) receptor by chorionic gonadotropin (hCG).

Serum TBG concentrations rise almost twofold because estrogen increases TBG production and TBG sialylation, which results in decreased clearance of TBG. TBG excess leads to an increase in both serum total thyroxine (T4) and triiodothyronine (T3) concentrations, but not serum free T4 and T3 concentrations.

The optimal iodine intake for pregnant women is uncertain. Markedly excessive iodine intake can lead to fetal hypothyroidism and goiter, while maternal iodine deficiency during pregnancy can result in cretinism and mental retardation. Commonly used iodine supplements can have divergent effects on maternal and fetal thyroid function, and are more pronounced in areas of deficient iodine intake

hCG-MEDIATED HYPERTHYROIDISM

► hCG is a weak thyroid stimulator that may cause hyperthyroidism during pregnancy. Three syndromes have been described:

► Transient subclinical hyperthyroidism occurs in 10 to 20 percent of normal pregnant women during the period of highest serum hCG concentrations; these women do not require treatment

► Hyperemesis gravidarum is a syndrome defined as nausea and vomiting associated with weight loss of more than five percent during early pregnancy. It may be caused by high serum hCG and estradiol concentrations or secretion of hCG with increased biological activity. Many of these women have either subclinical or mild overt hyperthyroidism, which resolves with the hyperemesis and rarely requires antithyroid treatment

► Trophoblastic hyperthyroidism occurs in about 60 percent of women with a hydatidiform mole or choriocarcinoma. The hyperthyroidism may be severe, and is primarily treated by evacuation of the mole or therapy directed against the choriocarcinoma.

► Recurrent gestational hyperthyroidism has been described in one family due to a mutant thyrotropin receptor that is hypersensitive to physiologic concentrations of hCG. 

HYPERTHYROIDISM COMPLICATING PREGNANCY

► hyperthyroidism is associated with increased rates of the following:

► Spontaneous abortion

► Premature labor

► Low birth weight

► Stillbirth

► Preeclampsia

► Heart failure

► Very rare cases of thyroid storm precipitated by labor, infection, preeclampsia, or cesarean section have been reported.

► Although hyperthyroidism from any cause can complicate pregnancy, Graves' hyperthyroidism is the most common cause. It usually becomes less severe during the later stages of pregnancy, perhaps mediated by a change in the activity of TSH receptor antibodies from stimulatory to blocking.

► In one report of 433 women with subclinical hyperthyroidism, there was no evidence of adverse pregnancy outcomes.

Diagnosis

► The diagnosis of hyperthyroidism during pregnancy may be difficult because of the changes associated with normal pregnancy.

► TBG excess results in high serum total T4 concentrations, but not high serum free T4 concentrations

► High serum hCG concentrations during early pregnancy, as are found in women with hyperemesis gravidarum or multiple pregnancies, may result in transient subclinical or rarely overt hyperthyroidism

Diagnosis

► The diagnosis of hyperthyroidism in pregnant women should be based primarily on a serum TSH value <0.01 mU/L and also a high serum free T4 value. ► Free T3 measurements may be useful in women with suppressed serum TSH concentrations and normal or minimally elevated free T4 values. Because radioiodine administration is contraindicated, it may not be possible to ascertain the cause of the hyperthyroidism during pregnancy. Treatment ► Treatment options for pregnant women with hyperthyroidism are limited because therapy may be harmful to the fetus. However, a good fetal and maternal outcome depends upon controlling the mother's hyperthyroidism. The goal of treatment is to maintain the mother's serum free T4 concentration in the high normal range using the lowest drug dose. ► This requires assessment of free T4 frequently (ie, at four week intervals) with appropriate adjustment of medication. Treatment ► Radioiodine is absolutely contraindicated. Fetal thyroid tissue is present by 10 to 12 weeks and therefore can be ablated by radioiodine. Many experienced clinicians, however, have encountered one or two women inadvertently treated with radioiodine during early pregnancy; the anecdotal impression is that radioiodine given before about 8 to 10 weeks of pregnancy does not cause fetal hypothyroidism or birth defects. ► If treatment is given inadvertently then or later, there needs to be full disclosure. Depending on the couple's wishes, termination of pregnancy might be considered. ► Beta blockers — Beta blockers may be given to ameliorate the symptoms of moderate to severe hyperthyroidism in pregnant women. However, if possible, they should be weaned as soon as the hyperthyroidism is controlled by thionamides and/or toward the end of pregnancy because occasional cases of neonatal growth restriction, hypoglycemia, respiratory depression, and bradycardia have been reported after maternal administration. ► There also has been one report suggesting a higher rate of spontaneous abortion for hyperthyroid women treated with both a thionamide and propranolol compared with a thionamide alone. ► Thionamides — Thionamides are recommended for treatment of moderate to severe hyperthyroidism complicating pregnancy. Available thionamides include propylthiouracil (PTU), methimazole (MMI), and carbimazole (CBZ), which is completely metabolized to MMI. ► Both methimazole (MMI) and propylthiouracil (PTU) cross the placenta with equal transfer kinetics , and have similar effects on the fetus. In one report of 77 newborns of euthyroid mothers treated with PTU or MMI, there were no significant differences in TSH concentrations measured in cord blood at birth . ► Low thyroid function at birth is found in approximately one-half of neonates whose mothers received PTU or MMI during pregnancy and who had serum T4 concentrations within the normal (non-pregnant) range. ► In spite of these observations, two studies reported that the IQ scores of children who were exposed to thionamides in utero (but were euthyroid at birth) were normal. ► Possible teratogenicity — Methimazole has been associated with possible teratogenic effects including: Case reports of aplasia cutis, a scalp defect, in newborns of mothers treated with (or exposed to) MMI. ► More serious congenital malformations such as:  tracheoesophageal fistulas and  choanal atresia have been observed with maternal MMI and carbimazole, but not PTU use. ► Choice of drug — In the past, PTU was considered the drug of choice throughout pregnancy for women with hyperthyroidism, because of concerns about the possible teratogenic effects of MMI. ► However, reports of severe PTU-related liver failure have now raised concern about the routine use of PTU, including the use of PTU in pregnancy. ► Although MMI has been associated with liver disease, it is typically due to cholestatic dysfunction, not hepatocellular inflammation. ► We agree with the change in recommendations for antithyroid drugs as outlined by the American Thyroid Association, and the US Food and Drug Administration. ► We recommend that PTU not be used as a first-line drug in children or adults. ► For pregnant women with hyperthyroidism, we suggest that PTU use be limited to the first trimester only. ► Although the teratogenic effects of MMI are not well proven, they are potentially serious, and are likely confined to the first trimester during organogenesis. ► After the first trimester, the potential risk of PTU-associated hepatotoxicity, although extremely rare, is thought to outweigh any potential risks of MMI. ► Women who are taking MMI and learn they are pregnant should be switched to PTU at the time of the positive pregnancy test. ► In the second trimester, we suggest switching from PTU to an equivalent dose of MMI. ► Although the ratio of potencies of PTU and MMI is uncertain, clinical experience suggests that methimazole is 20 to 30 times as potent on a milligram to milligram basis. ► Therefore, 300 mg of PTU would be roughly equivalent to 10 or 15 mg of MMI. ► Thyroid function testing should be performed within a few weeks of the switching to methimazole to be sure that a euthyroid state has been maintained. ► Subsequent monitoring of thyroid function should be performed every four weeks. ► Extra caution is necessary after switching from PTU to MMI to avoid maternal overtreatment and fetal hypothyroidism. ► PTU-associated liver failure, which can occur at any time during the course of treatment, has a sudden onset and a rapidly progressive course. ► Therefore, routine monitoring of liver function is not currently suggested by the ATA and FDA. Patients should be advised to stop their medication and contact their physician if they develop:  weakness,  malaise,  nausea and vomiting,  jaundice,  dark urine or light-colored stools. ► Some clinicians and their patients prefer to monitor liver function every four weeks when blood is being drawn to assess thyroid function. ► If this approach is chosen, PTU should be discontinued if serum transaminases are >3 times the upper limit of normal.

► This approach has not been shown to reduce the risk of PTU-associated liver failure.

► If the patient develops a rash when switched to MMI, the drug should be stopped and PTU resumed.

► Whenever possible, thionamides should be tapered and discontinued during the third trimester.

► Dose and monitoring — To minimize the risk of hypothyroidism in the fetus, we give the lowest dose of thionamide necessary to control thyroid function.

► In patients with severe hyperthyroidism, full initial doses may be required (PTU 100 mg three times per day) or MMI (10 to -30 mg daily) in order to normalize thyroid function.

► Our goal is to maintain persistent but minimal mild hyperthyroidism in the mother in an attempt to prevent fetal hypothyroidism.

► Pregnant women with mild hyperthyroidism may be followed with no treatment.

► Transient central hypothyroidism may be seen in infants whose mothers had poorly controlled hyperthyroidism during pregnancy, presumably due to suppression of the fetal pituitary-thyroid axis. Assessment of neonatal thyroid function should therefore include both serum free T4 and TSH levels.

► The thionamide dose should be adjusted monthly to maintain serum free T4 concentrations in the high-normal range for nonpregnant women or total T4 up to 18 mcg/dL (50 percent above the upper limit of normal for nonpregnant women), and serum TSH concentrations in the low-normal or suppressed range.

► Ultimately, low doses of PTU or MMI (eg, 50 mg twice daily or less for PTU; 2.5-5 mg a day for MMI) may be all that is required.

► It is possible to discontinue the thionamide during the third trimester in one-third of women; the amelioration of hyperthyroidism as pregnancy progresses is due to a fall in serum TSH receptor-stimulating antibody concentrations, or rarely, a rise in TSH receptor-blocking antibodies. However, Graves' hyperthyroidism can worsen postpartum.

► Monitoring throughout pregnancy is important, because maternal hyperthyroidism in the third trimester may increase the risk of low birth weight (independent of the risk of neonatal Graves' disease).

► As an example, in a study of 181 women with a current or past history of hyperthyroidism, the risk of low birth weight was increased fourfold in the 35 women who had clinical and biochemical evidence of hyperthyroidism in the third trimester.

Nursing

► Both methimazole and PTU have been rated as safe for nursing mothers by the American Academy of Pediatrics.

► However, given the concerns about potential PTU-associated hepatotoxicity, we suggest methimazole rather than PTU for nursing mothers.

T4 administration

► The use of T4 with thionamide therapy during pregnancy is not recommended.

► Little T4 crosses the placenta, making it more difficult to determine the minimal dose of thionamide needed to control hyperthyroidism in the mother.

Surgery

► Thyroidectomy during pregnancy may be necessary in women who cannot tolerate thionamides because of allergy or agranulocytosis. The indications for surgery are similar to those in non-pregnant women and men. Surgery during pregnancy, however, is associated with an increased risk of spontaneous abortion or premature delivery. These risks are minimized by operating during the second trimester.

Iodine

► One study of 35 women with mild to moderate Graves' hyperthyroidism suggested that low doses of iodine are safe during pregnancy. Prolonged high-dose iodine therapy, however, can cause fetal goiter.

► We do not generally recommend the use of pharmacologic doses of iodine in pregnant women, but its use could be considered in selected cases when thionamides are contraindicated.

Fetal and neonatal Graves' disease

► One to 5 percent of neonates born to women with Graves' disease have hyperthyroidism due to transplacental transfer of TSH receptor-stimulating antibodies. The incidence is unrelated to maternal thyroid function.

► High fetal heart rate (>160 beats/min), fetal goiter, advanced bone age, poor growth, and craniosynostosis are manifestations of fetal hyperthyroidism. Cardiac failure and hydrops may occur with severe disease. All fetuses of women with Graves' disease should be monitored for signs of fetal thyrotoxicosis by determination of fetal heart rate and assessment of fetal growth.

HYPOTHYROIDISM DURING PREGNANCY

General issues

Overt hypothyroidism complicating pregnancy is unusual.

Two factors contribute to this finding:

► some hypothyroid women are anovulatory;

► and hypothyroidism (new or inadequately treated) complicating pregnancy is associated with a high rate of first trimester spontaneous abortion.

Increased rates of fetal loss have also been reported in euthyroid women with high serum anti-thyroid peroxidase antibody concentrations.

In continuing pregnancies, hypothyroidism has been associated with an increased risk of several complications, including:

► Preeclampsia and gestational hypertension

► Placental abruption

► Nonreassuring fetal heart rate tracing

► Preterm delivery, including very preterm delivery (before 32 weeks)

► Low birth weight (which was likely due to preterm delivery for preeclampsia in one study, but not in a second study where the rate of preeclampsia was negligible.

► Increased rate of caesarean section

► Perinatal morbidity and mortality

► Neuropsychological and cognitive impairment

► Postpartum hemorrhage

The risk of these complications is greater in women with overt, rather than subclinical, hypothyroidism.

Subclinical hypothyroidism

► Neuropsychological impairment has also been observed in offspring of women with subclinical hypothyroidism, as illustrated by the following:

► It has been suggested that the upper limit of normal for TSH should be 2.5 mU/L instead of the 4.5 to 5.0 mU/L used by most laboratories. Limited data suggest that pregnancy outcome for women undergoing in vitro fertilization may be worse among those with pre-conception TSH levels higher than 2.5 mU/L.

► As an example, in one study of delivery outcomes after in vitro fertilization, gestational age and birth weight were higher for 150 deliveries where pre-conception TSH was <2.5 mU/L compared to 45 deliveries where TSH was >2.5 mU/L.

► In contrast, the FASTER Trial did not find a consistent pattern of adverse outcome with subclinical hypothyroidism. This prospective multicenter investigation evaluated Down syndrome risk in an unselected obstetric population carrying singleton pregnancies. A subset of subjects without fetal aneuploidy had first- and second-trimester serum samples assayed for TSH, freeT4, and antithyroglobulin and antithyroid peroxidase antibodies.

► Subclinical hypothyroidism (normal free T4 and TSH > 97.5 percentile of 4.3 and 3.9 mU/L in the first and second trimester, respectively) was diagnosed in 2.2 percent of these women and was not associated with an increased risk of adverse outcome.

► In areas of borderline iodine deficiency, maternal thyroid status is affected negatively in the presence of concomitant iron deficiency. In a study of pregnant Swiss women, those who were iron deficient had higher serum TSH values and/or low serum T4 concentrations when compared to women with normal iron stores.

Low maternal free T4

► The effect of low maternal serum free T4 concentrations (but normal TSH) on neonatal outcome is unclear.

► In a study of 10-month-old infants, those whose mothers had serum free T4 concentrations below the tenth percentile at 12 weeks gestation had impaired psychomotor function.

► In another study of three week old infants, those whose mothers had serum free T4 below the tenth percentile at 12 weeks gestation had impaired Neonatal Behavioral Assessment Scales.

► In a third study, maternal serum free T4 concentrations below the 2.5 percentile (with normal TSH) were not associated with adverse pregnancy outcomes, but neonatal psychomotor function was not studied.

Screening

► A clinical consensus group concluded that there is insufficient evidence to recommend for or against screening in pregnant women or those hoping to become pregnant.

► The American College of Obstetricians and Gynecologists recommends testing only in symptomatic pregnant women or those with a family history of thyroid disease.

► The Endocrine Society clinical practice guidelines also recommend targeted case finding rather than universal screening.

► However, subsequent to these publications, a study of 1560 consecutive pregnancies demonstrated that targeted screening (women with a personal or family history of thyroid disease or another autoimmune disorder) found only two-thirds of the women with TSH >4.2 mU/I;

► an accompanying editorial suggests that case finding is no longer an acceptable approach, and advocates universal screening.

► In summary, professional societies recommend testing pregnant women for thyroid dysfunction only if they are symptomatic or have a family history of thyroid disease.

► However, more recent data suggest that this approach may miss up to one-third of women with hypothyroidism, and preliminary data suggest that universal screening is cost-effective.

► Therefore, we suggest universal screening for thyroid dysfunction in pregnant women or those hoping to become pregnant.

T4 therapy during pregnancy

► Women need more thyroid hormone during pregnancy and, unlike normal women, those with hypothyroidism are unable to increase thyroidal T4 and T3 secretion. The goal of therapy is to normalize the mother's serum TSH concentration. Approximately 75 to 85 percent of women with preexisting hypothyroidism need more T4 during pregnancy.

► This is especially true for women with thyroid cancer who have received radioiodine therapy, or patients with post-ablative or surgical hypothyroidism for Graves' disease or goiter.

► Several factors are responsible for the increased T4 requirement during pregnancy. They include weight gain and increased T4 pool size, high serum TBG concentrations, placental deiodinase activity, transfer of T4 to the fetus, and reduced gastrointestinal absorption due to iron in prenatal vitamins.

► Levothyroxine dose requirements may increase by as much as 50 percent during pregnancy, and the increase occurs as early as the fifth week of gestation.

Recommendations

► Given the importance of maternal euthyroidism for normal fetal cognitive development, serum TSH should be measured four to six weeks after conception, four to six weeks after any change in the dose of T4, and at least once each trimester.

► The T4 dose can be reduced to prepregnancy levels after delivery, but serum TSH should be measured four to six weeks later to confirm that the reduction was appropriate.

Congenital hypothyroidism

► Most cases of congenital hypothyroidism are due to agenesis or dysgenesis of the fetal thyroid, congenital dyshormonogenesis, or iodine deficiency in endemic areas. 

THYROID PEROXIDASE ANTIBODIES

► An increased rate of fetal loss has been reported in euthyroid women with high serum antithyroid peroxidase antibody (TPO antibodies) concentrations.

► In a prospective study of 115 TPO antibody positive patients, half were given T4, and half were not treated, and comparison was made with 869 TPO antibody negative patients.

► Miscarriage rates were 3.5 percent in TPO antibody positive treated patients, 2.4 percent in the TPO antibody negative patients, and 13.8 percent in TPO antibody positive untreated patients.

► Premature delivery rates were 7 percent, 8.2 percent, and 22.4 percent, respectively .

► In the same study, some euthyroid women with TPO antibodies developed subclinical hypothyroidism.

► In early pregnancy the TPO positive women had significantly higher serum TSH levels than TPO negative women, although the level was in the normal range.

► Approximately 20 percent of TPO positive women subsequently developed subclinical hypothyroidism by term if left untreated.

► In a second report of TPO antibody positive women undergoing assisted reproductive technologies (ART), thyroid hormone therapy did not lower the risk of early pregnancy loss.

► However, these results are confounded by the presence of additional infertility factors in women undergoing ART.

► Most pregnant women are unlikely to know their antithyroid antibody status because universal screening is not routinely done

► However, since carefully monitored thyroid hormone treatment is safe, we suggest levothyroxine treatment of TPO antibody positive pregnant patients until additional data becomes available.

► Levothyroxine also appears to reduce anti-TPO antibody titers in non-pregnant patients. In a study of 38 patients, titers were reduced by 45 percent after one year and 70 percent after five years.

► Increased urinary iodine excretion during pregnancy may deplete thyroidal iodine stores by as much as 40 percent.

► Plasma iodide concentrations may decrease during pregnancy due to increased maternal renal clearance and fetal uptake of iodide.

► Goiter during pregnancy is common in regions where iodine intake is low, occurring in 16 to 70 percent of women in iodine-deficient regions of Western Europe. In areas of moderate iodine deficiency, thyroid volume in women correlates with the number of previous pregnancies.

► Goiter during pregnancy is rare in the United States. However, studies from Europe show that iodine depletion relative to the nonpregnant states leads to mild thyroid enlargement detectable sonographically (mean increase in volume:18 percent), a change that is clinically detectable in some women.

► Significant thyroid growth during pregnancy should be considered abnormal, requiring further investigation.

► A pregnant woman found to have a thyroid nodule should be evaluated in the same way as if she were not pregnant. Thyroid radionuclide scanning is contraindicated.

► Therefore, fine-needle-aspiration biopsy of the nodule should be done (as it would be for most nonpregnant patients).

► Women with benign nodules are followed. Those whose nodules enlarge should have another biopsy, but surgery, when indicated, is usually deferred until after delivery.

THYROID CANCER

► Women with differentiated thyroid cancer require surgery.

► The safest time for any type of surgery during pregnancy is the second trimester.

► However, whenever possible, surgical procedures are postponed until after delivery to minimize maternal and fetal complications.

► Gvien the typically indolent nature of thyroid cancer, thyroidectomy is usually delayed until the postpartum period.

► A California cancer registry that identified 129 antepartum and 466 postpartum thyroid cancers found no difference in overall prognosis compared to women with thyroid cancer not associated with pregnancy. 

POSTPARTUM THYROID DYSFUNCTION

► Postpartum thyroiditis

Postpartum thyroiditis occurs in 5 to 10 percent of women in the United States , and in up to 25 percent of women with type 1 diabetes.

It may occur after delivery or pregnancy loss (miscarriage, abortion, ectopic pregnancy) as well as after normal delivery.

In addition to the usual clinical consequences of thyroid dysfunction, postpartum hypothyroidism may decrease milk volume.

Two patterns of postpartum dysfunction can be defined:

► postpartum thyroiditis; and

► a postpartum exacerbation of chronic lymphocytic (Hashimoto's) thyroiditis.

Postpartum thyroiditis is characterized by transient hyperthyroidism, or transient hyperthyroidism followed by transient or rarely permanent hypothyroidism.

Postpartum exacerbation of Hashimoto's thyroiditis may cause transient or permanent hypothyroidism, and may be associated with transient or permanent increase in goiter.

► Women with postpartum thyroiditis are likely to have recurrent thyroiditis after subsequent pregnancies.

► Postpartum thyroid dysfunction can also occur in women already taking thyroid hormone replacement for hypothyroidism antedating pregnancy (eg, goitrous autoimmune thyroiditis) if the gland was not destroyed.

► Selenium supplementation may decrease inflammatory activity in patients with autoimmune thyroiditis, and may reduce the risk of postpartum thyroiditis in women who are positive for thyroid peroxidase (TPO) antibodies.

Graves' disease

► Women may develop Graves' disease postpartum or experience an exacerbation. In addition, women in remission after antithyroid drug therapy have a higher incidence of relapse during the postpartum period than at times unrelated to pregnancy. 

SUMMARY AND RECOMMENDATIONS

► Several professional societies recommend testing pregnant women for thyroid dysfunction only if they are symptomatic or have a family history of thyroid disease. However, more recent data suggest that this approach may miss up to one-third of women with hypothyroidism. Therefore, we suggest universal screening for thyroid dysfunction in pregnant women or those hoping to become pregnant (Grade 2C).

► Since carefully monitored thyroid hormone treatment is safe, we suggest levothyroxine treatment of TPO antibody positive pregnant patients until additional data becomes available (Grade 2C).

► A pregnant woman found to have a thyroid nodule should be evaluated in the same way as if she were not pregnant, except that thyroid radionuclide scanning is contraindicated.

► Postpartum thyroiditis occurs in 5 to 10 percent of women in the United States. It may occur after delivery or pregnancy loss (miscarriage, abortion, ectopic pregnancy) as well as after normal delivery.

Prof.: Mahmoud F. Midan

Prof. & Head Of Obstet.& Gynecology Department Al-Azhar University,

Damietta, Egypt.