Endocrine Disorders in Pregnancy
Rana Malek
Kashif M. Munir
E. Albert Reece
Introduction
In this chapter on endocrine disorders in pregnancy, changes in endocrine function that occur during normal pregnancy will be reviewed. Following this, those endocrine disorders whose diagnosis, course, or treatment is affected by pregnancy will be discussed. This chapter is intended to present a practical review of these issues and will emphasize the most common dilemmas facing the practicing clinician. The diagnostic and therapeutic areas of confusion or controversy will be reviewed in the greatest detail to provide the information necessary for decisions in patient management.
Endocrine Changes Associated With a Normal Pregnancy
There are a number of endocrine changes that occur during normal pregnancy. Although the mechanisms for these changes are not always understood, they presumably occur for the health of the mother and her developing offspring. The known mechanism(s) of these changes and the importance to the physician of understanding these changes will be reviewed. Some of these changes occur through the existing maternal endocrine system, and some occur as a result of effects of placental hormones on the maternal endocrine system.
Pituitary
Lactotroph hyperplasia causes an increase in pituitary size during normal pregnancy, mainly due to estrogen stimulation of the pituitary lactotrophs. Prolactin levels rise progressively during pregnancy in preparation for lactation. Prolactin levels rise to 100 to 400 ng/mL by late pregnancy, levels in the range of those seen in pituitary prolactinomas in the nonpregnant patient.1,2 The new diagnosis of a prolactinoma in a pregnant patient is not a common problem, as substantial prolactin elevations typically result in amenorrhea and infertility. However, it is important to be aware that prolactin levels are normally elevated during pregnancy to avoid confusion in diagnosis.
Cortisol Physiology in Pregnancy
A series of physiological changes in pregnancy result in increases in cortisol and adrenocorticotrophic hormone (ACTH) levels during pregnancy. There is a two to threefold increase in total plasma cortisol in pregnant women compared to nonpregnant women, values that match levels seen in Cushing syndrome.3 The rise in estrogen levels results in increased cortisol binding globulin (CBG) levels resulting in an increase in total cortisol and a decrease in cortisol clearance.4 Placenta corticotropin-releasing hormone (CRH) and ACTH starts to rise in the seventh week of pregnancy resulting in increased activation of adrenal production in the mother.5 Urinary free cortisol levels increase about 180% during pregnancy.6 Despite the hypercortisolism seen in pregnancy, the diurnal rhythm of ACTH is unchanged during pregnancy.7 An understanding of this physiological change becomes important when considering disease of cortisol excess in pregnancy.
Salt and Water Metabolism
Pregnancy results in an alteration in the renin-angiotensin-aldosterone system (RAAS). Renin levels are elevated, angiotensinogen production is increased, and angiotensin-converting enzyme is reduced.8 As a result, both aldosterone and angiotensin II levels are higher in pregnancy. Further increase in aldosterone levels is driven by progesterone-induced sodium loss in the renal tubules.9
In normal pregnancy, there is a decrease in plasma osmolality to a level of about 10 mOsmol/kg
below normal.10 This seems to result from a new steady-state setpoint caused by a decrease in the osmotic thresholds for both thirst and vasopressin suppression, similar to that seen in the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
below normal.10 This seems to result from a new steady-state setpoint caused by a decrease in the osmotic thresholds for both thirst and vasopressin suppression, similar to that seen in the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Calcium Metabolism
During pregnancy, alterations in calcium metabolism occur to allow growth of the fetal skeleton.11 A drop in serum albumin in the setting of increased intravascular volume results in a decrease in total calcium (measured as bound to albumin), but ionized calcium levels remain normal. Parathyroid hormone (PTH) levels decrease to the low-normal range, sometimes even going below normal in the first trimester.12 By the third trimester, PTH levels are in the mid-normal range with maternal calcium intake and vitamin D status influencing the levels.13 PTH-related peptide (PTH-rp) starts to increase in the third week of gestation and is three times higher at term than at prepregnancy.12 Sources for the increase include both the placenta14 and the breasts.15 It is this rise in PTH-rp that is believed to lower PTH levels and stimulate the rise in calcitriol.13
In the first trimester, 1,25 (OH)2D levels start to increase and are two- to threefold higher by delivery.16 This rise in 1,25 (OH)2D results in an increase in calcium absorption in the intestine and decrease in PTH. It is believed that most of the increase in calcitriol is from the kidneys with some contribution from the placenta and fetus.17 At the level of the kidney, possibly driven by PTH-rp, there is increased expression of CYP27b1 (1α hydroxylase).18 This enzyme is responsible for the increased conversion of 25(OH) D to 1,25(OH)2D. Despite increased conversion of 25(OH)D to 1,25 (OH)2D, levels of 25(OH)D appear to mostly remain stable with a few studies suggesting slightly lower levels.19,20,21,22 The mother is the sole source of 25(OH)D for the fetus23—it crosses the placenta while 1,25(OH)2D does not and is made by the fetal kidneys.24 Cord blood 25(OH)D concentrations are 50% to 80% of maternal serum 25(OH)D levels.23 Because the fetus is dependent on the mother for 25(OH)D, maternal sufficiency is important. Altogether, the rise in PTH-rp leading to a rise in 1,25(OH)2D results in increased calcium absorption from the intestine and increased renal filtered calcium load leading to hypercalciuria. The low PTH levels add to the hypercalciuria and the increased risk of kidney stones in pregnancy. Calcitonin levels also rise in pregnancy and it is believed that this helps protect the mother’s skeleton from demineralization.13 Women of childbearing age are recommended to have intakes of 1000 mg calcium/day, with supplementation for women who do not meet that requirement.25
Thyroid
Thyroid-binding globulin (TBG) levels increase during pregnancy as a result of increased estrogen levels, and lead to increases in total thyroxine (T4) and total triiodothyroxine (T3), peaking at approximately 16 weeks’ gestation and remaining high until delivery.26 The increase in TBG does not affect free thyroid hormone or thyroid-stimulating hormone (TSH) levels. However, there is often a transient rise in free T4 (although usually within the normal range) during the first trimester of pregnancy associated with a mild decrease in TSH due to the high circulating human chorionic gonadotropin (hCG) levels (see section below on hCG). This requires different normal ranges for TSH during each trimester of pregnancy. In some cases, these changes may be more pronounced and may be considered an abnormal change in thyroid function during pregnancy rather than “normal.” This has been referred to as gestational transient thyrotoxicosis. This syndrome may also overlap with the transient thyrotoxicosis associated with hyperemesis gravidarum (see section below on Thyrotoxicosis). In addition to changes in thyroid hormone levels, an increase in thyroid size sometimes occurs during pregnancy, which may be related to a relative iodine deficiency (see section on Goiter).26
Placental/Fetal Hormones Affecting the Maternal Endocrine System
Human Chorionic Gonadotropin
hCG is a glycoprotein, a unique gonadotropin produced by the syncytiotrophoblast of the placenta. It is an analog of luteinizing hormone (LH). Although its main function is maintenance of the corpus luteum, the fetal testis is a target organ for hCG. It is largely responsible for the early development of the fetal testis and for testosterone production prior to fetal LH control. The main effect of this hormone relevant to maternal endocrine function is the well-documented thyrotropic effect, which, in
cases of trophoblastic disease, can cause hyperthyroidism in the mother.27 This thyrotropic effect in normal women causes a mild lowering of TSH early in pregnancy, recognized by most laboratories, which report lower normal ranges of TSH during pregnancy. It is important that this be recognized and taken into consideration when considering the diagnosis of hyperthyroidism in the mother, another fairly common condition that is discussed in more detail below.
cases of trophoblastic disease, can cause hyperthyroidism in the mother.27 This thyrotropic effect in normal women causes a mild lowering of TSH early in pregnancy, recognized by most laboratories, which report lower normal ranges of TSH during pregnancy. It is important that this be recognized and taken into consideration when considering the diagnosis of hyperthyroidism in the mother, another fairly common condition that is discussed in more detail below.
Thyrotropin-Releasing Hormone
Thyrotropin-releasing hormone (TRH) is produced by the placenta and enters the maternal and fetal circulation.28 However, it seems to be more important in fetal thyroid function than in maternal thyroid function.
Human Placental Lactogen (Human Chorionic Somatomammotropin)
Human placental lactogen (HPL), also known as human chorionic somatomammotropin, is a polypeptide that has a structure very similar to that of human growth hormone. Its major function is to provide the nutritional needs of the fetus during pregnancy. The role of HPL in pregnancy relates more to its metabolic properties than to its somatotropic or lactogenic effects.28 Its major effect on the maternal endocrine system relates to its effect on carbohydrate and fat metabolism, playing a role in the shift of energy metabolism from carbohydrate to fat during pregnancy. Despite these effects, there is a lack of conclusive evidence regarding the role of HPL in altering glucose and insulin levels during pregnancy.29
Placental Growth Hormone
There is a placental growth hormone variant synthesized by the syncytiotrophoblast and secreted into the circulation during pregnancy, the levels of which relate to fetal growth. This also results in increased insulin-like growth factor (IGF)-1 levels during pregnancy.30 Although there is a specific antibody for measuring the placental growth hormone variant, some commercial growth hormone assays may measure this along with the maternal pituitary growth hormone. Thus, elevated growth hormone and IGF-1 levels may confuse the diagnostic evaluation of a patient with a possible growth hormone-secreting pituitary tumor during pregnancy.
Insulin-Like Growth Factor
IGF-1 is a peptide that is important for fetal and placental growth during pregnancy. IGF-1 levels increase during pregnancy as a result of increasing levels of placental growth hormone.31 Levels of IGF-1 and its binding proteins, IGFBP-1 and IGFBP-3, may be associated with fetal birthweight and predict risk of preeclampsia.32,33
Endocrine Disorders of Pregnancy
There are a variety of endocrine disorders that, when associated with pregnancy, have unique aspects of importance to the mother, newborn, or both that may alter usual diagnostic or therapeutic strategies. In some instances, the disease is more likely to occur or may be worsened by the pregnancy; in others, changes resulting from the pregnancy and/or the associated alterations in metabolism influence the diagnostic evaluation; and, still others may require alterations to avoid detrimental effects to the fetus.
Thyroid Disorders
Thyroid disorders in pregnancy are relatively common in the general population and are much more common than previously thought because of increased screening and the increased sensitivity of current diagnostic techniques. Overt hypothyroidism and hyperthyroidism have clearly been shown to have detrimental effects on the pregnancy and the fetus. It is more difficult to establish the risk to the fetus of untreated mild hypothyroidism or hyperthyroidism. Due to conflicting data and unclear benefit of treating subclinical thyroid dysfunction, there is no clear consensus on thyroid screening of all pregnant women. However, women should be screened with a TSH at the initial prenatal visit if symptoms or a history of thyroid disease, personal or family history of autoimmunity, obesity, age >30 years, or prior treatment with neck radiation are present.26 This review of thyroid diseases during pregnancy will emphasize practical management issues.
Goiter
Clinical Presentation
Thyroid size has historically been said to increase in pregnancy. However, thyroid growth is more pronounced in the presence of iodine insufficiency. It is recommended that pregnant and lactating women consume approximately 250 µg of iodine daily to avoid thyroid, cognitive, and psychomotor effects of iodine deficiency.34
Thyrotoxicosis
Clinical Presentation
The term thyrotoxicosis is used for an increased metabolic state associated with excess thyroid hormone levels from any source. Hyperthyroidism is the term reserved for thyrotoxicosis due to thyroid gland hyperfunction, ie, Graves disease or toxic nodular goiter. Although both thyroid hyperfunction and hypofunction may be associated with infertility, these conditions are not uncommonly seen in pregnancy.
Clinical Assessment
Thyrotoxicosis in pregnancy can be challenging to evaluate and manage. Being certain that one is dealing with hyperthyroidism as the cause of thyrotoxicosis may be difficult as performing a radioactive iodine uptake is contraindicated in pregnancy. Silent thyroiditis (postpartum thyroiditis) may occur during late pregnancy and may cause transient thyrotoxicosis. This may be difficult to differentiate from Graves hyperthyroidism and gestational thyrotoxicosis. However, measurement of thyroid receptor antibodies may help to differentiate Graves disease from other etiologies of thyrotoxicosis.26 Painful subacute thyroiditis is no more likely to occur in the pregnant than in the nonpregnant state. This condition is recognized by the presence of an enlarged, painful, tender thyroid gland, sometimes with fever, and may be associated with transient thyrotoxicosis. It is generally self-limited and resolves in a few weeks.
Transient gestational thyrotoxicosis may occur in 1% to 3% of pregnancies. It is only present in the first half of pregnancy and is often associated with nausea or seen with hyperemesis gravidarum. Such patients usually do not have severe clinical features of thyrotoxicosis, and free T4 and TSH generally return to normal by 15 to 20 weeks of gestation. Treatment with anti-thyroid medications is not recommended for transient gestational thyrotoxicosis. Supportive care with antiemetics, hydration, or beta-blockers may help treat symptoms.35
Pharmacologic Management
Even after hyperthyroidism is established as the probable cause of thyrotoxicosis, management is complicated by the fact that the antithyroid drugs propylthiouracil (PTU), methimazole (MMI), and carbimazole cross into the fetal circulation readily, whereas thyroid hormone does so less readily.26 Inadequate treatment of maternal hyperthyroidism is associated with prematurity, low birthweight infants, small for gestational age infants, stillbirths, and increase in neonatal intensive care admissions.35,36 On the other hand, aggressive treatment of maternal thyrotoxicosis may cause fetal goiter, fetal hypothyroidism, and the associated consequences of either fetal loss or impaired intellectual development.
Radioactive iodine therapy is contraindicated in hyperthyroidism in the pregnant mother. The greatest risk appears to be if radioactive iodine is given late in the first trimester, at the time of fetal thyroid development and high sensitivity to radioactive iodine. Thus, surgical thyroidectomy or antithyroid drug therapy are the only two therapeutic options for hyperthyroidism in pregnancy. The main indication for surgical thyroidectomy is the hyperthyroid patient who cannot tolerate thionamide therapy, or whose hyperthyroidism cannot be adequately controlled with thionamides. Thus, in the vast majority of patients, therapy with a thionamide, either PTU or MMI in the United States or carbimazole in Europe, has become the preferred therapy.
In view of the risks of untreated or undertreated hyperthyroidism as well as overtreatment of hyperthyroidism, one must always evaluate the risk/benefit ratio of treating maternal hyperthyroidism on a case by case basis. In cases of mild hyperthyroidism with symptoms of tachycardia or tremor, beta-blockers such as metoprolol or propranolol are effective in controlling symptoms in a short period of time and appear to be safe. However, long-term treatment with beta-blockers (more than 6 weeks), is not recommended due to potential risk of fetal growth retardation (especially with atenolol or labetalol) or neonatal hypoglycemia, particularly when used during the third trimester.37,38
Management in Pregnancy
The mainstay of treatment for maternal hyperthyroidism is to treat the mother with a thionamide. The dose should be sufficient to keep the free T4 level in the upper normal or mildly elevated range, which is usually accompanied by a low or suppressed TSH. This approach balances minimizing the risk of overt hyperthyroidism to fetal development and survival while at the same time avoiding the risk of excessive thionamide therapy, which may affect fetal thyroid development and function and fetal survival.26 PTU has traditionally been preferred over MMI because
PTU was thought to cross the placenta less well and because of reports of cutis aplasia and other possible congenital abnormalities in the infant related to MMI therapy. However, evidence indicates both PTU and MMI have potential teratogenic effects, although the birth defects with PTU appear less severe.39 Consideration may be given to limiting the use of PTU for the first trimester of pregnancy and changing to MMI for the remainder of pregnancy to avoid potential PTU-related liver toxicity; however, this is not universally recommended.26 Women on preexisting thionamide therapy may consider switching to PTU once they decide on trying to conceive. If Graves hyperthyroidism is well controlled on thionamide therapy, a woman can discontinue treatment as soon as pregnancy is detected, especially if on lower doses of thionamide and treatment has persisted for >6 months, with close monitoring of thyroid function tests, at least every 4 weeks. A pregnant woman who has hyperthyroidism should be monitored at 4- to 6-week intervals during the entire pregnancy.
PTU was thought to cross the placenta less well and because of reports of cutis aplasia and other possible congenital abnormalities in the infant related to MMI therapy. However, evidence indicates both PTU and MMI have potential teratogenic effects, although the birth defects with PTU appear less severe.39 Consideration may be given to limiting the use of PTU for the first trimester of pregnancy and changing to MMI for the remainder of pregnancy to avoid potential PTU-related liver toxicity; however, this is not universally recommended.26 Women on preexisting thionamide therapy may consider switching to PTU once they decide on trying to conceive. If Graves hyperthyroidism is well controlled on thionamide therapy, a woman can discontinue treatment as soon as pregnancy is detected, especially if on lower doses of thionamide and treatment has persisted for >6 months, with close monitoring of thyroid function tests, at least every 4 weeks. A pregnant woman who has hyperthyroidism should be monitored at 4- to 6-week intervals during the entire pregnancy.
As the third trimester approaches, hyperthyroidism in the mother frequently improves, allowing dose reduction or discontinuation of antithyroid drug therapy. There is evidence that improvement is associated with a decline in thyroid-stimulating antibodies and TSH-binding inhibitory immunoglobulins during pregnancy.40 As symptomatic Graves hyperthyroidism commonly recurs in the postpartum period, careful frequent monitoring during the postpartum period with reinstitution of antithyroid therapy as soon as biochemical hyperthyroidism recurs may prevent clinically symptomatic hyperthyroidism during this time.
In addition, measuring TSH receptor-stimulating antibodies and/or thyroid-stimulating immunoglobulins in a pregnant woman with Graves disease should be done early in pregnancy to detect risk of fetal thyrotoxicosis. These antibodies cross the placenta and can produce transient hyperthyroidism in the infant. It should be emphasized that all women with a history of Graves disease, even if not hyperthyroid during the present pregnancy, may have these circulating antibodies and should have them measured early in pregnancy and again in the third trimester.
Fetal hyperthyroidism in the infant occurs in about 1% to 5% of patients with active or past-treated Graves disease and the risk relates to the antibody titer.41 TSH receptor-blocking antibodies may also be present, which can lead to transient fetal hypothyroidism. It is probably not necessary to measure blocking antibodies routinely, but obtaining TSH levels in the newborn is typically done. Ultrasonographic monitoring of fetal growth and thyroid size during thionamide therapy, or if high levels of TSH-receptor antibodies are present, is recommended to help identify and treat any fetus at risk for fetal hyperthyroidism or malformations.
Regarding continued management during the postpartum period, an advantage of PTU over MMI is that it appears to be secreted in breast milk in lower concentrations. However, due to very low levels of all thionamides in breast milk, current evidence supports the view that breastfeeding with a moderate dose of any of the thionamides appears to be safe for the infant.42 Obtaining a radioactive iodine uptake and administering radioactive iodine therapy should be withheld until breastfeeding has been completed.
Hypothyroidism
Clinical Presentation
Worldwide, iodine deficiency is a common cause of hypothyroidism and may be more common in Western societies than previously thought. Other causes include primary thyroid gland failure resulting from radioactive iodine treatment of hyperthyroidism, surgical thyroidectomy, or Hashimoto thyroiditis. Rarely, hypothyroidism may be due to underlying pituitary disease. This is unlikely as patients with pituitary hypothyroidism often also have pituitary hypogonadism and are less likely to achieve a pregnancy.
Primary hypothyroidism may be diagnosed prior to pregnancy or may be first diagnosed during pregnancy. Gestational hypothyroidism is linked to fetal cognitive development and an increased rate of fetal death. This relationship has been most clearly established for severe hypothyroidism and less well-established for mild hypothyroidism.
Management in Pregnancy
Hypothyroidism is readily preventable by supplemental doses of dietary iodine. There is a consensus that clinical and subclinical maternal hypothyroidism requires early detection and treatment. Complications from untreated hypothyroidism include preeclampsia, preterm delivery, pregnancy loss, placental abruption, and cognitive impairment in the child.43,44 In addition to screening pregnant
women at risk with a TSH for the presence of primary hypothyroidism, any woman on replacement L-thyroxine therapy should have their TSH and free T4 levels monitored at least monthly during the first half of pregnancy as L-thyroxine requirements often increase during pregnancy. The average increase in T4 requirement in pregnant women can be up to 50% during the first half of pregnancy. Therefore, because of the known importance of maternal thyroid function for normal fetal cognitive development, and the fact that increased T4 requirements may occur as early as the fifth week of pregnancy, it has been recommended that treatment be initiated as soon as pregnancy is confirmed. Patients should be given about a 30% increase in their thyroid hormone dose and then be monitored and have their T4 dose adjusted as necessary. TSH levels should be maintained <2.5 to 3.0 mU/L during preconception planning and during pregnancy.26
women at risk with a TSH for the presence of primary hypothyroidism, any woman on replacement L-thyroxine therapy should have their TSH and free T4 levels monitored at least monthly during the first half of pregnancy as L-thyroxine requirements often increase during pregnancy. The average increase in T4 requirement in pregnant women can be up to 50% during the first half of pregnancy. Therefore, because of the known importance of maternal thyroid function for normal fetal cognitive development, and the fact that increased T4 requirements may occur as early as the fifth week of pregnancy, it has been recommended that treatment be initiated as soon as pregnancy is confirmed. Patients should be given about a 30% increase in their thyroid hormone dose and then be monitored and have their T4 dose adjusted as necessary. TSH levels should be maintained <2.5 to 3.0 mU/L during preconception planning and during pregnancy.26
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