Parathyroid Diseases in Pregnancy
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Parathyroid diseases are uncommon in pregnancy, may produce significant perinatal and maternal morbidity and mortality if not diagnosed and properly managed. Primary hyperparathyroidism (PHP) is an uncommon disease in women of childbearing age. The incidence of the disease is unknown, but it is definitely rare; and most of the reported cases have been single ones complemented with a review of the literature. More than 150 cases have been documented in the English literature until 1999 (1), and since then, isolated cases have been reported. The two most common causes of neonatal morbidity in PHP are prematurity and neonatal hypocalcemia, the latter related to levels of maternal hypercalcemia. Parathyroid hormone (PTH) (84 amino acids, mw 9500) is synthesized in the parathyroid glands by sequential cleavage of pro-PTH. Circulating PTH is composed of at least three forms: 1) the intact hormone (1-84, which is biologically active with a half-life of 10 minutes) and constitutes 10% of the PTH pool; 2) the amino-terminal fragments, which are also biologically active, have a similar short half-life, and represent 10% of the PTH pool; and 3) the carboxy-terminal fragments, which are biologically inactive and make up 80% of the PTH pool. The heterogeneity of circulating forms of PTH represents a major problem in the understanding of the metabolism and inactivation of this hormone. Recently, however, the development of an immunoradiometric assay for the intact and biologically active forms of PTH has clarified this unsettled problem.
The purpose of this document is review calcium homeostasis, primary hyperparathyroidism, hypoparathyroidism, and osteoporosis during pregnancy. PTH promotes resorption of calcium from the bones. Thus, all events of PTH action are directed at increasing serum calcium levels. The successful treatment of maternal PHP may transiently improve some of the clinical findings of preeclampsia and preterm labor.
Calcium Metabolism in Pregnancy:
Serum calcium is tightly regulated and maintained within normal limits by parathyroid hormone (PTH) and vitamin D. Approximately 50% of serum calcium is protein bound, mostly to albumin; 10% is complexed to anions; and 40% circulates free as ionized calcium. During pregnancy, there is an active transfer of maternal calcium to the fetus. A full-term infant requires 25 to 30 g of calcium during the course of pregnancy for new bone mineralization. Total serum calcium during gestation is 8% below postpartum levels (2). The upper limit of normal calcium is 9.5 mg/mL. This decrease in total serum calcium is due to the physiologic hypoalbuminemia secondary to the normal expansion of the intravascular volume observed early in pregnancy. Ionized calcium levels, however, remain unchanged throughout gestation. The physiologically active form of vitamin D is 1,25(OH)2D3 which is responsible for increasing intestinal absorption of calcium, and also bone absorption. The parathyroid glands, which produce PTH, are stimulated by hypocalcemia and suppressed by high concentrations of calcium, magnesium, and 1,25(OH)2D3 and also by hypomagnesemia. PTH influences calcium metabolism, not only by directly reabsorbing bone, but also by stimulating 1,25(OH)2D3 formation. There are three major forms of circulating calcium, namely ionized, protein-bound, and chelated fractions. The ionized fraction is physiologically active and homeostatically regulated. Maternal serum PTH levels, when measured by a sensitive assay that accurately measures the levels of intact PTH, are slightly decreased in the first half of pregnancy (about 20% of the mean non-pregnant values) and return to normal by mid-gestation (3). Blood levels of 1,25(OH)2D3 (calcitriol) increase early in gestation as a result of stimulation of renal 1?-hydroxylase activity by estrogen, placental lactogen, and PTH, as well as synthesis of calcitriol by the placenta (4). Both free and total 1,25(OH)2D3 are increased in pregnancy, the total because of an increase in vitamin D-binding protein.
Although the mechanisms responsible for placental transport of calcium are poorly understood, large amounts of calcium and phosphorus are transferred against a concentration gradient from the mother to the fetus, the net fetal accumulation of calcium being 25 to 30 gm by term (mostly in the third trimester). Maternal calcium absorption mediated through increases in PTH and 1,25(OH)2D3 synthesis rises during pregnancy to meet these demands. Depending on calcium intake, the net effect of pregnancy on the maternal skeleton could be positive or negative; under normal conditions there is little influence on bone mineral content. Paralleling a decline in serum albumin, total serum calcium concentrations decline during gestation, with little change in ionized calcium (2). In response to placental calcium transfer as well as an expanding extracellular volume and increased urinary calcium loss, maternal PTH concentrations rise during pregnancy. Serum 25(OH)D concentrations remain essentially unchanged, while 1,25(OH)2D3 levels also rise during pregnancy, peaking at term; there may be placental contribution latter. There are no consistent changes in calcitonin concentrations in pregnancy.
Fetal parathyroid tissue has been identified by 6-weeks gestation, and skeletal mineralization is apparent by the eighth week. Total and ionized calcium concentrations are elevated in the fetus at term and decrease to normal in the newborn period. PTH levels are low in fetus and increase after birth. Calcitonin is elevated in the fetus. During lactation the average daily loss of calcium in human milk is 220 to 340 mg. There is a small drop in serum calcium, accompanied by a rise in PTH and 1,25(OH)2D3 concentrations. It is summarized below:
Minerals and Hormones Involved in Calcium Homeostasis:
Parathyroid hormone-related protein (PTHrP), a peptide responsible for the hypercalcemia found in many malignant tumors, increases in early pregnancy. A steady increase in plasma values are observed throughout pregnancy, with a peak in the third trimester and high values in cord blood (2)(3). The plasma concentration in the postpartum period was directly related to the degree of breast-feeding. The source of maternal serum PTHrP is multiple; both fetal and maternal sites have been postulated (placenta, amnion, deciduas, fetal parathyroid glands, breast, umbilical cord). PTHrP plays a role in placental calcium transport and also may have a role in protecting the maternal skeleton during pregnancy because the carboxyl-terminal portion of PTHrP ("osteocalcin") has been shown to inhibit osteoclastic bone resorption (3). PTHrP may be involved in the transfer of maternal calcium into breast milk. The alteration in calcium and bone metabolism that accompanies human lactation represents a physiologic response that is independent of calcium intake.
The role of calcium in mediating myometrial contractility is well-established (8), as is the use of calcium channel blockers to arrest preterm labor (9). By contrast, the role of calcium, PTH and vitamin D in blood pressure regulation is less clear (10). Although cytosolic calcium regulates vascular tone, it is unknown whether systemic calcium or vitamin D deficiencies can cause hypertension. Such deficiencies have been postulated to increase the risk of preeclampsia, but maternal calcium supplementation has not proven preventive (10)(11).
Primary hyperparathyroidism (PHP) is generally associated with excess autonomous production of PTH by a solitary adenoma (incidence 80%) involving only one gland, leading to hypercalcemia and hypercalciuria (5). Primary hyperplasia of the four parathyroid glands accounts for about 15% of the cases reported, 3% are due to multiple adenomas, and only a few cases due to parathyroid carcinoma have been reported in the literature. In adults, the prevalence of hyperparathyroidism ranges from 0.15% to 1%. Even though the condition is 2 to 3 times more common in women, PHP during pregnancy is rare. Almost 70% of patients are asymptomatic in the nonpregnant state, and the diagnosis is made through the routine use of biochemical screening. In pregnancy, because routine calcium determinations are not performed, manifestations of the disease are present in almost 70% of the diagnosed patients. Parathyroid cancer is a rare cause of hyperparathyroidism, but few cases have been reported in the literature. In these cases serum calcium levels are significantly higher than in other causes of PHP (6). Perinatal mortality and morbidity are significantly higher. Hypercalcemia with values higher than 13 mg/mL in the presence of a palpable neck mass should raise a strong suspicion of parathyroid carcinoma. On the contrary, in the presence of mild hypercalcemia and a neck mass, the most common cause of the neck lesion is a thyroid nodule. One other characteristic clinical feature of parathyroid carcinoma is the patient's poor response to the usual clinical therapeutic measures such as intensive hydration and loop diuretics. Surgery is the only effective therapy.
Common symptoms and presentation of hyperparathyroidism include: renal calculi, pancreatitis, bone pain, muscle weakness, hypertension, and hypercalcemic crisis. Hyperparathyroidism should be considered in differential diagnosis of acute pancreatitis during pregnancy. Acute pancreatitis has been reported in 13% of women with primary hyperparathyroidism (7). The incidence of hyperparathyroidism in nonpregnant women is about 1.5%, and is less than 1% in normal pregnancy. This complication is associated with significant rates of neonatal and maternal morbidity (7). It is more common in primipara than in women who have had multiple pregnancies. Acute pancreatitis with PHP is most likely to occur during the last trimester of pregnancy or the postpartum period, but has also been reported in the first trimester of pregnancy, mimicking hyperemesis gravidarum. Serum calcium levels should be obtained in any pregnant woman with persistent significant nausea, vomiting, and abdominal pain. Hyperparathyroid crisis, a serious complication of PHP, has been reported during gestation and the postpartum period, and is characterized by severe nausea and vomiting, generalized weakness, changes in mental status, and severe dehydration.
To summarize maternal features of hypercalcemia:
Urinary system: nephrolithiasis, nephrocalcinosis and polyuria;
Differential Diagnosis of Hypercalcemia:
Although most young women with hypercalcemia have PHP, other unusual causes should be ruled out, mainly endocrine disorders, vitamin D or A overdose, the use of thiazide diuretics, or granulomatous disease. The three rare causes related to pregnancy are: familial hypocalciuric hypercalcemia (FHH), postpartum hypercalcemia in hypoparathyroidism and PTHrP-induced hypercalcemia. Other causes not related to pregnancy are: malignancy, endocrine -- thyrotoxicosis and/or adrenal insufficiency, vitamin D and A overdose, drugs -- thiazide diuretics, lithium, granulomatous disease -- sarcoidosis, tuberculosis, histoplasmosis, coccidioidomycosis, Milk alkali syndrome, acute and chronic renal failure and total parenteral nutrition.
FHH is an autosomal dominant condition with a high penetrance for hypercalcemia. The disorder is associated with an inactivating mutation in the gene for the calcium-sensor receptor (12). The main function of the receptor is in the regulation of calcium balance through changes in the parathyroid and kidneys. Mild hypercalcemia, slight elevation in serum PTH, mild hypermagnesemia, and low urinary calcium excretion are the typical findings. There is moderate hyperplasia of the four parathyroid glands. Total parathyroidectomy is seldom indicated owing to the benign course of the disease (12). Infants born to mothers with FHH may present with different clinical manifestations. First asymptomatic hypercalcemia can develop in an affected offspring if the mother is a carrier for FHH. In a second situation, severe neonatal hypocalcemia can occur in a mother with FHH syndrome. Although neonatal hypocalcemia could be severe, neonatal parathyroid function returns to normal a few weeks after delivery. In the third situation, severe neonatal hypercalcemia, also called neonatal severe hyperparathyroidism, occurs in infants homozygous for the FHH gene defect. Some infants require parathyroidectomy soon after birth.
Postpartum hypercalcemia may occur in women with treated hypoparathyroidism (13). The mechanism for hypercalcemia is not well understood. Nausea and vomiting develop a few days after delivery, dehydration ensues, and other manifestations of hypercalcemia develop, mainly mental changes. Serum calcium may be significantly elevated. Patients with treated hypoparathyroidism should be followed in postpartum with serum calcium determinations, and vitamin D should be discontinued if hypercalcemia occurs. In severe cases, intravenous fluids and glucocorticoid therapy are required (14).
A few cases of hypercalcemia, mediated by PTHrP during pregnancy and in the postpartum period have been reported (12)(13). In one case, hypercalcemia developed in two successive pregnancies. In the second pregnancy, serum PTHrP levels were elevated three times normal and the infant was born with mild hypercalcemia that returned to normal within 24 hours after delivery. In the other case, a 25-year-old woman had massive bilateral breast enlargement at 24 weeks' gestation. Her serum calcium level was 14.3 mg/mL, but her serum PTH level was undetectable. She underwent bilateral mastectomy during pregnancy (12). The immunohistochemical studies demonstrated PTHrP antigenic activity in breast tissue.
Complications of Hyperparathyroidism Affecting Mother and Infant:
Untreated severe PHP during pregnancy has been reported to result in maternal complication rates as high as 67%, in fetal complication rates as high as 83%, and neonatal complication rates as high as 53% (of which about 30% represent neonatal deaths) (15). Maternal complications include: hyperemesis, preterm labor, preeclampsia and eclampsia, generalized weakness, renal calculi, pancreatitis, and psychiatric problems. The overall maternal mortality remains low, however, fetal morbidity and mortality are significant. Neonatal hypocalcemia with tetany is usually a transient phenomenon related to suppression of fetal parathyroid glands resulting from maternal-fetal hypercalcemia, it may be more prolonged in the mature infants or infants with birth asphyxia.
For hyperparathyroidism presenting during pregnancy, standard practice favors surgical treatment. Parathyroidectomy during the second and third trimester is the current standard of care for symptomatic pregnant patients with severe PHP and hypercalcemia exceeding 12 mg/mL (16). However, there have been concerns about maternal/fetal complications due to surgery and prolonged general anesthesia. Nonetheless, post-surgical pregnancy outcomes showed a 4- to 5-fold decrease in maternal/fetal complication rates (17). Successful PHP treatment in pregnancy utilizing minimally invasive parathyroidectomy preceded by preoperative localization of the parathyroid adenoma and intraoperative monitoring with serial PTH measurements have been reported. In this report (17) preoperative tumor localization in pregnancy using Tc-99m-sestamibi scanning has been successful. Advantages include avoidance of unnecessary surgical exploration, decreased complication rates, and shortened anesthesia time. The low doses and short half-life minimize fetal radiation exposure (18). Serial intraoperative PTH measurements are easily obtained, confirm complete removal of the adenoma, and exclude multiglandular disease. In patients undergoing surgical treatment, hypocalcemia, albeit transient, may occur after surgery in some cases. Serum calcium should be checked every 6 hours, and if the patient develops hypocalcemic symptoms, intravenous calcium in the form of calcium gluconate, 10 to 20 mL of a 10% solution, should be given over a period of 5 to 10 minutes. Intermittent infusions in 5% dextrose or isotonic saline and infused continuously at 1 mg/kg body weight per hour. In patients with bone disease, postsurgical hypocalcemia may be profound, and aggressive treatment is needed. These patients may need vitamin D supplementation in the form of calcitriol 0.25 to 0.5 µg/day for a few days before operative intervention.
Conservative treatment of mild asymptomatic patients has also been suggested. The treatment of life-threatening hypercalcemia may be problematic and may require hydration, furosemide, phosphates, and even hemodialysis. Medical therapy is reserved for those patients with significant hypercalcemia who are not surgical candidates. Oral phosphate therapy as inorganic phosphorus in doses of 1.5 to 2.5 g/day has been shown to be effective in controlling hypercalcemia (12). Side effects of oral phosphate therapy include nausea, vomiting and hypokalemia. These problems can be easily avoided by decreasing the dose of medication. In patients in whom surgery is not advisable, it is important to prevent elevations in serum calcium. Good hydration, early treatment of urinary tract infections, and avoiding medications known to cause elevations in serum calcium such as vitamin D, vitamin A, aminophylline, and thiazide diuretics are all important therapeutic measures. Serum calcium should be determined on a regular basis.
Acquired hypoparathyroidism is most commonly the result of inadvertent removal or irreversible damage to the glands, usually to their blood supply, during thyroidectomy, parathyroidectomy, or radical neck dissection. Definitions of permanent postsurgical hypoparathyroidism vary, but the definition is generally accepted to be insufficient PTH to maintain normocalcemia 6 months after surgery. Hypoparathyroidism is estimated to occur after approximately 0.5 to 6.6% of total thyroidectomies; the rates of this complication are even higher in some case series, whereas reported rates at endocrine surgical centers with high volumes are 0.9 to 1.6% (19). Idiopathic hypoparathyroidism is a much less common cause of the disease, frequently associated with other autoimmune endocrinopathies, as part of the polyglandular autoimmune syndrome type 1. Antibodies directed against parathyroid calcium-sensing receptor have been detected in 56% of patients with idiopathic hypoparathyroidism. The requirement for calcium supplementation and vitamin D may decrease in some but not all women with hypoparathyroidism during the second half of pregnancy and lactation. In few cases, hypocalcemic symptoms ameliorate with progression of pregnancy.
Clinical features include tetany, which may be elicited in latent form using the Chvostek's (tapping of the facial nerve) and Trousseau's tests (the occurrence of tetany within three minutes of the induction of ischemia in the upper extremity). Other symptoms include paresthesia, stridor, muscle cramps, and mental changes including frank psychosis. The electrocardiogram may reveal prolongation of the Q-T interval.
Diagnosis is made by the combination of low calcium and phosphorus levels, with low PTH, 1,25(OH)2D3 and nephrogenous cAMP concentrations. Plasma alkaline phosphatase is usually normal. The differential diagnosis of hypocalcemia includes rickets, osteomalacia, and hypomagnesemia. Marked hypocalcemia may occur in severely ill patients. The etiology is unclear, and a return to normal serum calcium is the rule following recovery from the acute event (13). Measurements of urinary calcium, magnesium and creatinine in a 24-hour collection can also be helpful in the diagnosis of hypoparathyroidism.
Complication of Hypoparathyroidism Affecting Mother and Infant:
Vitamin D deficiency in the mother has been associated with decreased fetal growth (20). Maternal serum calcium may be normal or slightly decreased during pregnancy. There is a positive correlation between serum maternal ionized calcium levels and the crown-heel length of the newborn, suggesting vitamin D deficiency could interfere with fetal growth through an effect on maternal calcium homeostasis. Neonatal hyperparathyroidism may develop secondary to maternal hypocalcemia. This may cause fetal bone demineralization and growth restriction. Although this is transient, death complications of skeletal fractures may occur (20). The presentation can be highly variable, ranging from clinically and radiologically silent cases to neonates with severe skeletal disease and bone mineralization.
Treatment of hypoparathyroidism does not differ from the nonpregnant state, including a normal high-calcium diet and vitamin D supplementation. The normal calcium supplementation of pregnancy is about 1.2 g/day. Vitamin D requirements may decrease in some patients by the second half of gestation. Calcitriol 1 to 3 µg/day is used most routinely in most patients affected with hypoparathyroidism (21). Calcitriol must be given in single or divided doses, because its half life is much shorter than vitamin D. if vitamin D is used, the dose is in the range of 50,000 to 150,000 IU/weekly. The importance of compliance with medications should be strongly emphasized, particularly when calcitriol is prescribed, in view of its short half-life. The major problem in the treatment of hypoparathyroidism is the recurrence of hypercalcemia and hypocalcemia. Therefore, serum calcium determinants should be performed at regular intervals. The most common symptoms of vitamin D intoxication are nausea, constipation, fatigue, headaches, and in more severe cases, vomiting and dehydration. It is important to assess serum calcium and phosphorus during pregnancy, particularly in the postpartum period, to detect the early onset of hypercalcemia (21).
Acute symptomatic hypocalcemia is a medical emergency and should be treated with intravenous calcium; 10 mL of 10% calcium gluconate over ten minutes followed by an infusion of 0.5 to 2.0 mg/kg/hour of elemental calcium, diluted with dextrose to avoid irritation to veins (21). Lactation in mothers taking vitamin D may be contraindicated, because a metabolite of vitamin D 1,25(OH)2D3 has been detected in breast milk in high concentration in a mother taking 50,000 IU of vitamin D daily. Regardless of the form of vitamin D prescribed, serum calcium determinations should be in the postpartum period, particularly in breast-feeding mothers. High levels of vitamin D in breast milk may cause hypercalcemia and impaired linear growth in the infant.
Hypoparathyroidism is one of the few endocrinopathies for which hormone-replacement therapy is not readily available. Only a few small, randomized trials have assessed the use of injectable human PTH (1-34, Bachem California) in patients with this condition (23). In a 3-year trial comparing PTH (1-34) with calcitriol, both given every 12 hours with supplemental calcium, both treatments maintained the serum calcium level within or slightly below the normal range (7.6 to 8.8 mg/mL [1.9 to 2.2 mmol per liter]), but the use of PTH resulted in less urinary calcium excretion. Although PTH significantly increased biochemical markers of bone turnover (as compared with no significant change with calcitriol), there were no differences in bone mineral density between the groups (23). Creatinine clearances did not differ significantly between the groups, and they were stable in both groups during the study. PTH (1-34) is not approved by the Food and Drug Administration (FDA) for the use.
Pseudohypoparathyroidism encompasses several different disorders having as a common feature varying degrees of target organ resistance to PTH. Somatic changes are present in some forms of the syndrome, including short stature, obesity, round face, brachydactyly, and mental retardation, with brain calcifications. This variant is known as Albright's syndrome type 1a. Most patients suffer from hypocalcemia, due to a derangement of renal 1?-hydroxylase and production of calcitriol. A few cases have been reported in pregnancy (12)(13). Spontaneous normocalcemia occurred in two patients during four pregnancies. The authors provided evidence of placental synthesis of calcitriol to account for the normocalcemia. In both patients, serum PTH, which was significantly increased before pregnancy, was reduced by 50% during gestation. Serum cord calcium, phosphorus, and calcitriol concentrations were within normal limits. These infants are at risk for intrauterine fetal hyperparathyroidism, perhaps because of the relative maternal hypocalcemia during pregnancy.
Osteoporosis during Pregnancy:
In the last few years, there has been an increased interest in several clinical aspects of osteoporosis in pregnancy and lactation. In general, osteoporosis is suspected in pregnancy when the patient presents with severe, persistent back or hip pain and radiologic examination shows signs of osteopenia. Studies measuring calcitrophic hormones and biochemical markers of bone reabsorption in each trimester in pregnancy and in the postpartum period showed a slight decrease in bone mass in the third trimester, followed by recovery within the first 6 months postpartum (22). Osteoporosis may be diagnosed during pregnancy or in the postpartum period. Whether these are two different syndromes or represent the same clinical entity is unclear, because the symptoms may begin during pregnancy, but the diagnosis is made for the first time after delivery. Osteoporosis diagnosed during pregnancy may be localized in the hips, lumbar spine, or both. Pain in one hip or back pain is the presenting symptom in most cases, usually in the second half of gestation. Spontaneous recovery is the usually course a few months postpartum. The impact of lactation on osteoporosis is controversial. Given the controversy, the healthcare provider must decide if cessation of lactation is advisable in the management of osteoporosis. Heparin-associated osteoporosis has been reported (24). It may be related to the total dose of heparin. Treatment with calcium supplementation or calcitriol, although not proven, may be helpful in those patients receiving heparin therapy.
The initial evaluation of a patient with hyperparathyroidism and hypoparathyroidism should include a detailed family history, which may suggest a genetic cause and relevant medical history particularly regarding neck surgery and autoimmune disease. Laboratory testing should include measurements of serum total and ionized calcium, albumin, phosphorus, magnesium, and intact PTH levels. A cause-and-effect relationship between PHP and preeclampsia or preterm labor is possible. Successful treatment of maternal PHP may transiently improve some of the clinical findings of preeclampsia and preterm labor. Vitamin D metabolites and analogues are essential to the management of hypoparathyroidism. The key complication to avoid is vitamin D intoxication (hypercalcemia and hypercalciuria) with its adverse effects on the renal and central nervous systems. Calcitriol is preferred over vitamin D2 or D3, because of its potency and rapid onset and offset of action. Although osteoporosis has been diagnosed during pregnancy, pregnancy unmasks rather than causes low bone mass. Postural changes during pregnancy, including increased lordosis, when superimposed on a small and transient decrease in bone mass, may lead to pain and even fractures. Heparin adversely affects bone density in about one third of exposed patients.