The Laryngoscope Lippincott Williams & Wilkins © 2008 The American Laryngological, Rhinological and Otological Society, Inc.
Primary Hyperparathyroidism in Pregnancy: A Case Series and Review Mai Thy Truong, MD; M. Lauren Lalakea, MD; Paul Robbins, MD; Michael Friduss, MD
Objectives/Hypothesis: To review the clinical significance of primary hyperparathyroidism during pregnancy including the maternal, fetal, and neonatal sequelae. Additionally, to discuss treatment options and describe three cases where surgical parathyroidectomy was successful for treatment of hyperparathyroidism refractory to medical management during pregnancy. Study Design: Retrospective. Methods: We reviewed three cases of hyperparathyroidism during pregnancy and reviewed the literature. Results: Three women underwent surgical parathyroidectomy during their second and third trimester of pregnancy without any maternal, fetal, or neonatal complications. Conclusions: Hyperparathyroidism during pregnancy may be safely treated with surgical parathyroidectomy if refractory to medical management with low operative risk when performed during the second trimester. This surgical option should be considered in light of the known maternal, fetal, and neonatal risks because of the hypercalcemic state in pregnancy. Key Words: Hyperparathyroidism, pregnancy, parathyroidectomy. Laryngoscope, 118:1966 –1969, 2008
from maternal PHPT from 27% (1963–1975) to 5% (1976 – 1990), although the incidence of neonatal tetany remained high at 46%. The head and neck surgeon should be familiar with PHPT in pregnancy as an increasing role for parathyroidectomy has been proposed for this condition.5 We present three cases of PHPT treated successfully by parathyroidectomy during pregnancy.
CASE 1 A 38-year-old woman presented at 36 weeks’ gestation with right flank pain. Ultrasound was negative for nephrolithiasis and laboratory studies were consistent with PHPT (see Table I). The patient was initially treated with hydration, diuresis, and calcitonin nasal spray, with a modest decrease in her serum calcium (Ca2⫹) to 12.6 mg/dL, and ionized calcium (iCa2⫹) to 1.72 mmol/L. Ultrasound demonstrated a 3.6 ⫻ 1 ⫻ 1.3 cm3 mass in the area of the inferior left thyroid gland. The patient underwent elective bilateral surgical exploration during her third trimester with resection of an abnormal left inferior parathyroid gland. The patient went into spontaneous labor at 39 weeks’ gestational age without perinatal complications and neonatal serum calcium was within normal limits. The patient has remained eucalcemic for 5 years postoperatively.
CASE 2 INTRODUCTION The incidence of primary hyperparathyroidism (PHPT) in women of child-bearing age is reported to be 8/1,00,0001 and is even more rare during pregnancy. Only 147 cases of PHPT during pregnancy have been reported in the literature from 1930 to 1997.2 Over the past 30 years, an increasing awareness of the problems associated with PHPT in pregnancy has led to a decline in maternal and fetal/neonatal mortality and morbidity.3 Kelly4 reported a reduction in stillbirths and/or neonatal deaths
From the Stanford Hospital and Clinics (M.T.T.), Stanford, California, U.S.A.; Division of Otolaryngology/Head and Neck Surgery, (M.L.L.), Santa Clara Valley Medical Center, San Jose, California, U.S.A.; and Kaiser Permanente Hospital (P.R., M.F.), Santa Clara, California, U.S.A. Editor’s Note: This Manuscript was accepted for publication May 16, 2008. Presented at the 2008 Western Section Triological Meeting, Palm Springs, California, U.S.A., January 31–February 2, 2008. Send correspondence to Mai Thy Truong, MD, 801 Welch Road, Stanford, CA 94305. E-mail:
[email protected] DOI: 10.1097/MLG.0b013e318180276f
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A 35-year-old woman presented with recurrent nephrolithiasis and was found to have laboratory studies consistent with PHPT (see Table I). Preoperative sestamibi scan and neck ultrasound were nonlocalizing. The patient was scheduled for an elective parathyroidectomy, but before surgery, became pregnant. Surgery was postponed, and the Endocrine and Obstetrics services were consulted to assist with her care. As the patient continued to develop renal stones, requiring frequent oral opiates for pain control, parathyroidectomy was undertaken in her second trimester. An abnormal right superior parathyroid was resected, with a drop in intraoperative parathyroid hormone (PTH) from 115 to 71 pg/mL at 10 minutes after gland removal. Further exploration identified a second abnormal gland (left inferior) which was resected. The patient delivered at term, without perinatal complications, and neonatal serum calcium levels were within normal limits. She has remained eucalcemic for 1 year postoperatively.
CASE 3 A 28-year-old woman presented during her first pregnancy with nausea and nephrolithiasis, and was diagnosed with PHPT. She had a strong family history of hyperparathyroidism. Her serum Ca2⫹ was 10.5 mg/dL with a PTH level of 75 pg/mL at 5
Truong et al.: Primary Hyperparathyroidism in Pregnancy
TABLE I. Patient Demographics and Laboratory Values. Case 1
Age (yrs) Symptom Gestational age at diagnosis (trimester or weeks) Serum Ca2⫹ (mg/dL) iCa2⫹ (mmol/L) PTH (pg/mL) Trimester at surgery Pathology
38 Right flank pain 3rd trimester
Maternal complications Fetal complications
None None
15.3 2.02 656 3rd Parathyroid adenoma
Case 2
Case 3
35 Recurrent nephrolithiasis Diagnosed before pregnancy
28 Intractable nausea Diagnosed during previous pregnancy 11.6 N/A 75 2nd Double parathyroid adenomas None None
11.7 1.43 115 2nd Double parathyroid adenomas None None
PTH ⫽ parathyroid hormone; N/A ⫽ not applicable.
months gestation. Because of her limited symptoms and mild hypercalcemia, it was decided to follow her clinically to term. Her calcium levels remained stable, and she delivered uneventfully with no evidence of neonatal hypocalcemia. Surgical parathyroidectomy was planned postpartum. A sestamibi scan was localizing to the left inferior pole. Before she could be scheduled for surgery she again became pregnant. With her second pregnancy, her symptoms of nausea were more severe, requiring hospitalization for supportive therapy twice during her first trimester. Her hypercalcemia elevated to a high of 11.6 mg/dL. Because of intractable nausea she was brought to surgery at approximately 20weeks gestation with resection of double adenomas. The patient’s nausea improved by 1 week after parathyroidectomy, she remained eucalcemic, and underwent a spontaneous term delivery without maternal or neonatal complications.
DISCUSSION Calcium Homeostasis in Pregnancy A term infant requires 25 to 30 g of calcium for bone mineralization during fetal development. This calcium is actively transported across the placenta, and fetal blood obtained by cordocentesis has a higher concentration of calcium compared with maternal levels by 0.5 to 1 mEq/L, resulting in suppression of fetal PTH secretion until after delivery. In maternal PHPT, the gradient is further elevated, resulting in a state of profound fetal PTH suppression and to a potential hypocalcemic state and tetany after delivery.6
Maternal Complications Associated with PHPT In a review of 70 women with maternal PHPT, Carella and Gossain7 reported the following symptomatology: gastrointestinal symptoms such as nausea, vomiting, and anorexia in 36%, weakness and fatigue in 34%, mental symptoms (headache, lethargy, agitation, emotional liability, confusion, inappropriate behavior, delirium) in 26%, whereas 24% of women were asymptomatic. Maternal complications of PHPT can occur in up to 67% of cases,8 the most common reported being nephrolithiasis.5 Hyperemesis gravidarum is also more common, and an increased incidence of preeclampsia in patients Laryngoscope 118: November 2008
with PHPT is also reported.9 Pancreatitis is more common in pregnant patients with PHPT (13%) than in nonpregnant with the disease (1.5%), or pregnancy alone (⬍1%)3 and is considered a ominous sign of disease severity. In a review by Hong et al.,10 11 cases of pancreatitis secondary to maternal PHPT were reviewed. Complications included one spontaneous abortion, two maternal deaths, three induced labors, four cesarean sections, and five cases of neonatal hypocalcemia in which three infants required ventilatory support. The most feared complication of hypercalcemic crisis is described as serum calcium levels ⬎14 mg/dL with nausea, vomiting, dehydration, weakness, mental status changes, and a rapid progression to uremia, coma and death. This complication may occur during pregnancy or postpartum, when the placenta is no longer shunting calcium to the fetus.5 See Table II for a complete summary of maternal symptoms and sequelae.
Fetal Complications Associated with Maternal PHPT Fifty percent of neonates born from mothers with untreated PHPT may suffer from profound neonatal hypocalcemia with risk of tetany because of fetal PTH suppression.11 However, neonatal complications have been reported in up to 53% in mothers managed medically throughout pregnancy, with one-third reported to be neonatal death.5 Norman et al. reported a 50% risk of fetal death in women with calcium levels above 11.5 mg/dL, and up to 85% when the calcium levels approached 13 mg/dL in a review of 77 patients. J. Norman et al. (unpublished data, 2008) noted that two thirds of women in his study diagnosed with hyperparathyroidism during pregnancy had a history of miscarriage, with 100% successful pregnancies after parathyroidectomy. After delivery, hypocalcemia most frequently occurs from day of life 2 to 14,10 though a case of hypocalcemic seizure has been reported in an infant aged 2.5 months.11 Neonatal hypoparathyroidism may be profound as result of persistent fetal hypercalcemia and Truong et al.: Primary Hyperparathyroidism in Pregnancy
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TABLE II. Symptoms and Sequelae of Maternal Hyperparathyroidism. Symptoms
Nausea/vomiting Abdominal pain Constipation Polyuria Dehydration Weakness/fatigue Headache Agitation Emotional lability Confusion Altered mental status Depression Memory loss
Sequelae
Anorexia Nephrolithiasis Recurrent urinary infections Renal failure Cardiac arrhythmia Delirium Pancreatitis Osteopenia Hypertension Coma Death
impaired fetal parathyroid gland development in utero.6 See Table III for a summary of fetal and neonatal complications.
Diagnosis Routine prenatal screening does not screen for maternal PHPT. The clinician should be suspicious if there is a history of, or the patient presents with, nephrolithiasis, peptic ulcer disease, pancreatitis, osteoporosis, severe nausea and vomiting, or a history of spontaneous abortions/stillbirths or neonatal death. Mothers delivering infants with hypocalcemia or tetany should be immediately evaluated for maternal PHPT, as there is a risk of significant postpartum maternal hypercalcemia. The 1990 National Institutes of Health guideline entitled, “Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism,” suggests that parathyroidectomy should be considered for asymptomatic patients with serum calcium elevations 1 to 1.6 mg/dL (0.25– 0.4 mmol/L) above the accepted normal range, i.e., 11.4 to 12 mg/dL (2.85–3.0 mmol/L), given a normal range of 8.8 to 10.4 mg/dL (2.2–2.6 mmol/L).12 These calcium levels apply to nonpregnant patients, as calcium norms are somewhat
TABLE III. Intrauterine and Neonatal Complications of Primary Hyperparathyroidism During Pregnancy. Intrauterine Premature rupture of membranes Preterm delivery Spontaneous abortion Stillbirth Intrauterine growth retardation
Neonatal Fetal tetany Seizures Hypotonia Poor feeding Jitteriness Low birth weight Respiratory distress requiring intubation Death
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different in pregnancy. Carella and Gossain7 stated that total serum calcium concentration greater than 10.1 mg/dL (2.52 mmol/L) or 8.8 mg/dL (2.2 mmol/L) during the second or third trimester, respectively, should prompt the clinician to suspect possible hyperparathyroidism. In pregnancy, parathyroid localization is best done with ultrasound, as radiolabeled scans such as sestamibi scans present a risk to the fetus. If ultrasound fails to localize an adenoma, magnetic resonance imaging is safe during pregnancy and can be considered.
Treatment Treatment plans for PHPT in pregnancy should be individualized based on severity, symptoms, gestational age, medical condition, and the reliability of the mother. Medical therapy may be considered for initial management. In cases of significant hypercalcemia, the mother should be admitted for further studies, fetal evaluation, and intravenous hydration with normal saline. A low or normocalemic diet can be provided with nutritionalist consult. Standard pharmacologic intervention in pregnancy includes oral phosphates (1.5–2.5 g of inorganic phosphorus daily), though this can be associated with nausea, vomiting, and hypokalemia. Calcium wasting diuretics, such as furosamide, and calcitonin can be used safely. Bisphosphonates and mithramycin are not typically recommended during pregnancy.6 Because of the significant maternal, fetal, and neonatal risks associated with maternal PHPT, and the improved safety of general anesthesia during pregnancy, surgical management during pregnancy has been increasingly recommended.2,5,6 When surgery is elected, parathyroidectomy in the second trimester is favored, when the risk of anesthesia-induced preterm delivery is lowest and organogenesis is complete.7 Kelly compared 70 medically managed patients with 39 patients who had surgical intervention during pregnancy. Medically managed patients had a neonatal complication rate of 37%, and neonatal mortality of 16%, compared with 10% and 3%, respectively, in those treated surgically.4 Surgery during the third trimester classically has a higher risk of preterm labor that progressively increases as the mother approaches term.2 Carella and Gossain reviewed 38 women who underwent parathyroidectomy 7 women during first trimester, 18 during second, and 12 during third trimester. One fetal loss because of spontaneous abortion occurred after an early second trimester parathyroidectomy. A 58% perinatal complication rate was reported after third trimester parathyroidectomy: one premature delivery, one infant with intrauterine growth retardation, two infants with hypocalcemia, one neonatal death, and one stillbirth.7 However, those complications cannot be distinguished from the consequences of the prolonged hypercalcemic state. Cases of uncomplicated third trimester parathyroidectomy have been increasingly reported,9 as demonstrated by case 1 in our series. We propose the following treatment algorithm. If the diagnosis is made in the first two trimesters, initial management is medical. Parathyroidectomy may be safely considered in the second trimester, particularly in patients who are symptomatic, or in those with serum Truong et al.: Primary Hyperparathyroidism in Pregnancy
Ca2⫹ ⬎11 mg/dL despite medical management. Surgical intervention in asymptomatic patients remains controversial. If the diagnosis is made in the third trimester, a discussion with the patient should be had regarding the risks and benefits of surgery. An assessment of fetal growth, maternal symptoms of PHPT, and the severity of maternal hypercalcemia are helpful in guiding risk stratification.
CONCLUSIONS PHPT during pregnancy is a rare but serious condition. With the known maternal, fetal, and neonatal risks of the hypercalcemic state, a larger role for parathyroidectomy may be appropriate in treating these patients.
BIBLIOGRAPHY 1. Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med 1980;302:189 –193. 2. Iqbal N, Aldasouqi S, Peacock M, Mohammed IA, Edmondson JW. Life-threatening hypercalcemia associated with primary hyperparathyroidism during pregnancy: case report and review of literature. Endocr Pract 1999;5: 337–342.
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3. Ficinski ML, Mestman JH. Primary hyperparathyroidism during pregnancy. Endocr Pract 1996;2:362–367. 4. Kelly TR. Primary hyperparathyroidism during pregnancy. Surgery 1991;110:1028 –1033; discussion 33. 5. Schnatz PF, Curry SL. Primary hyperparathyroidism in pregnancy: evidence-based management. Obstet Gynecol Surv 2002;57:365–376. 6. Kohlmeier L, Marcus R. Calcium disorders of pregnancy. Endocrinol Metab Clin North Am 1995;24:15–39. 7. Carella MJ, Gossain VV. Hyperparathyroidism and pregnancy: case report and review. J Gen Intern Med 1992;7: 448 – 453. 8. Kort KC, Schiller HJ, Numann PJ. Hyperparathyroidism and pregnancy. Am J Surg 1999;177:66 – 68. 9. Schnatz PF, Thaxton S. Parathyroidectomy in the third trimester of pregnancy. Obstet Gynecol Surv 2005;60: 672– 682. 10. Hong MK, Hsieh CT, Chen BH, Tu ST, Chou PH. Primary hyperparathyroidism and acute pancreatitis during the third trimester of pregnancy. J Matern Fetal Med 2001;10: 214 –218. 11. Ip P. Neonatal convulsion revealing maternal hyperparathyroidism: an unusual case of late neonatal hypoparathyroidism. Arch Gynecol Obstet 2003;268:227–229. 12. Potts J, Ackerman I, Barker C. Diagnosis and management of asymptomatic primary hyperparathyroidism. NIH Consens Statement 1990;7:1–18.
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