Malignant hypercalcemia in pregnancy: effect of pamidronate on uterine contractions

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of massive subchorionic hematomas associated with the use of enoxaparin as seen in our patient. Massive subchorionic hematomas have been reported with the use of thrombolytic therapy and warfarin.7,8 Subchorionic hematomas are associated with miscarriage, preterm labor, fetal demise, and abruption.9 They most likely occur from bleeding vessels at the edge of the placenta because there are no other large vessels underlying the chorion. Specialists providing care for pregnant women requiring intense anticoagulation with enoxaparin should be aware of this complication of anticoagulation in pregnancy.

3.

Laurent P, Dussarat GV, Bonal J, Jego C, Talard P, Bouchiat C, et al. Low molecular weight heparins: a guide to their optimum use in pregnancy [published erratum appears in Drugs 2002 62:1314]. Drugs. 2002;62:463–77.

4.

Levine HJ, Pauker SG, Salzman EW, Eckman MH. Antithrombotic therapy in valvular heart disease. Chest 1992;102(suppl 4): 434S–44S.

5.

Lepercq J, Conard J, Borel-Derlon A, Darmon JY, Boudignat O, Francoual C, et al. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG 2001;108:1134–40.

6.

Nyberg DA, Cyr DR, Mack LA, Wilson DA, Shuman WP. Sonographic spectrum of placental abruption. AJR Am J Roentogenol 1987;148:161–4.

7.

Usta IM, Abdallah M, El-Hajj M, Nassar AH. Massive subchorionic hematomas following thrombolytic therapy in pregnancy. Obstet Gynecol 2004;103:1079–82.

8.

Ho HC. Massive subchorionic hematoma. Arch Pathol Lab Med 1983;107:438.

9.

Ball RH, Ade CM, Schoenborn JA, Crane JP. The clinical significance of ultrasonographically detected subchorionic hemorrhages. Am J Obstet Gynecol 1996;174:996–1002.

REFERENCES 1.

2.

Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1998;114:489S–510S. Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1998;114:524S–530S.

Malignant Hypercalcemia in Pregnancy Effect of Pamidronate on Uterine Contractions

CONCLUSION: Pamidronate in pregnancy successfully reduced severe maternal hypercalcemia and uterine contractions. Although the reduction in calcium level did not prevent the development of preeclampsia or further deterioration in the mother’s condition, it was not associated with any adverse effects on the neonate. (Obstet Gynecol 2006;108:789–91)

Emily C. Culbert, MD, and Barry S. Schfirin, MD BACKGROUND: Hypercalcemia in pregnancy can have devastating effects on both mother and fetus. Pamidronate, a bisphosphonate and inhibitor of bone resorption, has been used to treat hypercalcemia, but it is considered contraindicated in pregnancy. CASE: A 40-year-old multigravida presented at 24 weeks of gestation with metastatic breast cancer. After unsuccessful chemotherapy, at 28 weeks of gestation she had deteriorating renal function, frequent contractions, and a calcium level of 17.6 mg/dL. When conventional treatment of hypercalcemia failed, pamidronate dramatically decreased both the calcium levels and the frequency of uterine contractions.

From the Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon; and Department of Obstetrics and Gynecology, Loma Linda University School of Medicine, Loma Linda, California. Corresponding author: Emily C. Culbert, MD, Department of Obstetrics and Gynecology, Oregon Health and Science University, 3181 Sam Jackson Park Road, Mail Code L-466, Portland, OR 97239; e-mail: [email protected]. © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06

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reast cancer during pregnancy is relatively uncommon with an estimated incidence of 1 in 1,000 to 3,000 pregnancies. Nevertheless, it is the most common cancer in pregnant women, accounting for approximately 25% of all cancers during pregnancy. Although breast cancer may not be more aggressive during pregnancy, it is usually diagnosed at a later stage because of delay in diagnosis and breast changes which occur normally during gestation.1 Cancers which metastasize to bone can result in hypercalcemia. We report on a patient who was diagnosed at 28 weeks of gestation with severe hypercalcemia from metastatic breast cancer and whose pregnancy was further complicated by premature uterine contractions. When initial therapy with intravenous hydration and diuretics proved unsuccessful, she was prescribed pamidronate, a bisphosphonate that crosses the placenta, which is usually considered contraindicated during pregnancy. Pamidronate decreased both her calcium level and her uterine contractions without any apparent ill effects on the fetus.

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CASE A 40-year-old gravida 5 para 4 presented for prenatal care at 24 weeks of gestation age by last menstrual period. Her medical and obstetric histories were unremarkable. She had no history of hypertension, proteinuria, or bone or renal disease, nor had she taken calcium supplements. An abdominal examination was consistent with a normally progressing pregnancy. Further examination of the right breast revealed an 8 cm ⫻ 10 cm mass with significant nipple retraction and a serous nipple discharge. A fineneedle aspiration of the mass revealed an infiltrating ductal carcinoma, moderately differentiated; with negative estrogen and progesterone receptor status. Initial blood work showed a normal complete blood count and electrolyte panel, including calcium of 9 mg/dL (normal range 8.4 – 10.2 mg/dL). Initial chest X-ray revealed bilateral pleural effusions and a chest computed tomography showed significant adenopathy in the right axilla. Abdominal ultrasonography revealed multiple hyperechoic liver nodules. A bone scan demonstrated increased uptake in the mid-thoracic, lowthoracic, and upper lumbar spine. The obstetric ultrasound examination demonstrated fetal size consistent with gestational age, a normal amniotic fluid index, and no obvious calcifications of the placenta. The patient received 21 days of palliative chemotherapy (doxorubicin and paclitaxol) without significant improvement. She returned to the emergency department several days later, lethargic and depressed, reporting back and left shoulder pain. Her oxygen saturation was 87% on room air. On admission, her hemoglobin was 9.1 mg/dL, unchanged from her prenatal values. Her calcium level, however, was 17.6 mg/dL, and her magnesium level was 1.2 mg/dL (normal range 1.8 –2.5 mg/dL). Her parathyroid hormone level (PTH) was low at 3 pg/mol (normal range 11–54 pg/mol). Her alkaline phosphatase, creatinine, potassium, bicarbonate, and blood urea nitrogen were all normal for pregnancy, while her uric acid was elevated at 9.1 mg/dL (normal range 2.2–7.2 mg/dL). A fetal heart rate (FHR) monitor and tocometer revealed contractions every 3 to 5 minutes. The FHR was reactive in the 140- to 150-beats/min range without decelerations. The patient was given a fentanyl patch and intravenous morphine for pain. To treat the hypercalcemia, she was prescribed a low-calcium diet with intravenous normal saline at 200 mL/h, and she was given 60 mg of intravenous furosemide. These medications had no effect on either the calcium level or the uterine contractions over a period of 48 hours. Given the circumstances, 90 mg of intravenous pamidronate was given over a period of 6 hours. Within 48 hours the serum calcium had decreased to 12.8 mg/dL, and contractions had abated entirely. The FHR remained in the 140s with persistent reactivity, and the patient received 2 doses of betamethasone to accelerate fetal lung maturation. Three days after initiating pamidronate therapy, the serum calcium was 9.9 mg/dL, with a magnesium level of 1.8 mg/dL, and the uterus was quiescent.

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Over the next 2 days the patient’s blood pressure increased significantly up to 178/108 mm Hg. Laboratory studies revealed 2⫹ proteinuria, increased uric acid of 11 mg/dL, and diminished platelets of 128,000/␮L. The patient was diagnosed with preeclampsia. Despite an oxygen saturation of 94% on 3 L/min oxygen by nasal canula, she was quite dyspneic. Chest X-ray confirmed bilateral pleural effusions. She was given magnesium sulfate for seizure prophylaxis and had a cesarean delivery for breech presentation and preeclampsia at 28 weeks of gestation. The neonate was a viable female weighing 1,147 g with Apgar scores of 8 and 9. She was initially intubated for transient respiratory distress but was extubated on the first day of life. No abnormalities were noted on physical examination, and the baby’s initial ionized calcium was 6.6 mg/dL, (normal range 3.5–7 mg/dL) and PTH was 6.3 pmol/L (normal range less than 7.3 pmol/L). Presumably the baby’s PTH had adequately responded to the maternal hypercalcemia. Cranial ultrasound examination results were normal, and there were no signs of retinopathy of prematurity. The baby was discharged from the neonatal intensive care unit at a gestational age of 36 weeks. On post operative day 3, the patient became dyspneic and reported severe left shoulder pain. A thoracentesis was performed and 500 mL of clear fluid was withdrawn and shown to be malignant on cytology. The malignant pleural effusion reaccumulated over the next 4 days. A chest X-ray revealed a lucent area in the head of the left humerus, and a bone scan showed increased uptake on the left humerus and on multiple areas within the spine. The following week neither additional therapeutic thoracenteses, nor palliative radiation therapy relieved her dyspnea and her condition deteriorated. She died 13 days after the birth of her child.

COMMENT Serum calcium is closely controlled by PTH, which is produced by the parathyroid glands and vitamin D. Parathyroid hormone is primarily stimulated by hypocalcemia and suppressed by high concentrations of calcium. It increases bone resorption and stimulates vitamin D (1,25(OH)2) formation. During pregnancy, maternal absorption of calcium increases to assist in the transfer of calcium to the placenta against a concentration gradient. This active transport of calcium across the placenta provides a degree of protection against maternal hypercalcemia. Most hypercalcemia is caused by hyperparathyroidism. Hypercalcemia is the most common lifethreatening metabolic disorder associated with cancer; the incidence is highest with metastatic breast carcinoma. Symptoms of hypercalcemia include headache, agitation, confusion, nausea, vomiting and abdominal pain, renal stones, polyuria, hypertension, preeclampsia, pancreatitis, and seizures. Hypercalcemia in the fetus can cause intrauterine growth restric-

Pamidronate for Hypercalcemia in Pregnancy

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tion, preterm delivery, intrauterine fetal demise, and perinatal death.3 Treatment of hypercalcemia usually involves hydration, restriction of calcium intake, diuretics, oral phosphates for chelation of calcium and, lastly, hemodialysis. The use of alternative therapies to decrease bone resorption includes bisphosphonates, calcitonin, and mithramycin, which are all controversial in pregnancy.4,5 Bisphosphonates act on osteoclastic cells and inhibit bone resorption. In patients with breast cancer, bisphosphonates may have a direct effect on the bone-forming cells, osteoblastic cells.6 Pamidronate, one of the most potent of the commercially available bisphosphonates, is particularly effective in patients with osteolytic metastases. Rabbit and rat studies have demonstrated that pamidronate crosses the placenta and at doses 10 times above the recommended human dose and can result in skeletal abnormalities, general underdevelopment, and embryonic demise.5 Secondary to these concerns, the use of pamidronate in pregnancy is limited to circumstances in which the mother’s life is at stake. A systematic, all language literature review using MEDLINE and the MeSH terms “breast cancer,” “hypercalcemia,” “pregnancy,” “uterine contractions,” and “bisphosphonates” (including individual bisphosphonates such as pamidronate), from 1960 to December 2005 was performed. This appears to be the third reported case of pamidronate in pregnancy and the first to report on its effect on uterine contractions. There have been two case reports of pregnant women with hypercalcemia from metastatic breast cancer who were given pamidronate without significant ill effects. In the first case, a women at 24 weeks of gestation was given pamidronate. The newborn had an elevated calcium level at birth which normalized by postnatal day 9.8 Another woman was given pamidronate at 34 weeks of gestation.7 At 36 weeks of gestation, the neonate was born with a low calcium level, but within 5 days of birth, the calcium level had normalized. The newborn in our case had a normal calcium and PTH level at birth, both which remained normal. None of the three infants demonstrated any skeletal abnormalities from the pamidronate. This is the third case report of pamidronate given in pregnancy. As illustrated in this report, calcium levels appear to have a direct impact on the frequency of uterine contractions. Indeed, in earlier years it was commonplace to administer calcium to cause uterine contractions during protracted labor, and currently, we use

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calcium channel blockers as tocolytics. The reduction in uterine activity with pamidronate was immediate. Despite its efficacy in the reduction of both uterine contractions and calcium levels, pamidronate did not stop the development and progression of preeclampsia, which ultimately prompted the preterm delivery. It may have exacerbated the hypertension, although previous reports have not noted this complication. There was no evidence that the magnesium sulfate affected the calcium level, which remained stable even after discontinuation of the magnesium. In our case report, pamidronate significantly reduced the amount of uterine contractions at 28 weeks of gestation. This suggests that the use of calcium antagonists, such as calcium channel blockers might be preferred as a first line tocolytic in women with hypercalcemia and preterm labor. When standard therapy fails to significantly decrease calcium, pamidronate can rapidly reduce severe hypercalcemia, thus reducing the risk of maternal seizures, hypertension, and impaired renal function. Given the concerning animal data, the use of pamidronate in pregnancy should be limited, but in three reported cases including ours, no short-term adverse fetal effects have been noted. REFERENCES 1. Barthelmes L, Davidson LA, Gaffney C, Gateley CA. Pregnancy and breast cancer. BMJ 2005;330:1375–8. 2. Mestman JH. Parathyroid disorders of pregnancy. Semin Perinatol 1998;22:485–96. 3. Cherry TA, Kauffman RP, Myles TD. Primary hyperparathyroidism, hypercalcemic crisis and subsequent seizures occurring during pregnancy: a case report. J Matern Fetal Neonatal Med 2002;12:349–52. 4. Munns CF, Rauch F, Ward L, Glorieux FH. Maternal and fetal outcome after long-term pamidronate treatment before conception: a report of two cases. J Bone Miner Res 2004;19: 1742–5. 5. Graepel P, Bentley P, Fritz H, Miyamoto M, Slater SR. Reproduction toxicity studies with pamidronate. Arzneimittelforschung 1992;42:654–67. 6. Reinholz GG, Getz B, Sanders ES, Karpeisky MY, Padyukova N, Mikhailov SN, et al. Distinct mechanisms of bisphosphonate action between osteoblasts and breast cancer cells: identity of a potent new bisphosphonate analogue. Breast Cancer Res Treat 2002;71:257–68. 7. Dunlop DJ, Soukop M, McEwan HP. Antenatal administration of aminopropylidene diphosphonate. Ann Rheum Dis 1990; 49:955. 8. Illidge TM, Hussey M, Godden CW. Malignant hypercalcaemia in pregnancy and antenatal administration of intravenous pamidronate. Clin Oncol (R Coll Radiol) 1996;8:257–8.

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