Case Report

PRIMARY HYPERPARATHYROIDISM DURING PREGNANCYCASE REPORT

Voichita Mogos1, Simona Mogos1, D. D. Branisteanu *1, M. Onofriescu 2, Elena Cotea 3, E. Tircoveanu 3, Niculina Florea 4, E. Zbranca 1
of Endocrinology, 2 Department of Obstetrics and Gynaecology, 3 Department of General Surgery, Gr.T.Popa University of Medicine and Pharmacy Iai 4 Laboratory of Pathology, St.Spiridon University Hospital , Iai
1 Department

Abstract
We present the case of a 28 year old pregnant primiparous woman, suspected of primary hyperparathyroidism due to hypercalcemia discovered by routine calcium assessment at 30 weeks of gestation. Diagnosis was strongly suggested by elevated serum calcium (15.2 mg/dL, normal range: 8.4-10.3 mg/dL), low serum phosphorus (0.55 mg/dL, normal range: 2.5-5 mg/dL) and increased urinary hydroxyproline excretion (118 mg/24h, normal range: 10- 40 mg/24h), suggesting high bone turnover and confirmed by coexistence of high levels of parathyroid hormone (PTH, 145 pg/mL, normal range 10-65 pg/mL). Neck ultrasound identified a solid nodule of 33x58x20.5 mm situated behind the inferior pole of a normal thyroid left lobe, suggestive for a solid parathyroid tumour located within the left inferior parathyroid gland. Medical treatment with furosemide and hydration decreased serum calcium level but failed to normalize it. After a 3 day preparation for lung maturation with dexamethasone (16 mg per day), successful adenomectomy was performed under local anaesthesia, without major intraoperative or postoperative events. The few uterine contractions were easily managed with papaverine and progesterone. Calcium levels immediately returned to normal after surgery. Our patient delivered a healthy newborn at 40 weeks by caesarean section. A DXA BMD assay performed after one year showed significant bone loss of the mother at radius level (T score of - 2.6). Key words: hyperparathyroidism, hypercalcemia, pregnancy.

INTRODUCTION
Primary hyperparathyroidism during pregnancy involves a significant risk for both mother and foetus, which is related to hypercalcemia. Although mild forms are seldom accompanied by major risks for pregnancy outcome, severe hypercalcemia increases the risk of prematurity, dystrophy and stillbirth. Postpartual
*Correspondence to: Dumitru D. Branisteanu, MD, PhD, Clinic of Endocrinology, St. Spiridon University Hospital, Independentei Str. 1, Iasi, Romania, Tel. 0232 213 226, Fax 0232 278 224, email: dumitru_branisteanu@yahoo.com Acta Endocrinologica (Buc), vol. IV, no. 3, p. 337-343, 2008 337

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hypocalcaemia and tetany may be observed as the result of neonatal hypoparathyroidism caused by chronic maternal and thus also foetal hypercalcemia. Primary hyperparathyroidism occurs in women at childbearing age in 25% of cases (1). However, only 0.8 % of 850 cases of primary hyperparathyroidism were found to be associated with pregnancy (2). The evolution of primary hyperparathyroidism during pregnancy is frequently silent, therefore the real incidence of the association between pregnancy and hyperparathyroidism is not known. Schnatz (3) found less than 200 reported cases of which only 10 were surgically treated during the third trimester. Two out of 3 cases were retrospectively diagnosed after birth, due to hypocalcemia and tetany of the newborn (4), or due to severe complications occurring in mother or foetus (1). Routine determination of calcium during pregnancy increased the number of cases diagnosed and successfully treated prenatally (1). When indicated, surgery must be performed preferably during the second trimester, in order to avoid the increased risk for foetal complications (premature labour or death in 58 % of cases) (5), but recent successful results showed that parathyroidectomy may be performed regardless of gestational age (1). We further describe a case of asymptomatic pregnancy-associated primary hyperparathyroidism with high serum calcium levels and high turnover bone loss, surgically cured in the third trimester without maternal or foetal complications.

CASE REPORT
A 28 year old primiparous pregnant woman was diagnosed with hypercalcemia at routine laboratory examination. The patient was 30 weeks pregnant and revealed no hypercalcemia-related signs or symptoms, beside a mild polyuro-polydipsic syndrome, with diuresis lower than 2.5L/24h and mild asthenia. She had no history of pathological fractures or nephrolithiasis. The patient was unaware of her serum calcium levels before pregnancy and no previous serum calcium measurement was found in her medical file. Pregnancy had a normal evolution, without hyperemesis or preeclampsia. Her initial biochemical parameters at her admission were, however, severely disturbed: serum calcium: 15.2 mg/dL (normal range 8.4-10.3), phosphorus: 0.55 mg/dL (normal 2.5 5.5), urinary hydroxyproline: 118 mg/24h (normal 10-40). PTH was inadequately elevated (145 pg/mL, normal range 10-65 pg/mL) confirming the diagnosis of primary hyperparathyroidism and excluding malignancy-associated hypercalcemia. Urinary calcium and phosphate excretion were not measured. Neck ultrasound identified a normal thyroid gland and a solid tumour of 33x58x20.5 mm. situated behind the inferior pole of the left thyroid lobe, highly suggestive for an adenoma of the left inferior parathyroid gland (Fig. 1). Pelvic ultrasound examination showed 30 weeks pregnancy, with normal foetal heart beats and normal insertion of placenta. Conservative therapy with furosemide (10 to 20 mg/day, iv) and appropriate hydration with normal saline (2L/day, for 3 days) was only partially efficient, serum
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Figure 1. Solid tumor localized in the area of the left inferior parathyroid gland, of 33x58x20.5 mm (neck ultrasound, left) with perinodular vascularisation (Doppler signal, right).

calcium being reduced to a minimum of 12.64 mg/dL. The persistence of high serum calcium levels with more than 1 mg/dL above the upper level of normal is an indication for parathyroidectomy. A decision for parathyroidectomy was therefore taken, after obtaining the patients informed consent. Before surgery, the patient was submitted to a three day dexamethasone therapy (16 mg per day) in order to induce foetus lung maturation in case of possible premature labour induced by the surgical intervention. Parathyroidectomy was performed under local anaesthesia and careful intraoperatory monitoring of foetal status by the gynaecologist. Uterine contractions occurred after surgery, but were successfully managed with papaverine, hydroxyprogesterone caproate and oestradiol valerate. Calcium levels drastically decreased immediately after surgery to 10.1 mg/dL and subsequently to 9 mg/dL during one week, but they did not further decrease into the hypocalcemic range. Histological examination of the excised parathyroid lesion revealed a clear cell parathyroid adenoma (Fig. 2).

Figure 2. Clear cell parathyroid adenoma (haematoxylin - eosin stain). 339

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Pregnancy evolution to term was normal. She delivered by caesarean section a healthy boy of 3900 g, Apgar score: 9, at 40 weeks of gestation. The newborn had serum calcium in the low normal range (8.7 mg/dL). The mother had a calcium of 8.8 mg/dL one year later. Her bone mineral density (BMD) was assessed by DXA (dual X-ray absorptiometry) examination. T score was - 0.6 SD and Z score was 0.6 SD at lumbar spine level, but BMD was in the osteoporosis range at the radius level (T score of - 2.6 SD and Z score of - 2.4 SD). Other risk factors for osteoporosis, such as familial aggregation, low calcium diet, low BMI, decreased sunlight exposure, were excluded. Our case was considered to be successfully resolved during the third trimester, due to the diagnosis made during pregnancy at a routine determination of calcium, the preoperatory localisation of the parathyroid adenoma with limited intervention under local anaesthesia and to the good collaboration of the members of a team of endocrinologists, gynaecologists and surgeons.

DISCUSSION
Hypercalcemia during pregnancy poses a risk to both the mother and foetus and represents a complex management issue. Although hypercalcemia from any cause can occur during pregnancy, primary hyperparathyroidism is the most common cause (1,3,6). However, other possible causes are co-existence of malignant diseases, granulomatous diseases, drug intoxication, renal failure, thyrotoxicosis, pheochromocytoma, adrenal crisis (6). Our case of parathyroid adenoma in a pregnant woman is to our knowledge the first described in Romania. The first case of primary hyperparathyroidism during pregnancy was reported by Hunter and Turnbull in 1931, cited by Schnatz and Curry(1). Parathyroid adenomas are the main causes of primary hyperparathyroidism during pregnancy described in the literature (81.2%) (7). Other causes described are parathyroid hyperplasia, parathyroid carcinoma (7) and even a case of asymptomatic hyperparathyroidism during pregnancy as part of a MEN type 1, described by Smythe (8). The divergence between serum calcium and phosphate levels in our patient, as well as high bone turnover were strongly suggestive for inadequate secretion of PTH. Measurement of PTH confirmed the diagnosis of primary hyperparathyroidism and excluded malignancy-associated hypercalcemia. Although urinary calcium and phosphate excretion were not measured, familial benign hypocalciuric hypercalcemia was highly improbable, taking into account the paucity of the described clinical cases, the very high level of serum calcium in our patient and the ultrasound image of a parathyroid adenoma. Maternal severe symptoms and complications associated with primary hyperparathyroidism, such as hyperemesis, pre-eclampsia, muscle weakness, mental status changes, ventricular arrhythmias, bone loss including osteitis fibrosa cystica, nephrolithiasis, nephrocalcinosis, recurrent urinary tract infections, may sometimes
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occur in primary hyperparathyroidism (1,2). Hypercalcemic crisis (calcium 15-20 mg/dL) is generally associated with severe muscle weakness, nausea, vomiting, dehydration, cognitive changes and may evolve to renal failure and death (1,2). Pancreatitis has been found in 7-13 % of pregnant women with hyperparathyroidism, leading to neonatal morbidity in 35-40 % of cases (1,4). Most frequent foetal complications are spontaneous abortion, intrauterine foetal death, premature delivery, intrauterine growth retardation and neonatal death (1,2,4). Postpartum neonatal hypocalcemia, due to chronic inhibition of foetal parathyroid function by hypercalcemia, may result in tetany and seizures that occur between days 5 to 14 after birth, or later (one month) if the infant is breastfed. Infants must be treated by vitamin D and calcium supplementation and phosphate restriction (2). Primary hyperparathyroidism needs therefore early recognition in pregnancy and must be suspected in pregnant women with unexplained nausea, vomiting and abdominal pain. Patients with primary hyperparathyroidism frequently have only mild and nonspecific complaints: fatigue, nausea, anorexia, constipation, transient depression (9). Moreover, primary hyperparathyroidism during pregnancy is often silent - up to 80 % of cases may be asymptomatic (1,4,5), as, for instance, our patient. Many reports present, however, cases retrospectively diagnosed due to neonatal hypocalcemia and tetany (2). Therefore, even if the diagnosis is more difficult, mild or asymptomatic hyperparathyroidism should also be diagnosed during pregnancy, in order to prevent unwanted foetal complications. Mere asymptomatic hypercalcemia accidentally discovered at routine check-up should increase the suspicion of hyperparathyroidism in pregnancy. This clue was the main factor that led to our diagnosis. The association of hypercalcemia and hypophosphatemia in the presence of ultrasound-discovered parathyroid adenoma supported the initial diagnosis. The authors (10) strongly suggest routine investigation of calcium metabolism as early as the first trimester of pregnancy, in order to rule out pregnancy-associated asymptomatic or mild hyperparathyroidism. The importance of hyperparathyroidism diagnosis is stressed by the decrease in the incidence of foetal complications from 80% in untreated cases to 53% in medically treated cases (11). Medical treatment is indicated in the first trimester, in patients with mild symptoms before parathyroidectomy, but could result in poor disease control and postpone a more appropriate immediate surgical approach. Furosemide (10-20 mg), saline hydration (2-4 L/day, for 1-3 days) and oral phosphates are the first line treatment. Calcitonin is the second line treatment, because it does not cross the placenta and promptly decreases calcium level due to the inhibition of osteoclastic activity. The use of intravenous bisphosphonates (pamidronate 60-90 mg or zoledronate 4 mg iv) is still controversial concerning their action on the foetus and is safer to be replaced by surgery in severe cases of hypercalcemia, when possible (1). Although the patient was asymptomatic and the foetus showed no signs of distress, we were concerned by the high calcium levels, therefore conservative therapy with furosemide and appropriate hydration were started. Conservative intervention may be appropriate under certain circumstances,
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as a bridge to parathyroidectomy, but excision of a parathyroid adenoma remains the only definitive treatment, accompanied by a four-fold decrease in perinatal complications (1). The decision for surgical intervention is preferred when the lesion can be localised and minimal invasive surgery is possible, under local anaesthesia. The patient should be informed of the potential maternal and foetal complications of hypercalcemia, as well as of the benefits and risks of such an intervention and his written consent has to be obtained before the intervention. This was the case of our patient. The Consensus Development Conference Statement on the surgical treatment of primary hyperparathyroidism during pregnancy (1) recommends that parathyroidectomy should be performed during the second trimester for a better chance of foetal survival. Parathyroidectomy performed during the third trimester may result in complications in the fetus in 17.7-23.5 % of cases and in maternal complications in 18.8-25 % of cases (3). Cases diagnosed during the third trimester should therefore be best treated medically, unless severe complications occur (5). Schnatz considers, however, that, if the disease is not fully controlled by medical treatment, surgery may be performed regardless the age of gestation (1,3). Localization of the parathyroid lesion may represent a difficulty for surgical approach. Ultrasound examination is most useful in pregnancy, unless the affected parathyroid is ectopic. The persistence of high calcium levels despite medical therapy, the good medical condition of the mother and foetus and the clear preoperative ultrasound localization of the parathyroid adenoma, allowing limited intervention under local anaesthesia, were arguments in favour of surgical adenomectomy in this particular case. Efficient team work of endocrinologists, gynaecologists and general surgeons allowed quick therapeutic decisions and the complete cure of our patient, with minimal risks for foetus evolution and child birth. Intraoperative video-assisted parathyroidectomy, not tried in pregnant women until now, might offer new cure perspectives with fewer risks for these patients and their children (1). Wrist-localized subperiostal bone loss is typical for primary hyperparathyroidism and is fully reversible at a young age after primary disease has been cured.

CONCLUSIONS
Routine determination of calcium values is mandatory during pregnancy and allows early diagnosis of mild forms of primary hyperparathyroidism. Although surgery is better to be performed in the second trimester, parathyroidectomy may be performed in selected cases during the third trimester without important risks for mother and foetus. The management of primary hyperparathyroidism during pregnancy needs medical team work, allowing appropriate decisions and monitoring of both mother and foetus.

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References
1. Schnatz PF, Curry ST.Primary hyperparathyroidism in pregnancy: evidence-based management. Obstet.Gynecol.Surv. 2002; 57: 365-376. 2. Kort KC, Schiller HJ, Numann PJ. Hyperparathyroidism and pregnancy. Am J Surg 1999; 177(1):66-68. 3. Schnatz PF. Surgical treatment of primary hyperparathyroidism during the third trimester. ObstetGynecol 2002; 99(5 Pt 2):961-963. 4. Wilson DT, Martin T, Christiansen R, Hoyee A, Raynolds C. Hyperparathyroidism in pregnancy: acase report and review of the literature. Can. Med. Assoc. J. 1983; 129: 986-989. 5. Carella MJ, Gossain VV. Hyperparathyroidism during pregnancy. J.Gen.Intern.Med. 1992; 7: 448-455 6. Kohlmeier L, Marcus R. Calcium disorders of pregnancy. Endocrinol Metab Clin North Am. 1995;24(1):15-39. 7. Schnatz PF, Thaxton S. Parathyroidectomy in the third trimester of pregnancy. Obstet Gynecol Surv 2005; 60(10):672-682. 8. Smythe AR 2nd, McFarland KF, Yousufuddin M, Meredith WD. Multiple endocrine adenomatosis type I in pregnancy. Am J Obstet Gynecol 1990; 163(3):1037-1038.; discussion 1038-1039. 9. Beatie GC, Ravi HR, Lewis M, Williams H, Blair AW, Campbell IW, Browning GGP. Rarepresentation of maternal primary hyperparathyroidism. BMJ 2000; 321: 223-224. 10. Primary hyperparathyroidism and acute pancreatitis during pregnancy. Report of a case and a review of the English and Japanese literature. 1998; 24: 43-47. 11. Delmonico FL, Neer RM, Cosimi AB, Barnes AB, Russell PS. Hyperparathyroidism during pregnancy. Am J Surg 1976; 131(3):328-337.

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