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Nausea and vomiting are common complaints during pregnancy. Their severity and persistence can lead to the diagnosis of hyperemesis gravidarum, which is associated with weight loss, ketonuria, and decreased fetal birth weight. Hypercalcemia in pregnancy can confound these common gastrointestinal symptoms as well as have its own intrinsic maternal-fetal risks. A 23-year-old woman was diagnosed with primary hyperparathyroidism after multiple visits to the emergency department and the obstetrical clinic with symptoms of nausea and vomiting. Her symptoms were initially attributed to hyperemesis gravidarum and only after multiple hospital visits was her hypercalcemia discovered. Her workup led to the diagnosis of primary hyperparathyroidism caused by a solitary parathyroid adenoma. The patient was treated conservatively with intravenous fluids and eventually surgical resection of the parathyroid adenoma which led to complete resolution of her symptoms. This case demonstrates the diagnostic and therapeutic challenges associated with hyperparathyroidism in pregnancy.
Hypercalcemia affects several organ systems and patients typically present with multiple complaints including anorexia, nausea, constipation, polydipsia, polyuria, nephrolithiasis, bone pain, weakness, fatigue, and neuropsychiatric disturbances. Untreated hypercalcemia during pregnancy can lead to complications such as spontaneous abortion, still birth, neonatal death, or neonatal tetany.1 Although the differential diagnosis for hypercalcemia is limited, the most common cause in the outpatient population is hyperparathyroidism.2 The treatment is based on the severity of the disease determined by both symptoms and serum calcium levels. In patients with hyperparathyroidism, increased serum calcium levels have been shown to correlate with increased symptoms of hypercalcemia.3 This correlation has also been found to hold true in pregnant patients with hyperparathyroidism and therefore both serum calcium levels and symptom severity are considered in the management of the patient.
Primary hyperparathyroidism is treated similarly in pregnant and non-pregnant patients using medical and surgical therapies. An additional consideration in treatment of the pregnant patient is prevention of harm to the fetus. Medical treatments of hyperparathyroidism include intravenous fluids, correction of electrolytes as well as pharmacologic treatments including bisphosphonates, calcimimetics, and vitamin D analogues.4 Due to the rarity of hypercalcemia in pregnancy and ethical considerations in studying drugs in pregnant patients, these medications have been classified as pregnancy category C and have not been well-studied; their safety in pregnancy is based on limited numbers of case reports, precluding them from routine use. Surgery should be considered because parathyroidectomy is the definitive treatment and can be safely performed in the second trimester of pregnancy.5
A 23-year-old Caucasian woman at 15 weeks gestation presented to the emergency department with nausea, vomiting, and 15 pounds weight loss. She had been treated for similar symptoms for the previous six weeks with a trial of antiemetics and intravenous fluids with minimal relief of her symptoms. On presentation, she also noted worsening lightheadedness, diffuse abdominal pain, and was admitted to the hospital due to her inability to tolerate oral fluids. Admission lab tests were significant only for an elevated calcium level of 12.8mg/dL (reference range 8.8–10.2mg/dL). Her past medical history included nephrolithiasis as a teenager. She had no family history of hypercalcemia. She was not taking any medications except antiemetics and prenatal vitamins. Her vital signs were unremarkable and her abdominal exam showed a gravid uterus and diffuse tenderness to palpation without peritoneal signs.
Additional workup revealed an ionized calcium of 1.6 mmol/L (reference range 1.1–1.3 mmol/L), albumin of 5.1 g/dL (reference range 3.7–5.5 g/dL), phosphorus of 1.4mg/dL (reference range 2.7–4.5 mg/dL), 25-OH vitamin D of 22 ng/mL (reference range 30–100 ng/mL), and 1.25-OH vitamin D of 82pg/mL (reference range 18–72 pg/mL). Parathyroid hormone (PTH) was 78 pg/mL (reference range 18–72 pg/mL). PTH-related peptide was 13 pg/mL (reference range 14–27 pg/mL), TSH and FT4 were within normal limits. She was diagnosed biochemically with primary hyperparathyroidism and treated with aggressive intravenous hydration, which lowered her calcium to 10.7mg/dL. She had a dramatic initial response to treatment with resolution of her symptoms; however, after discharge she had recurrent daily vomiting and struggled to maintain adequate hydration.
A parathyroid ultrasound was performed which revealed a 4x3x2mm hypoechoic focus in her right inferior thyroid pole consistent with a parathyroid adenoma (Figure 1). At 25 weeks gestation, she underwent a right parathyroidectomy with intraoperative PTH level monitoring. A 300 mg parathyroid adenoma was resected with a subsequent drop in PTH levels suggesting cure of her disease. She was discharged with daily calcium supplementation after complete resolution of her nausea and hyperemesis. Her calcium level at 3 week post-operative follow-up was normal and her symptoms had not returned. She had an uncomplicated delivery and surveillance calcium levels have been within normal limits.
Nausea and vomiting of pregnancy (NVP) is common, affecting up to 80% of pregnancies. The onset of symptoms typically begins around 4 to 5 weeks of gestation and improves by week 12, but can persist longer. A minority of these women, 0.3% to 1.5%, will have a severe form of NVP called hyperemesis gravidarum.6 This is a spectrum of disease manifested by these commonly accepted criteria: persistent vomiting, weight loss exceeding 5% of pre-pregnancy body weight, and ketonuria unrelated to other causes.7 This patient met the criteria for hyperemesis gravidarum due to persistent vomiting associated with weight loss and ketonuria.
The differential diagnosis for the non-specific complaint of nausea and vomiting is broad and makes a complete evaluation lengthy. In the pregnant woman, evaluation and diagnosis is targeted to disease severity and exclusion of other causes. It includes measurement of weight, blood pressure, heart rate, electrolytes, serum ketones, and urinalysis. Routine obstetrical ultrasound can exclude multiple gestation and hydatidiform mole which are both associated with increased incidence of hyperemesis. Although calcium levels are not part of the general evaluation, it is a selective test that can be considered on a patient-specific basis.
An elevated calcium level is particularly notable because total calcium levels are normally lower during pregnancy due to the increased calcium demands of fetal growth.8 Primary hyperparathyroidism is a rare complication of pregnancy, occurring in 0.5%–1.4% of all cases.9 It is the most common cause of hypercalcemia and further testing of serum PTH is indicated in cases of hypercalcemia in pregnancy. PTH is unaffected by pregnancy and a normal or elevated PTH level in the setting of hypercalcemia is diagnostic of primary hyperparathyroidism.10 Ionized calcium levels are unchanged by pregnancy and are also helpful to rule out a pseudohypercalcemia. Vitamin D levels (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) should also be measured to evaluate for vitamin D intoxication or granulomatous disease such as sarcoidosis. Malignancy as a cause of hypercalcemia should be explored, as well as contributing factors such as acute renal failure, immobilization, or other endocrinopathies as clinically indicated.
Medical treatments of hyperparathyroidism include intravenous fluids and correction of electrolyte abnormalities which are initial treatments and safe in pregnancy. Calcitonin, pregnancy category C, does not cross the placenta and has been used safely in pregnancy to suppress bone resorption and promote urine calcium excretion.11 Oral phosphate, pregnancy category C, is used to bind calcium but has not been well studied. Bisphosphonates, pregnancy category C, cross the placenta and may interfere with endochondral bone development.12 Cinacalcet, pregnancy category C, has been used safely in two patients.13 High-dose magnesium also acts on the calcium receptor to decrease PTH and serum calcium and is commonly used in preeclampsia. Ethical concerns have limited testing of these drugs in pregnant patients and their risks remain unknown. Watchful waiting is a reasonable treatment for patients with mild, asymptomatic hypercalcemia. However, parathyroidectomy is the only definitive treatment and is recommended for symptomatic patients or those with severe hypercalcemia, generally defined as greater than 11 mg/dL. Surgery is generally only recommended in the second trimester due to the increased risks of incomplete organogenesis during the first trimester and preterm labor during the third trimester.14 Although third-trimester parathyroidectomy is associated with a reported 58% fetal mortality,15 there have been several case reports of third-trimester parathyroid surgery without complications and it may be reasonable when the benefits outweigh the risks of surgery.16,17 The risk of inducing premature labor increases in the third trimester; the risk of spontaneous abortion from general anesthesia is reported to be minimal, particularly in extraperitoneal surgery.18 The maternal risks of parathyroidectomy are similar to non-pregnant patients including those risks associated with general anesthesia, injury of the recurrent laryngeal nerve, and post-operative hypocalcemia.19
Hyperparathyroidism presenting in pregnancy can cause symptoms such as hyperemesis, gastrointestinal upset, and nephrolithiasis which may be misdiagnosed on initial presentation. Medical and surgical options are available for treatment although maternal-fetal risks should be considered prior to treatment. Surgery should be performed in the second trimester and considered in the third trimester when symptoms are refractory to medical management since the benefits of parathyroidectomy may outweigh the risks of surgery.
The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.
The authors have no disclosures and no conflicts of interest to declare. This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.