Endocrinological cause behind recurrent miscarriages: primary hyperparathyroidism

Background

Under physiological conditions in pregnancy, great amounts of Ca transfer through the placenta while Ca regulators such as calcitonin and PTH do not (1). Ca is transported from mother to fetus at a rate of 50 mg per day at week 20 and reaches its peak at week 35 when 330 mg of Ca is transferred each day (1). Ca is important for the fetus as maternal hypercalcemia can result in its growth restriction and sometimes in neonatal hypoparathyroidism and hypocalcemic crisis during the first few days after birth (2). Pregnancy loss or early miscarriage is usually caused by chromosomal abnormalities (<70%), maternal anatomic abnormalities (such as uterine leiomyomas, polyps, adhesions), and trauma (3, 4, 5, 6). Infection, uterine malformation, thrombophilias and others can be additional causes of miscarriage during the second trimester of pregnancy (7). Rarely pregnancy loss can be caused by hypercalcemia, which is uncommon in pregnant women and is usually induced by primary hyperparathyroidism (PHPT) (>90% of cases) (2). The consequences of miscarriage, and especially recurrent miscarriage, are both physical, such as bleeding or infection, and psychological, such as anxiety, depression, post-traumatic stress disorder, and suicide; therefore, timely identification of the possible cause of miscarriage is very important (8). We would like to present a clinical case of a patient suffering from recurrent miscarriages caused by undiagnosed primary hyperparathyroidism with clinically expressed hypercalcemia. It is worth to emphasise that when encountering a patient with pregnancy loss and without any prominent gynecological cause, it is essential to consider a rare but easily determined endocrinological pathology – primary hyperparathyroidism with hypercalcemia, a condition that if diagnosed early would enable to reach adequate treatment decision and correspondingly safeguard the woman from a possible miscarriage along with complications that arise from it.

Case presentation

A 39-year-old woman visited our Endocrinology clinic in search of a cause of infertility. The patient was unable to get pregnant after trying for 6 to 8 months. Previously done blood tests showed normal levels of anti-thyroid peroxidase, thyrotropic hormone, free thyroxine, glucose, cholesterol, potassium, and hemoglobin. The levels of 25-hydroxyvitamin D levels were 48.02 nmol/L, keeping in mind that the patient was using vitamin D supplements.

Investigation

During physical assessment it was determined that the patient was 1.80 m tall and weighed 61 kg, her BMI being 18.83 kg/m², the thyroid gland was unpalpable, none of the clinical signs of hypercortisolism were observed, hairiness was normal, and there were no signs of galactorrhea. The patient menstruated regularly and was routinely examined by a gynecologist. More blood tests were performed at the Endocrinology clinic – patient presented with low anti-Mulerrian hormone (AMH) level of 0.4 mIU/L (normal range (NR): 0.0–12.6 mIU/L) and high Ca level – 2.61 mmol/L (NR:< 2.55 mmol/L). In order to get pregnant successfully, AMH levels are expected to be higher than 1.0 mIU/L. Ionized Ca levels were 1.4 mmol/L (NR: 1.2–1.43 mmol/L). No previous medical history associated with hypercalcemia was known. The woman did not mention having any specific symptoms associated with higher Ca levels in the serum, such as nausea, vomiting, constipation, stomach or bone pain, and muscle aches. It was recommended to conduct more tests to find the cause of the hypercalcemia. To differentiate between hypogonadism, hyperandrogenism and DHEA-secreting adrenal tumor, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), and DHEA sulfate amounts were examined. Results came in normal. Prolactin, 17-hydroxyprogesterone (17-OHP), and alkaline phosphatase (ALP) were also in normal range. To differentiate between PHPT and familial hypocalciuric hypercalcemia (FHH), calcium to creatinine clearance ratio (CCCR) was calculated, and it was higher than 0.01 meaning that FHH was unlikely in our patient. Additional analysis regarding Ca metabolism such as intact PTH, bone-specific ALP, cyclic AMP (cAMP), nephrogenous cAMP, fractional excretion of Ca, and tubular reabsorption of phosphate was not carried out regarding Lithuanian protocols. The patient did not have history of nephrolithiasis. A month and a half later, we learned that the woman had gotten pregnant for the first time and did not visit the Endocrinology clinic for any further testing.

Three months later the patient visited the Endocrinology clinic for a repeated consultation and it became known that the patient miscarried at nine weeks due to unknown causes. In order to determine the cause of hypercalcemia, a detailed examination was carried out. A neck ultrasound was performed – no significant changes were found in the thyroid (its size, echogenicity and homogeneity were normal). Nevertheless, a 0.6 x 1.0 cm mixed isoechoic nodule was found in the right thyroid lobe with no evident malignancy and a hypoechoic 1.6 x 0.8 cm formation was found behind the thyroid gland (Fig. 1). The blood flow in the hypoechoic formation was not evaluated using Doppler flow as it is not common in clinical practice. Lymph nodes were nonpathologic. It was concluded that these changes were characteristic of nodular goiter. Upper left parathyroid gland adenoma was suspected. During the detailed examination, it was found that the patient was pregnant for the second time. Since the fifth week of pregnancy, the patient had been using 600 mg of Progestin one time per day. Parathyroid gland scintigraphy needed for further hypercalcemia investigation was contraindicated for the time being.

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Ultrasound scan of the neck depicting parathyroid adenoma.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0356

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Four weeks later, the patient visited the Endocrinology clinic again for test results. Findings from the tests showed that the patient had hypercalcemia (2.76 mmol/L), hypophosphatemia, high levels of Ca in the urine (more than 10 mg/24h), increased levels of PTH (8.28 pmol/L), and parathyroid gland adenoma in the left thyroid lobe. Based on the examination, primary hyperparathyroidism was diagnosed. It was also speculated that higher levels of PTH could be the cause of vitamin D deficiency (22.0 nmol/L) as previously used vitamin D supplements were discontinued. Therefore, the patient was prescribed 4000 IU of vitamin D to be taken every day but later the vitamin use was discontinued seeing that Ca levels went up dynamically (Table 1).

Treatment

Medical specialists concilium (consisting of endocrinologists, gynecologists, surgeons, and nephrologists) was held, and it was determined that the main treatment for primary hyperparathyroidism should be an operation. The patient was 9 weeks pregnant at that time, and the safest time period for surgery would be the second trimester (≥12 weeks). Therefore, in order to manage hypercalcemia until it was possible to perform the operation, 1.5 liters of i.v. hydration and diuretics (60 mg of Furosemide 1x/day) were recommended. Cinacalcet was not prescribed for the patient, as it is used when the previously mentioned treatment has no effect.

The woman was admitted to the Endocrinology clinic for Ca treatment. Until the operation, her Ca level in blood was 2.98 mmol/L (NR:< 2.55 mmol/L). The following day per vaginal bleeding was observed. The patient was consulted by a gynecologist – no fetal heart activity was registered, and a miscarriage was stimulated. Without any clear chromosomal aberration, the patient suffered a second miscarriage. Later, the patient was examined by gynecologists in search of possible secondary causes of miscarriage such as antiphospholipid syndrome, thrombophilia, and other gynecologic causes. No evidence for any of them was found. The reason for miscarriage was still unknown.

Two months after the second miscarriage, the patient was operated on and the upper left parathyroid lobe adenoma was removed. Macroscopically it was described as 1.9 x 1.2 x 0.9 cm nodule formation. After a histologic examination, it was identified as dark chief cells parathyroid adenoma. Ca level in the blood after the operation dropped to a normal range – 2.1–2.3 mmol/L. Following the surgery, PTH levels also decreased to 3.34 pmol/L (NR: 1.26–6.74 pmol/L). A DEXA scan was not performed in this case because the duration of primary hyperparathyroidism was not long, the patient's young age did not raise suspicion of possible secondary osteoporosis, and the woman did not have other risk factors of osteoporosis, such as familial history or tobacco use.

After a genetic consultation, multiple endocrine neoplasia (MEN) syndrome was ruled out.

Outcome and follow-up

Five months after the operation, the patient got pregnant for the third time, and the pregnancy went smoothly, resulting in a healthy baby. Ca and PTH levels through all periods of pregnancy were normal (Fig. 2

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An illustration depicting the timeline of the patient’s pregnancies, miscarriages, visits to the Endocrinology clinic, Ca levels in the blood, and diagnosis and treatment of primary hyperparathyroidism (PHPT).

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0356

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Discussion

Primary hyperparathyroidism is a common condition that is distinguished by elevated or normal levels of PTH and hypercalcemia (9). Excessive secretion of PTH causes higher levels of Ca reabsorption in the intestines and kidneys, decreased Ca secretion in the kidneys, and increased osteoclast activity in the bones leading to high levels of Ca in the blood (10). In primary hyperparathyroidism, elevated amounts of PTH are being secreted from one or more of the parathyroid glands (11). Solitary parathyroid adenomas are the most frequent cause of PHPT (11). They are found in 80–85% of cases (12). Additional reasons of PHPT are parathyroid hyperplasia (10–15% of cases), multiple adenomas (5% of cases), and in rare cases parathyroid cancer (<1– 5% of cases) (12).

Even though primary hyperparathyroidism is quite a common disease, accounts of PHPT during pregnancy are scarce, with reported prevalence in 1% of cases (13). Gestational PHPT can be symptomatic in some cases and present with nephrolithiasis, pancreatitis, or nonspecific symptoms such as nausea, hyperemesis, or fatigue (14). PHPT during pregnancy can even lead to maternal and infant mortalities in some cases (15). Fetal complications are associated with neonatal tetany, polyhydramnios, miscarriage, or stillbirth (16, 17). Nevertheless, gestational PHPT can be hard to diagnose because it is usually asymptomatic during pregnancy (17). Therefore, it is crucial to diagnose gestational PHPT correctly and in time. PHPT is diagnosed when elevated levels of Ca and PTH are found in the blood (18). Instrumental examination such as ultrasound is also important in diagnosing PHPT, especially during pregnancy (14). Our 9 weeks pregnant patient presented with asymptomatic hypercalcemia and elevated PTH levels. Also, a parathyroid gland adenoma was located using neck ultrasound.

Some studies have shown that elevation of Ca to as little as 2.67 mmol/L can cause miscarriages, but pregnancies usually proceed normally with mild hypercalcemia (19). Nonetheless, pregnancy losses transpire more commonly when Ca levels exceed 2.85 mmol/L (13). When 3.0 mmol/L of Ca is found in the serum, an uneventful pregnancy is even more improbable (19). During our patient`s second miscarriage, serum Ca level was 2.98 mmol/L, which would indicate a high probability of a pregnancy loss. The patient’s Ca level during the first miscarriage is unknown due to the patient not visiting the Endocrinology clinic.

Management of gestational PHPT can be demanding, because some treatments are avoided during pregnancy (13). The only definitive treatment for PHPT remains parathyroidectomy (14). Surgery is recommended for patients whose Ca levels continually are greater than 2.75 mmol/L, especially with recurrent miscarriages with unknown etiology and/or for managing fetal or maternal complications that occur due to hypercalcemia (13). PHPT can also be treated conservatively with diuretics, oral hydration, low-Ca diet, and vitamin D supplementation (13, 16). Conservative treatment can be applied when surgery is unavailable, for instance, in cases of gestational PHPT during the first or the third trimester of pregnancy when an operation is unadvised due to unfinished organogenesis in the first trimester or can lead to preterm delivery in the third trimester (13). The highest percentage of normal infant outcomes (95.5%) occurs with surgeries performed during the second trimester, compared to 75% in the first and 79% in the third trimester (20). The complication rate in the third trimester was lower after performing surgeries, compared to the group treated conservatively (20). In our case, it was decided to wait till the second trimester to perform surgery due to better fetal outcomes. Until the parathyroidectomy could be performed, the patient was treated conservatively with hydration and diuretics. A miscarriage occurred prior to the surgery. Parathyroidectomy was performed after the pregnancy loss and led to normal Ca levels in the blood.

In conclusion, with this clinical case, emphasis is placed on the fact that recurrent pregnancy losses without clear gynecological origin can be caused by a rarer but easily diagnosed endocrinological pathology – primary hyperparathyroidism. PHPT presents with clinically expressed hypercalcemia that can be easily diagnosed by measuring Ca levels in the blood. All pregnant patients with hypercalcemia should be assessed for the presence of primary hyperparathyroidism as it is likely the cause (2). To conclude, we would like to put forward the idea that an evaluation of Ca level in the blood should be included in the protocol for treating patients with recurrent miscarriages. Early detection of hypercalcemia can improve the outcomes of the disease that primary hyperparathyroidism can cause. Swift and accurate decrease of serum Ca correspondingly safeguards the woman from a possible pregnancy loss along with complications that arise from it.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This workh did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

G G wrote the manuscript and created and described all the figures. D Š critically reviewed the manuscript and provided revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.