Case Presentation: A 30-year-old G3P1011 female with a past medical history significant for locally metastatic ER/PR+ mucinous breast cancer previously on maintenance tamoxifen, presented to obstetrics triage with chief complaints of nausea, vomiting, constipation, and urinary frequency. The patient intentionally discontinued tamoxifen therapy in order to conceive and was 18 weeks gestation at presentation. She was lethargic and tachycardic on exam but was otherwise stable. Labs at presentation were significant for normocytic anemia and calcium of 15.2 with an ionized calcium of 2.1. CT angiography revealed extensive lymphadenopathy, hepatic metastatic disease, and new skeletal metastatic disease. Despite aggressive fluid resuscitation and use of calcitonin, her symptomatic hypercalcemia remained refractory and required hemodialysis for further treatment. These measures failed to maintain normocalcemia, so paclitaxel was initiated by Oncology after shared decision making with the patient. Paclitaxel was selected based on its overall favorable profile in the setting of the patient’s disease and her pregnancy, which she wished to continue. A total of six cycles were completed while inpatient, with minimal effect on calcium. Even while on continuous renal replacement therapy (CRRT), hypercalcemia remained refractory. A multidisciplinary decision was made in conjunction with the patient to initiate bisphosphonate therapy. 90 milligrams of intravenous pamidronate was given a total of three times during admission, for which dialysis had to be held for at least 24 hours due to pamidronate being dialyzable. After each dose, ionized calcium levels declined and HD remained paused while ionized calcium was below 1.8mmol/L. Intravenous fluids and spot dosed calcitonin were continued. The patient overall tolerated these interventions well despite a complex medical course. She later developed pre-eclampsia with severe features and underwent delivery via Caesarean section at 29 weeks and 6 days gestation. She delivered a 1.29 kilogram male infant who required NICU admission for respiratory distress. At present, the patient’s disease is stable on a combination of letrozole and abemaciclib. The child is noted to have a gastrostomy tube due to an unclear reason but is otherwise healthy.
Discussion: At the time of the multidisciplinary conference, the literature regarding bisphosphonate use in pregnancy was reviewed. A relatively small number of cases of bisphosphonate therapy in pregnant patients have been documented, and even fewer in pregnant patients with hypercalcemia of malignancy. Hesitation to use bisphosphonates in pregnancy appears multifactorial, with the concern for congenital defects as well as the uncertain understanding of how the drug interacts with the placenta as primary factors. Animal models have demonstrated multiple anomalies (primarily skeletal) in the setting of high doses of bisphosphonates, though the same anomalies have not been overwhelmingly observed in infants exposed during gestation.
Conclusions: In this case, a pregnant patient with hypercalcemia of malignancy was treated with bisphosphonate therapy with no apparent side effects to the fetus at 21 weeks 6 days gestation. Further evidence is necessary to determine at which stage of gestation bisphosphonates pose less risk than continued hypercalcemia.