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Course and Outcome of Pregnancy in a Patient with Mild, Asymptomatic, Primary Hyperparathyroidism Diagnosed before Conception
Course and Outcome of Pregnancy in a Patient with Mild, Asymptomatic, Primary Hyperparathyroidism Diagnosed before Conception STEVEN R. TOLLIN, MD
ABSTRACT: Primary hyperparathyroidism (PHP) during pregnancy is well known to confer an increased risk of complications to both the mother and the fetus. However, the risks and optimal management of patients with mild, asymptomatic disease during pregnancy are much less clear. We observed a patient with mild, asymptomatic PHP who was diagnosed before conception through pregnancy. The patient remained asymptomatic through the first 22 weeks of pregnancy, and her calcium levels remained under 11 mg/dL. This occurred despite a dramatic elevation in the level of 1,25-dihydroxyvitamin D and marked hypercalciuria. Parathyroid surgery was performed at 22 weeks of gestation and a parathyroid
adenoma was removed. Postoperatively, the patient’s calcium level normalized and the rest of the pregnancy was uncomplicated. The patient delivered a healthy baby at 40 weeks of gestation. The neonatal course was unremarkable. We conclude that mild, asymptomatic PHP during early pregnancy is compatible with normal fetal development and an uncomplicated pregnancy and that the serum calcium level in such patients can remain stable with medical management alone, despite the marked changes in maternal calcium metabolism that characterize normal pregnancy. KEY INDEXING TERMS: Asymptomatic primary hyperparathyroidism; Pregnancy [Am J Med Sci 2000;320(2):144–7.]
A
with calcium levels below 12 mg/dL without signs or symptoms of hypercalcemia. Several years ago, guidelines for the management of patients with this condition were developed at a consensus conference.2 Recent evidence suggests that many patients with this condition remain asymptomatic with stable calcium levels and do not develop end organ complications of hyperparathyroidism.3 However, whether patients who are pregnant and have mild, asymptomatic PHP face a similar risk of complications and should be managed in a fashion similar to other patients with PHP during pregnancy is not clear. We recently had the opportunity to observe a woman with mild, asymptomatic PHP that was diagnosed before pregnancy. This gave us the opportunity to observe the effects of this condition on early fetal development and to follow the course of this condition throughout much of pregnancy. It also gave us the unique opportunity to follow changes in calcium metabolism and calcium regulating hormones prospectively in a pregnant patient with PHP.
lthough primary hyperparathyroidism (PHP) is the most common cause of hypercalcemia seen in the outpatient setting, the occurrence of PHP during pregnancy is a relatively rare event; a relatively small number of cases have been reported in the medical literature to date. An increased incidence of fetal and maternal morbidity has been noted in a substantial percentage of these reported cases. Consequently, it has been recommended that most women with PHP during pregnancy undergo a parathyroidectomy in the second trimester to attempt to reduce this risk. However, it must be recognized that this recommendation is based largely on cases of pregnant women with symptomatic hypercalcemia with calcium levels generally above 12 mg/dL.1 Asymptomatic PHP is an increasingly recognized condition. This condition is commonly associated
Department of Medicine, Division of Endocrinology and Metabolism, Winthrop-University Hospital and The State University of New York at Stony Brook School of Medicine, Mineola, New York. Submitted October 18, 1999; accepted in revised form January 28, 2000. Correspondence: Steven R. Tollin, M.D., Lincoln Green Apartments, 4000 Presidential Blvd., Apt. 1510, Philadelphia, PA 19131 (E-mail: [email protected]).
144
Case Report A 27-year-old woman was referred for the evaluation of mild hypercalcemia that had been found on routine blood testing. The August 2000 Volume 320 Number 2
Tollin
Table 1.
Pregnancy Week
Serum Calcium (mg/dL)
Serum Albumin (g/dL)a
Urine Calcium (mg/24 h)
Serum PTH (pg/mL)b
Serum, 1,25-(OH) Vitamin D (pg/mL)c
7 8 9 10 11 14 18 22d 26 30 37
11.0 NM NM 11.0 10.9 10.9 10.1 NM 9.4 9.3 8.8
4.3 NM NM NM 4.2 4.2 3.7 NM 3.7 3.7 NM
NM NM 803 NM NM NM 438 NM 394 NM 533
36 NM NM NM 66 NM 44 NM 10 NM 12
NM 31.9 NM NM ⬎75 NM 100.3 NM 96.6 NM 76.9
a
Serum albumin, nonpregnant reference range, 3.5–5.5 g/dL. Serum PTH, nonpregnant reference range, 11–54 pg/mL. c 1.25-dihydroxyvitamin D, nonpregnant reference range, 24 – 65 pg/mL. d Surgery performed at this time. NM, not measured. b
patient reported none of the typical symptoms of hypercalcemia. Her past medical history was unremarkable. She reported no family history of calcium disorders. Her only medications at this time were phentermine and fenfluramine, which had been prescribed for weight loss. Her physical examination revealed a blood pressure of 120/80 mm Hg, pulse of 72 beats/min. Examination of the neck revealed a normal thyroid and no neck masses. Muscle strength was normal, as were deep tendon reflexes. The rest of the physical examination was unremarkable. Initial laboratory evaluation revealed a mildly elevated serum calcium level of 10.8 mg/dL (reference range, 8.5–10.3 mg/dL) with a serum albumin level of 4.3 gm/dL (reference range, 3.2–5.2 gm/dL), and normal renal function. A serum parathyroid hormone (PTH) level obtained with a mid-region assay was in the mid-normal range at 230 pg/mL (reference range, 50 –340 pg/mL). Level of thyroid stimulation hormone was normal at 1.02 IU/mL (reference range, 0.35–5.50 IU/mL). Level for 24-hour urinary calcium was elevated at 400 mg/24 hr (reference range, 100 –300 mg/24 hr). A parathyroid ultrasound revealed an enlarged right parathyroid gland consistent with an adenoma. Because of this evaluation, the patient was considered to have asymptomatic PHP. Based on the patient’s age and the recommendations of the consensus conference2 that patients under age 50 with asymptomatic PHP undergo parathyroid exploration surgery, it was recommended that the patient obtain a surgical consultation. However, before this could be arranged, 14 weeks after the initial consultation, the patient was found to be at 7 to 8 weeks of pregnancy. This was the patient’s first pregnancy and there was no significant past obstetrical history. We therefore elected to treat the patient with medical management alone. She was told to maintain adequate hydration and to avoid calcium-containing supplements. She was advised of the symptoms of hypercalcemia and told to call immediately if any of these developed. The patient was seen in our office at various times throughout the first 18 weeks of pregnancy. She was questioned about symptoms of hypercalcemia at each visit. At no time did she report symptoms consistent with hypercalcemia. Her blood pressure remained normal. Serial fetal ultrasounds demonstrated normal fetal growth and development. The patient had measurements made of serum calcium, albumin, phosphorus, intact PTH, 1,25dihydroxyvitamin D, and urinary calcium excretion at several of these follow-up visits. These results are listed in Table 1. As can be seen, the patient’s serum calcium level remained stable throughout the first 18 weeks of pregnancy, never rising above 11
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mg/dL. This occurred despite a significantly elevated serum level of 1,25-dihydroxyvitamin D and a further increase in the level of urinary calcium excretion. Based on previous recommendations concerning the management of patients with PHP during pregnancy, the decision was made to perform parathyroid exploration surgery in the second trimester. This was done at 22 weeks of gestation. Surgery revealed an enlarged right inferior parathyroid gland; the other three glands were normal in size. The enlarged gland was removed and was found to be consistent pathologically with a parathyroid adenoma. Postoperatively, the patient did well. Her serum calcium level normalized. The rest of pregnancy was uncomplicated. Her serum calcium level remained normal during the remainder of pregnancy, and her PTH level returned to normal. She continued to have an elevated serum level of 1,25-dihydroxyvitamin D and hypercalciuria. She delivered a normal, healthy baby at 40 weeks of gestation by spontaneous vaginal delivery. The baby had Apgar scores of 8 at 1 minute and 9 at 5 minutes. The baby had a normal serum calcium level of 8.9 mg/dL and a normal intact PTH level of 24 pg/mL. The neonatal course was uncomplicated. The growth, development, and health of the baby have been excellent through age 2.
Discussion This patient’s case demonstrates that mild, asymptomatic PHP, even when present at the onset of pregnancy, is compatible with normal fetal development and an uncomplicated pregnancy, at least during the first 22 weeks. In addition, this case demonstrates that the serum calcium level in such a patient may remain stable with medical management alone, despite the marked alterations in maternal calcium metabolism that characterize normal pregnancy. We elected to have the patient undergo a parathyroidectomy based on previous recommendations in the medical literature concerning the management of patients with PHP during pregnancy. Whether the outcome would have been equally as good with medical management alone is purely a matter of speculation. 145
Primary Hyperparathyroidism in Pregnancy
Table 2.
Case Report Author(s)
Maternal Serum Calcium Level (mg/dL)
Patient Management During Pregnancy
Rubin et al.4 Delmonico et al5
11.6 11.4
Parathyroidectomy in 2nd trimester Parathyroidectomy in 2nd trimester
Lowe et al6 Lowe et al6 Leug and Dawkins7b Gershberg and Young8 Kristofferson et al9 Kort et al10
11.1 11.6–11.8 10.0–11.3 10.8–11.3 11.5–12.1 10.5–11.3
Medical management alone Medical management alone Medical management alone Parathyroidectomy in 2nd trimester Parathyroidectomy in 2nd trimester Medical management alone
Outcome of Pregnancy Uneventfula Transient, asymptomatic neonatal hypocalcemia Uneventful Uneventful Uneventful Uneventful Uneventful Uneventfulc
a
Patient reported a history of delivering an infant during a previous pregnancy who experienced neonatal tetany. Maternal calcium level during that pregnancy not known. b During a previous pregnancy of the same patient, serum calcium levels ranged from 10.9 to 13.1 mg/dL. The patient was also managed medically during this pregnancy and the outcome was uneventful. c Patient reported a history of delivering 2 infants with neonatal tetany during previous pregnancies. Maternal calcium levels during those pregnancies not known.
It is well established that PHP with calcium levels over 12 mg/dL during pregnancy poses substantial risks for both the mother and the fetus. In a substantial percentage of previously reported cases, an increased incidence of spontaneous abortion, stillbirth, and neonatal death have been reported. Most neonatal deaths have been caused by neonatal tetany, which occurs because of suppression of the fetal parathyroid glands by maternal hypercalcemia. Maternal complications have included most commonly nephrolithiasis, pancreatitis, and hypercalcemic crisis, both during pregnancy and during the postpartum period. Retrospective analysis of reported cases comparing patients managed medically and surgically suggests that the incidence of these complications has been much lower in patients treated surgically. As a result, a standard recommendation has been to perform parathyroid surgery during the second trimester, a time after organogenesis has been completed but before the latter part of pregnancy, when the risk of inducing premature labor is greatly increased.1 There have been very few reported cases of patients with mild (serum calcium level ⬍12 mg/dL), asymptomatic PHP during pregnancy. This is surprising, given that this condition is relatively common. It probably reflects a tendency for only complicated cases associated with more significant degrees of hypercalcemia to be reported. These cases are listed in Table 2. These patients have been managed both medically and surgically during pregnancy, and most outcomes have been good. However, the presence of asymptomatic neonatal hypocalcemia in 1 patient and a reported history of neonatal tetany during previous pregnancies in 2 other patients suggests that even mild, asymptomatic maternal hypercalcemia has the ability to suppress fetal PTH secretion. Although most of the serum calcium levels remained stable in these patients during pregnancy, 146
in the report by Kristofferson et al,9 a patient who initially had asymptomatic hypercalcemia with a serum calcium level of 11.5 mg/dL progressed to symptomatic hypercalcemia with a serum calcium level of 12.1 mg/dL. This case emphasizes the importance of frequent monitoring of the serum calcium level in patients who are being medically managed and alerting patients to the signs and symptoms of hypercalcemia. During normal pregnancy, substantial changes in maternal calcium metabolism occur to supply the increased fetal calcium requirements. The nature of these changes has recently been clarified by Seely et al,11 who studied a group of normal women prospectively during the last 2 trimesters of pregnancy and postpartum. This study found that there is a substantial increase in the serum level of 1,25-dihydroxyvitamin D during normal pregnancy, which is thought to result from production of this hormone from the placenta. In this study, the mean levels of 1,25-dihydroxyvitamin D in the second and third trimesters were 113 pg/mL and 101 pg/mL, respectively, somewhat higher than the maximum level observed in our patient (100.3 pg/mL). This results in increased absorption of calcium from the gastrointestinal tract and a relative suppression of parathyroid hormone secretion during pregnancy. Although total serum calcium falls during pregnancy because of a fall in the albumin level, the ionized calcium level remains relatively stable. Hypercalciuria results from the increased gastrointestinal absorption of calcium and PTH suppression and is associated with an increased risk of nephrolithiasis during this time. In the study mentioned above, the mean urinary calcium excretion in the third trimester was 291 mg/24 h, well below maximal level observed in our patient (803 mg/24 h). Unfortunately, we did not measure our patient’s 1,25 dihydroxyvitamin D level before pregnancy, and the August 2000 Volume 320 Number 2
Tollin
PTH assay initially used was different from the one used during pregnancy. As such, we are unable to assess how these parameters changed from the nonpregnant hyperparathyroid state to the pregnant hyperparathyroid state. After surgery, the patient continued to manifest hypercalciuria accompanied by an elevated serum level of 1,25 dihydroxyvitamin-D, despite the fact that her PHP had been cured as reflected by normalization of the serum calcium and PTH level. Although the elevated serum PTH level in PHP contributes to enhanced renal production of 1,25-dihydroxyvitamin D and to hypercalciuria, in our patient these parameters were clearly elevated primarily as a result of the normal physiologic changes of pregnancy. Because of these changes, one might expect that in a pregnant patient with primary hyperparathyroidism, hypercalcemia might worsen as pregnancy progresses because of the increased 1,25-dihydroxyvitamin D production and the inability to adequately suppress PTH secretion. However, it seems from our case and the majority of reported cases of patients with mild, asymptomatic PHP during pregnancy that the patient’s serum calcium level can remain stable if adequate hydration is maintained, presumably by increasing renal calcium excretion. However, the case of Kristoffersson et al9 shows that hypercalcemia in these patients may also worsen during the course of pregnancy. Clearly, frequent monitoring of the serum calcium level is warranted during pregnancy in these patients, and if significant symptomatic hypercalcemia develops, surgery is usually indicated. If a symptomatic patient refuses surgery or is not a surgical candidate, it has been shown that oral phosphate can be effectively used to control hypercalcemia during pregnancy in these patients.12 Because of the small number of reported cases, the optimal management of patients with mild, asymptomatic hyperparathyroidism during pregnancy remains unclear. I hope that more cases of patients who experience normal outcomes as well as cases associated with complications will be reported. At
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present, because of the extremely limited amount of available data, no standard recommendation on patient management can be made. The decision to recommend surgical or medical management during pregnancy in these patients must be individualized. Acknowledgments I would like to thank Dr. David Garry, MaternalFetal Medicine Specialist and member of the Department of Obstetrics and Gynecology of WinthropUniversity Hospital, for his invaluable assistance in the management of this patient. References 1. Kohlmeier L, Marcus R. Calcium disorders of pregnancy. Endocrinol Metab Clin North Am 1995;24:15–24. 2. Consensus Development Conference Panel. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Int Med 1991;114:593–7. 3. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Longitudinal measurements of bone density and biochemical indices in untreated primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:723– 8. 4. Rubin A, Chaykin L, Ludwig GD. Maternal hyperparathyroidism and pregnancy. JAMA 1968;206:128 –30. 5. Delmonico FL, Neer RM, Cosimi AB, et al. Hyperparathyroidism during pregnancy. Am J Surg 1976;131:328 –37. 6. Lowe, DK, Orwoll, ES, Mclung MR, et al. Hyperparathyroidism during pregnancy. Am J Surg 1983;145:611– 4. 7. Lueg MC, Dawkins WE. Primary hyperparathyroidism and pregnancy. South Med J 1983;76:1389 –92. 8. Gershberg H, Young BK. Primary hyperparathyroidism in pregnancy: serum calcium levels after parathyroidectomy. NY State J Med 1984;84:323– 4. 9. Kristoffersson A, Dahlgren S, Lithner F, et al. Primary hyperparathyroidism in pregnancy. Surgery 1984;97:326 –30. 10. Kort KC, Schiller HJ, Numann PJ. Hyperparathyroidism and pregnancy. Am J Surg 1999;177:66 – 8. 11. Seely EW, Brown EM, DeMaggio DM, et al. A prospective study of calciotropic hormones in pregnancy and post partum: reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. Am J Obstet Gynecol 1996;175:14 – 21. 12. Montoro MN, Collea JV, Mestman JH. Management of hyperparathyroidism in pregnancy with oral phosphate therapy. Obstet Gynecol 1980;55:431– 4.
147
ABSTRACT: Primary hyperparathyroidism (PHP) during pregnancy is well known to confer an increased risk of complications to both the mother and the fetus. However, the risks and optimal management of patients with mild, asymptomatic disease during pregnancy are much less clear. We observed a patient with mild, asymptomatic PHP who was diagnosed before conception through pregnancy. The patient remained asymptomatic through the first 22 weeks of pregnancy, and her calcium levels remained under 11 mg/dL. This occurred despite a dramatic elevation in the level of 1,25-dihydroxyvitamin D and marked hypercalciuria. Parathyroid surgery was performed at 22 weeks of gestation and a parathyroid
adenoma was removed. Postoperatively, the patient’s calcium level normalized and the rest of the pregnancy was uncomplicated. The patient delivered a healthy baby at 40 weeks of gestation. The neonatal course was unremarkable. We conclude that mild, asymptomatic PHP during early pregnancy is compatible with normal fetal development and an uncomplicated pregnancy and that the serum calcium level in such patients can remain stable with medical management alone, despite the marked changes in maternal calcium metabolism that characterize normal pregnancy. KEY INDEXING TERMS: Asymptomatic primary hyperparathyroidism; Pregnancy [Am J Med Sci 2000;320(2):144–7.]
A
with calcium levels below 12 mg/dL without signs or symptoms of hypercalcemia. Several years ago, guidelines for the management of patients with this condition were developed at a consensus conference.2 Recent evidence suggests that many patients with this condition remain asymptomatic with stable calcium levels and do not develop end organ complications of hyperparathyroidism.3 However, whether patients who are pregnant and have mild, asymptomatic PHP face a similar risk of complications and should be managed in a fashion similar to other patients with PHP during pregnancy is not clear. We recently had the opportunity to observe a woman with mild, asymptomatic PHP that was diagnosed before pregnancy. This gave us the opportunity to observe the effects of this condition on early fetal development and to follow the course of this condition throughout much of pregnancy. It also gave us the unique opportunity to follow changes in calcium metabolism and calcium regulating hormones prospectively in a pregnant patient with PHP.
lthough primary hyperparathyroidism (PHP) is the most common cause of hypercalcemia seen in the outpatient setting, the occurrence of PHP during pregnancy is a relatively rare event; a relatively small number of cases have been reported in the medical literature to date. An increased incidence of fetal and maternal morbidity has been noted in a substantial percentage of these reported cases. Consequently, it has been recommended that most women with PHP during pregnancy undergo a parathyroidectomy in the second trimester to attempt to reduce this risk. However, it must be recognized that this recommendation is based largely on cases of pregnant women with symptomatic hypercalcemia with calcium levels generally above 12 mg/dL.1 Asymptomatic PHP is an increasingly recognized condition. This condition is commonly associated
Department of Medicine, Division of Endocrinology and Metabolism, Winthrop-University Hospital and The State University of New York at Stony Brook School of Medicine, Mineola, New York. Submitted October 18, 1999; accepted in revised form January 28, 2000. Correspondence: Steven R. Tollin, M.D., Lincoln Green Apartments, 4000 Presidential Blvd., Apt. 1510, Philadelphia, PA 19131 (E-mail: [email protected]).
144
Case Report A 27-year-old woman was referred for the evaluation of mild hypercalcemia that had been found on routine blood testing. The August 2000 Volume 320 Number 2
Tollin
Table 1.
Pregnancy Week
Serum Calcium (mg/dL)
Serum Albumin (g/dL)a
Urine Calcium (mg/24 h)
Serum PTH (pg/mL)b
Serum, 1,25-(OH) Vitamin D (pg/mL)c
7 8 9 10 11 14 18 22d 26 30 37
11.0 NM NM 11.0 10.9 10.9 10.1 NM 9.4 9.3 8.8
4.3 NM NM NM 4.2 4.2 3.7 NM 3.7 3.7 NM
NM NM 803 NM NM NM 438 NM 394 NM 533
36 NM NM NM 66 NM 44 NM 10 NM 12
NM 31.9 NM NM ⬎75 NM 100.3 NM 96.6 NM 76.9
a
Serum albumin, nonpregnant reference range, 3.5–5.5 g/dL. Serum PTH, nonpregnant reference range, 11–54 pg/mL. c 1.25-dihydroxyvitamin D, nonpregnant reference range, 24 – 65 pg/mL. d Surgery performed at this time. NM, not measured. b
patient reported none of the typical symptoms of hypercalcemia. Her past medical history was unremarkable. She reported no family history of calcium disorders. Her only medications at this time were phentermine and fenfluramine, which had been prescribed for weight loss. Her physical examination revealed a blood pressure of 120/80 mm Hg, pulse of 72 beats/min. Examination of the neck revealed a normal thyroid and no neck masses. Muscle strength was normal, as were deep tendon reflexes. The rest of the physical examination was unremarkable. Initial laboratory evaluation revealed a mildly elevated serum calcium level of 10.8 mg/dL (reference range, 8.5–10.3 mg/dL) with a serum albumin level of 4.3 gm/dL (reference range, 3.2–5.2 gm/dL), and normal renal function. A serum parathyroid hormone (PTH) level obtained with a mid-region assay was in the mid-normal range at 230 pg/mL (reference range, 50 –340 pg/mL). Level of thyroid stimulation hormone was normal at 1.02 IU/mL (reference range, 0.35–5.50 IU/mL). Level for 24-hour urinary calcium was elevated at 400 mg/24 hr (reference range, 100 –300 mg/24 hr). A parathyroid ultrasound revealed an enlarged right parathyroid gland consistent with an adenoma. Because of this evaluation, the patient was considered to have asymptomatic PHP. Based on the patient’s age and the recommendations of the consensus conference2 that patients under age 50 with asymptomatic PHP undergo parathyroid exploration surgery, it was recommended that the patient obtain a surgical consultation. However, before this could be arranged, 14 weeks after the initial consultation, the patient was found to be at 7 to 8 weeks of pregnancy. This was the patient’s first pregnancy and there was no significant past obstetrical history. We therefore elected to treat the patient with medical management alone. She was told to maintain adequate hydration and to avoid calcium-containing supplements. She was advised of the symptoms of hypercalcemia and told to call immediately if any of these developed. The patient was seen in our office at various times throughout the first 18 weeks of pregnancy. She was questioned about symptoms of hypercalcemia at each visit. At no time did she report symptoms consistent with hypercalcemia. Her blood pressure remained normal. Serial fetal ultrasounds demonstrated normal fetal growth and development. The patient had measurements made of serum calcium, albumin, phosphorus, intact PTH, 1,25dihydroxyvitamin D, and urinary calcium excretion at several of these follow-up visits. These results are listed in Table 1. As can be seen, the patient’s serum calcium level remained stable throughout the first 18 weeks of pregnancy, never rising above 11
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
mg/dL. This occurred despite a significantly elevated serum level of 1,25-dihydroxyvitamin D and a further increase in the level of urinary calcium excretion. Based on previous recommendations concerning the management of patients with PHP during pregnancy, the decision was made to perform parathyroid exploration surgery in the second trimester. This was done at 22 weeks of gestation. Surgery revealed an enlarged right inferior parathyroid gland; the other three glands were normal in size. The enlarged gland was removed and was found to be consistent pathologically with a parathyroid adenoma. Postoperatively, the patient did well. Her serum calcium level normalized. The rest of pregnancy was uncomplicated. Her serum calcium level remained normal during the remainder of pregnancy, and her PTH level returned to normal. She continued to have an elevated serum level of 1,25-dihydroxyvitamin D and hypercalciuria. She delivered a normal, healthy baby at 40 weeks of gestation by spontaneous vaginal delivery. The baby had Apgar scores of 8 at 1 minute and 9 at 5 minutes. The baby had a normal serum calcium level of 8.9 mg/dL and a normal intact PTH level of 24 pg/mL. The neonatal course was uncomplicated. The growth, development, and health of the baby have been excellent through age 2.
Discussion This patient’s case demonstrates that mild, asymptomatic PHP, even when present at the onset of pregnancy, is compatible with normal fetal development and an uncomplicated pregnancy, at least during the first 22 weeks. In addition, this case demonstrates that the serum calcium level in such a patient may remain stable with medical management alone, despite the marked alterations in maternal calcium metabolism that characterize normal pregnancy. We elected to have the patient undergo a parathyroidectomy based on previous recommendations in the medical literature concerning the management of patients with PHP during pregnancy. Whether the outcome would have been equally as good with medical management alone is purely a matter of speculation. 145
Primary Hyperparathyroidism in Pregnancy
Table 2.
Case Report Author(s)
Maternal Serum Calcium Level (mg/dL)
Patient Management During Pregnancy
Rubin et al.4 Delmonico et al5
11.6 11.4
Parathyroidectomy in 2nd trimester Parathyroidectomy in 2nd trimester
Lowe et al6 Lowe et al6 Leug and Dawkins7b Gershberg and Young8 Kristofferson et al9 Kort et al10
11.1 11.6–11.8 10.0–11.3 10.8–11.3 11.5–12.1 10.5–11.3
Medical management alone Medical management alone Medical management alone Parathyroidectomy in 2nd trimester Parathyroidectomy in 2nd trimester Medical management alone
Outcome of Pregnancy Uneventfula Transient, asymptomatic neonatal hypocalcemia Uneventful Uneventful Uneventful Uneventful Uneventful Uneventfulc
a
Patient reported a history of delivering an infant during a previous pregnancy who experienced neonatal tetany. Maternal calcium level during that pregnancy not known. b During a previous pregnancy of the same patient, serum calcium levels ranged from 10.9 to 13.1 mg/dL. The patient was also managed medically during this pregnancy and the outcome was uneventful. c Patient reported a history of delivering 2 infants with neonatal tetany during previous pregnancies. Maternal calcium levels during those pregnancies not known.
It is well established that PHP with calcium levels over 12 mg/dL during pregnancy poses substantial risks for both the mother and the fetus. In a substantial percentage of previously reported cases, an increased incidence of spontaneous abortion, stillbirth, and neonatal death have been reported. Most neonatal deaths have been caused by neonatal tetany, which occurs because of suppression of the fetal parathyroid glands by maternal hypercalcemia. Maternal complications have included most commonly nephrolithiasis, pancreatitis, and hypercalcemic crisis, both during pregnancy and during the postpartum period. Retrospective analysis of reported cases comparing patients managed medically and surgically suggests that the incidence of these complications has been much lower in patients treated surgically. As a result, a standard recommendation has been to perform parathyroid surgery during the second trimester, a time after organogenesis has been completed but before the latter part of pregnancy, when the risk of inducing premature labor is greatly increased.1 There have been very few reported cases of patients with mild (serum calcium level ⬍12 mg/dL), asymptomatic PHP during pregnancy. This is surprising, given that this condition is relatively common. It probably reflects a tendency for only complicated cases associated with more significant degrees of hypercalcemia to be reported. These cases are listed in Table 2. These patients have been managed both medically and surgically during pregnancy, and most outcomes have been good. However, the presence of asymptomatic neonatal hypocalcemia in 1 patient and a reported history of neonatal tetany during previous pregnancies in 2 other patients suggests that even mild, asymptomatic maternal hypercalcemia has the ability to suppress fetal PTH secretion. Although most of the serum calcium levels remained stable in these patients during pregnancy, 146
in the report by Kristofferson et al,9 a patient who initially had asymptomatic hypercalcemia with a serum calcium level of 11.5 mg/dL progressed to symptomatic hypercalcemia with a serum calcium level of 12.1 mg/dL. This case emphasizes the importance of frequent monitoring of the serum calcium level in patients who are being medically managed and alerting patients to the signs and symptoms of hypercalcemia. During normal pregnancy, substantial changes in maternal calcium metabolism occur to supply the increased fetal calcium requirements. The nature of these changes has recently been clarified by Seely et al,11 who studied a group of normal women prospectively during the last 2 trimesters of pregnancy and postpartum. This study found that there is a substantial increase in the serum level of 1,25-dihydroxyvitamin D during normal pregnancy, which is thought to result from production of this hormone from the placenta. In this study, the mean levels of 1,25-dihydroxyvitamin D in the second and third trimesters were 113 pg/mL and 101 pg/mL, respectively, somewhat higher than the maximum level observed in our patient (100.3 pg/mL). This results in increased absorption of calcium from the gastrointestinal tract and a relative suppression of parathyroid hormone secretion during pregnancy. Although total serum calcium falls during pregnancy because of a fall in the albumin level, the ionized calcium level remains relatively stable. Hypercalciuria results from the increased gastrointestinal absorption of calcium and PTH suppression and is associated with an increased risk of nephrolithiasis during this time. In the study mentioned above, the mean urinary calcium excretion in the third trimester was 291 mg/24 h, well below maximal level observed in our patient (803 mg/24 h). Unfortunately, we did not measure our patient’s 1,25 dihydroxyvitamin D level before pregnancy, and the August 2000 Volume 320 Number 2
Tollin
PTH assay initially used was different from the one used during pregnancy. As such, we are unable to assess how these parameters changed from the nonpregnant hyperparathyroid state to the pregnant hyperparathyroid state. After surgery, the patient continued to manifest hypercalciuria accompanied by an elevated serum level of 1,25 dihydroxyvitamin-D, despite the fact that her PHP had been cured as reflected by normalization of the serum calcium and PTH level. Although the elevated serum PTH level in PHP contributes to enhanced renal production of 1,25-dihydroxyvitamin D and to hypercalciuria, in our patient these parameters were clearly elevated primarily as a result of the normal physiologic changes of pregnancy. Because of these changes, one might expect that in a pregnant patient with primary hyperparathyroidism, hypercalcemia might worsen as pregnancy progresses because of the increased 1,25-dihydroxyvitamin D production and the inability to adequately suppress PTH secretion. However, it seems from our case and the majority of reported cases of patients with mild, asymptomatic PHP during pregnancy that the patient’s serum calcium level can remain stable if adequate hydration is maintained, presumably by increasing renal calcium excretion. However, the case of Kristoffersson et al9 shows that hypercalcemia in these patients may also worsen during the course of pregnancy. Clearly, frequent monitoring of the serum calcium level is warranted during pregnancy in these patients, and if significant symptomatic hypercalcemia develops, surgery is usually indicated. If a symptomatic patient refuses surgery or is not a surgical candidate, it has been shown that oral phosphate can be effectively used to control hypercalcemia during pregnancy in these patients.12 Because of the small number of reported cases, the optimal management of patients with mild, asymptomatic hyperparathyroidism during pregnancy remains unclear. I hope that more cases of patients who experience normal outcomes as well as cases associated with complications will be reported. At
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present, because of the extremely limited amount of available data, no standard recommendation on patient management can be made. The decision to recommend surgical or medical management during pregnancy in these patients must be individualized. Acknowledgments I would like to thank Dr. David Garry, MaternalFetal Medicine Specialist and member of the Department of Obstetrics and Gynecology of WinthropUniversity Hospital, for his invaluable assistance in the management of this patient. References 1. Kohlmeier L, Marcus R. Calcium disorders of pregnancy. Endocrinol Metab Clin North Am 1995;24:15–24. 2. Consensus Development Conference Panel. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Int Med 1991;114:593–7. 3. Silverberg SJ, Gartenberg F, Jacobs TP, et al. Longitudinal measurements of bone density and biochemical indices in untreated primary hyperparathyroidism. J Clin Endocrinol Metab 1995;80:723– 8. 4. Rubin A, Chaykin L, Ludwig GD. Maternal hyperparathyroidism and pregnancy. JAMA 1968;206:128 –30. 5. Delmonico FL, Neer RM, Cosimi AB, et al. Hyperparathyroidism during pregnancy. Am J Surg 1976;131:328 –37. 6. Lowe, DK, Orwoll, ES, Mclung MR, et al. Hyperparathyroidism during pregnancy. Am J Surg 1983;145:611– 4. 7. Lueg MC, Dawkins WE. Primary hyperparathyroidism and pregnancy. South Med J 1983;76:1389 –92. 8. Gershberg H, Young BK. Primary hyperparathyroidism in pregnancy: serum calcium levels after parathyroidectomy. NY State J Med 1984;84:323– 4. 9. Kristoffersson A, Dahlgren S, Lithner F, et al. Primary hyperparathyroidism in pregnancy. Surgery 1984;97:326 –30. 10. Kort KC, Schiller HJ, Numann PJ. Hyperparathyroidism and pregnancy. Am J Surg 1999;177:66 – 8. 11. Seely EW, Brown EM, DeMaggio DM, et al. A prospective study of calciotropic hormones in pregnancy and post partum: reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. Am J Obstet Gynecol 1996;175:14 – 21. 12. Montoro MN, Collea JV, Mestman JH. Management of hyperparathyroidism in pregnancy with oral phosphate therapy. Obstet Gynecol 1980;55:431– 4.
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