Association of Hypocalcemia and Magnesium Disorders With Thyroidectomy in Commercially Insured Patients

Key Points

Question

What factors are associated with hypocalcemia after total thyroidectomy?

Findings

In this cross-sectional analysis of 126 766 commercially insured patients, short- and long-term hypocalcemia was significantly more likely among women, those younger than 40 years, and those with a diagnosis of thyroiditis or cancer, vitamin D deficiency, concurrent neck dissection, intraoperative parathyroid or recurrent laryngeal nerve injury, and magnesium disorders. Magnesium disorders were associated with the highest odds of postoperative hypocalcemia at 30 days and at 1 year.

Meaning

Disorders of magnesium metabolism are a potentially modifiable target to reduce the incidence of hypocalcemia after total thyroidectomy.

Abstract

Importance

Hypocalcemia is a common complication of total thyroidectomy.

Objectives

To identify factors associated with hypocalcemia after total thyroidectomy and to explore the association between hypocalcemia, magnesium disorders, and costs of care.

Design, Setting, and Participants

A retrospective cross-sectional analysis was performed using data from the MarketScan Commercial Claim and Encounters database on 126 766 commercially insured patients younger than 65 years undergoing total thyroidectomy between January 1, 2010, and December 31, 2012. Statistical analysis was performed from January 1, 2016, to May 30, 2019.

Main Outcomes and Measures

Short- and long-term hypocalcemia and the costs of care were examined using multivariable regression modeling.

Results

Among the 126 766 patients in the study (81.6% women; mean age, 46.5 years [range, 18-64 years]), postoperative hypocalcemia was present in 19.1% of patients in the initial 30-day postoperative period and in 4.4% of patients at 1 year. Magnesium disorders were present in 2.1% of patients at the time of surgery. Short- and long-term hypocalcemia were significantly more likely in women (short-term: odds ratio [OR], 1.39 [95% CI, 1.29-1.50]; long-term: OR, 1.69 [95% CI, 1.52-1.89]), those younger than 40 years (short-term: OR for ages 40-64 years, 0.83 [95% CI, 0.78-0.87]; long-term: OR for ages 40-64 years, 0.73 [95% CI, 0.67-0.79]), those with a diagnosis of thyroiditis (short-term: OR, 1.48 [95% CI, 1.16-1.89]; long-term: OR, 1.60 [95% CI, 1.13-2.26]) or cancer (short-term: OR, 1.32 [95% CI, 1.05-1.67]; long-term: OR, 1.17 [95% CI, 0.83-1.63]), vitamin D deficiency (short-term: OR, 1.96 [95% CI, 1.74-2.21]; long-term: OR, 3.72 [95% CI, 3.30-4.18]), concurrent lateral neck dissection (short-term: OR, 1.51 [95% CI, 1.37-1.66]; long-term: OR, 1.95 [95% CI, 1.69-2.26]), concurrent central neck dissection (short-term: OR, 1.15 [95% CI, 1.07-1.24]; long-term: OR, 1.25 [95% CI, 1.12-1.40]), intraoperative parathyroid (short-term: OR, 1.58 [95% CI, 1.46-1.71]; and long-term: OR, 2.05 [95% CI, 1.82-2.31]) or recurrent laryngeal nerve injury (short-term: OR, 1.49 [95% CI, 1.27-1.74]; long-term: OR, 2.04 [95% CI, 1.64-2.54]), and magnesium disorders (short-term: OR, 8.40 [95% CI, 7.21-9.79]; long-term: OR, 25.23 [95% CI, 19.80-32.17]). Compared with the initial postoperative period, the odds of hypocalcemia decreased by 90.0% (OR, 0.10 [95% CI, 0.09-0.11]) at 6 months and 93.0% (OR, 0.07 [95% CI, 0.06-0.08]) at 1 year. After controlling for all other variables, magnesium disorders were associated with the highest odds of short- and long-term postoperative hypocalcemia. Hypocalcemia ($3392) and magnesium disorders ($14 314) were associated with increased mean incremental 1-year costs of care.

Conclusions and Relevance

Hypocalcemia is common after total thyroidectomy but resolves in most patients by 1 year. Magnesium disorders are significantly independently associated with short- and long-term hypocalcemia and are associated with greater costs of care. These data suggest a potentially modifiable target to reduce the incidence and cost of long-term hypocalcemia at patient and systemic levels.

This cross-sectional study examines factors associated with hypocalcemia after total thyroidectomy and explores the association between hypocalcemia, magnesium disorders, and costs of care.

Introduction

Temporary hypocalcemia is the most common complication of total thyroidectomy, with a reported incidence within the literature of 1.6% to more than 50%.^1,2 Although most cases of hypocalcemia resolve spontaneously, there is significant morbidity associated with hypocalcemia secondary to bronchospasm or laryngospasm, seizure, change in mental status, and cardiac dysrhythmia.³ Moreover, postoperative hypocalcemia may lead to prolonged hospital stays and may necessitate oral or intravenous calcium repletion, consequently leading to increased health care costs.⁴ Although rare, permanent postthyroidectomy hypocalcemia as a result of permanent hypoparathyroidism is an independent risk factor for mortality.⁵ As such, there is significant value in identifying modifiable risk factors for postthyroidectomy hypocalcemia.

Previous studies of postthyroidectomy hypocalcemia have identified female sex, preoperative hypocalcemia, preoperative hypovitaminosis D, large goiters, thyroid cancer with or without neck dissection, and reoperation as factors associated with transient hypocalcemia.^2,6 A subset of these risk factors (namely, concomitant neck dissection, reoperation for bleeding, Grave disease, and larger thyroid specimens) were associated with permanent hypocalcemia.^6,7 Recently, abnormal serum magnesium levels and, by extension, magnesium metabolism disorders have been implicated in postoperative hypocalcemia.^8,9,10,11,12 The serum magnesium level has been observed to mimic calcium levels postoperatively and potentially provides a modifiable risk factor in the development of surgical hypocalcemia.^8,9

To our knowledge, there has been no large database study examining the factors associated with and consequences of long-term hypocalcemia in patients after thyroidectomy. We sought to identify risk factors associated with both short- and long-term hypocalcemia after total thyroidectomy and to explore the association between hypocalcemia, magnesium disorders, and costs of care using claims data on young (<65 years) commercially insured patients.

Methods

Selection and Description of Study Patients

A cross-sectional analysis of patients undergoing total thyroidectomy was performed using data from the MarketScan Commercial Claims and Encounters database and the MarketScan Lab database (Truven Health Analytics). This large US-based, employment-based database contains individual-level inpatient and outpatient insurance billing claims for employees and their dependents from approximately 45 large employers covered by more than 100 commercial payers. MarketScan allows longitudinal tracking of patients across different sites of care over multiple years and contains information regarding inpatient and outpatient treatment, demographic data, primary and secondary diagnoses and procedures, and costs. This protocol was reviewed by the Johns Hopkins Medical Institutions Institutional Review Board and approved as exempt because all data were deidentified and publicly available.

Treatment was ascertained using all inpatient, outpatient, facility, and pharmaceutical claims files and using International Classification of Diseases, Ninth Revision (ICD-9) codes, Current Procedural Terminology codes, and Healthcare Common Procedure Coding System (HCPCS) codes for treatment. Adult patients (≥18 years of age) who underwent total thyroidectomy for benign or malignant disease between January 1, 2010, and December 31, 2012, comprised the study cohort (eTable 1 in the Supplement). Additional surgical procedures performed at the time of total thyroidectomy, including concurrent neck dissection (central or lateral), parathyroid reimplantation, and recurrent laryngeal nerve (RLN) repair, were defined by claims on the day of or within 30 days of thyroidectomy. Hypocalcemia was defined by a diagnosis of hypocalcemia or hypoparathyroidism, and RLN injury was defined by codes for RLN injury or repair (eTable 2 in the Supplement). Hypocalcemia or RLN injury was defined as present when they occurred in claims for care; when absent, we defined these conditions as resolved. Additional variables were derived from codes for disorders of magnesium metabolism, disorders of phosphate metabolism, vitamin D deficiency, and menopause or ovarian dysfunction, including codes for calcium and magnesium supplementation. Comorbidity was graded using the Romano adaptation of the Charlson Comorbidity Index, excluding ICD-9 codes for the index cancer diagnosis from the solid tumor category.^13,14,15 Patients were followed up from the index surgery date for 12 months or until death, termination of health insurance, or end of database availability.

Data Collection

The MarketScan Commercial Claims and Encounters database includes only commercially insured individuals; thus, patients 65 years or older, patients receiving Medicare or Medicaid, and uninsured patients are not included. Data on race/ethnicity, educational level, income, hospital characteristics and identifiers, American Joint Commission on Cancer tumor stage, tumor grade, histologic subtype, and survival after hospital discharge are not available from the MarketScan database. Metropolitan statistical area (MSA) is provided in MarketScan and is defined as a geographical region that contains a core population of 50 000 individuals or more, consisting of 1 or more counties that have a high degree of social and economic integration.¹⁶ The Census MSA-level median household income for the year of diagnosis was determined as an approximate measure of socioeconomic status via linkage to the US Census Bureau and was divided into quintiles.¹⁷

The MSA was also used to derive a surrogate for treatment volume. The mean annual number of total thyroidectomy cases performed per year of surgical activity was obtained by calculating the mean of the number of cases performed each year for each individual MSA, for the years in which at least 1 total thyroidectomy was performed within that MSA. We examined the distribution of the number of cases per MSA and stratified MSA volume by tertiles, which resulted in cutoff values for annual case volumes of 46 or fewer cases, 47 to 122 cases, and 123 cases or more, which were used to classify MSAs as low, intermediate, and high volume.

Postoperative hypocalcemia and overall costs of care were examined as dependent variables. Magnesium and phosphate metabolism disorders, vitamin D deficiency, and menopause or ovarian disorder were examined as independent variables and included diagnoses codes in claims as well as claims for magnesium, calcium, and vitamin D supplementation. These variables were defined as short-term when they occurred during the initial treatment period using claims dating from the date of total thyroidectomy up to 30 days after surgery, whereas long-term outcomes were defined as those occurring in claims occurring from 3 months to 12 months after surgery.

Secondary independent variables were age, sex, region, payer source (commercial, health maintenance organization, preferred provider organization, point of service, or other including consumer-driven health plans and high-deductible health plans), comorbidity, site (inpatient or outpatient), Census MSA-level median income quintile, MSA case volume, additional surgical procedures, RLN injury, and diagnosis. Costs were evaluated using all paid amounts from all standard analytic files, including inpatient, outpatient, facility, and pharmaceutical claims files. Costs were categorized as inpatient, outpatient, and other and combined into overall costs that were used in this analysis. Costs differ from charges in that costs reflect only the amount paid for care rendered. Costs were adjusted for inflation with results converted to 2018 US dollars.¹⁸

Statistical Analysis

Statistical analysis was performed from January 1, 2016, to May 30, 2019. Data were analyzed using Stata, version 12 (StataCorp). Associations between variables were analyzed using cross-tabulations and multivariable regression analysis. Data were structured as panel data for the analysis of outcomes or conditions that were measured over time. National projections of case volumes in the commercially insured population were extrapolated using a proprietary method developed by MarketScan, using sampling weights derived from similar subpopulations in the Medical Expenditure Panel Survey¹⁹ and corrected for changes in sampling over time. Variables with missing data for more than 10% of the population were coded with a dummy variable to represent the missing data in regression analysis. The primary clinical end point of hypocalcemia was evaluated using multivariable logistic regression analysis. Generalized linear regression modeling with a log link was used to analyze total costs for the 30-day initial treatment period as well as overall total costs at 1 year after surgery.

Results

A total of 126 766 cases met study criteria (Table 1). The mean patient age was 46.5 years (range, 18-64 years). Most patients were female (81.6%), 40 years of age or older (70.6%), with no comorbidity (93.0%), and had surgery in the southern United States (39.4%) and as outpatients (66.2%). The most common indication for surgery was malignant neoplasm (50.2%), followed by goiter (37.8%). Concurrent central neck dissection was performed in 15.9% of cases, and lateral neck dissection was performed in 6.9% of cases. Recurrent laryngeal nerve injury occurred in 2.2% of patients, with RLN repair performed in 0.8% of patients. Overall, vitamin D deficiency was recorded in 3.7% of cases, a magnesium disorder in 2.1%, phosphate disorder in 0.3%, and menopause or an ovarian disorder in 0.9% of cases. Hungry bone syndrome was present in less than 0.1% of cases and was excluded from analysis. Readmission within 30 days occurred in 3.9% of cases.

Table 1. Demographic Characteristics of Patients.

Characteristic	Patients, %			Proportion Difference (95% CI)
	All (N = 126 766)	Postoperative Hypocalcemia 30-d Initial Treatment Period
		Present (n = 24 159)	Absent (n = 102 607)
Pathologic finding
Nodule	1.5	1.2	1.6	−0.4 (−1.7 to 1.0)
Goiter	37.8	33.1	38.9	−5.8 (−6.9 to −4.7)
Thyroiditis	10.5	11.8	10.2	1.5 (0.2 to 2.8)
Cancer	50.2	53.9	49.3	4.6 (3.6 to 5.6)
Age, y
18-39	29.4	33.8	28.4	5.4 (4.2 to 6.5)
40-64	70.6	66.2	71.6	−5.4 (−6.2 to −4.6)
Sex
Male	18.4	14.9	19.2	−3.4 (−5.6 to −3.1)
Female	81.6	85.1	80.8	4.3 (3.8 to 4.9)
Comorbidity score
0	93.0	91.8	93.3	−1.6 (−2.0 to −1.1)
1	5.9	6.9	5.7	1.2 (−0.2 to 2.5)
2	0.9	1.1	0.8	0.3 (−1.1 to 1.7)
≥3	0.2	0.2	0.2	0.1 (−1.3 to 1.5)
Procedure location
Inpatient	33.8	40.0	32.3	7.6 (6.8 to 8.5)
Outpatient	66.2	60.0	67.7	−7.6 (−8.7 to −6.5)
Region
Northeast	21.6	21.1	21.7	−0.6 (−1.8 to 0.7)
North central	21.1	21.8	20.9	0.9 (−0.4 to 2.1)
South	39.4	38.9	39.6	−0.6 (−1.7 to 0.5)
West	17.9	18.1	17.8	0.3 (−0.1 to 1.5)
Census median income quintilea
Very low	19.9	18.7	20.2	−1.5 (−2.8 to −0.1)
Low	20.1	22.2	19.6	2.6 (1.2 to 3.9)
Medium	20.0	20.9	19.8	1.1 (−0.2 to 2.5)
High	19.7	20.1	19.6	0.5 (−0.9 to 1.8)
Very high	20.3	18.1	20.8	−2.7 (−4.1 to −1.3)
Payera
Comprehensive	2.0	2.1	2.1	0 (−1.5 to 1.5)
HMO	16.0	14.0	16.4	−2.4 (−3.7 to −1.0)
POS	8.3	6.8	8.6	−1.8 (−3.3 to −0.5)
PPO	66.3	69.3	65.6	3.7 (2.9 to 4.5)
Other	7.4	7.8	7.3	0.5 (−0.9 to 1.9)
MSA volumea
Low	33.8	33.6	33.8	−0.2 (−1.5 to 0.1)
Medium	34.0	33.8	34.1	−0.3 (−1.5 to 0.1)
High	32.2	32.6	21.1	0.5 (−0.7 to 1.7)
Central neck dissection
Yes	15.9	19.1	15.1	4.0 (2.7 to 5.2)
No	84.1	80.9	84.9	−4.0 (−4.5 to −3.3)
Lateral neck dissection
Yes	6.9	10.1	6.2	3.9 (2.6 to 5.2)
No	93.1	89.9	93.8	−3.9 (−4.4 to −3.5)
Parathyroid reimplantation
Yes	10.1	14.5	9.0	5.5 (4.1 to 6.8)
No	89.9	85.5	91.0	−5.5 (−5.9 to −4.9)
Postoperative radiotherapy
Yes	6.5	7.6	6.2	1.4 (0.1 to 2.8)
No	93.5	92.4	93.8	−1.4 (−1.8 to −1.1)
Postoperative radioactive iodine
Yes	29.0	32.9	28.1	4.8 (3.6 to 5.9)
No	71.0	67.1	71.9	−4.8 (−5.5 to −3.9)
RLN injury
Yes	2.2	3.2	2.0	1.2 (−0.2 to 2.5)
No	97.8	96.8	98.0	−1.2 (−1.4 to −0.9)
Vitamin D deficiency
Yes	3.7	6.4	3.1	3.3 (2.9 to 4.7)
No	96.3	93.6	96.9	−3.3 (−3.7 to −2.9)
Menopause
Yes	0.9	1.0	0.9	0.1 (−2.3 to 1.5)
No	99.1	99.0	99.1	−0.1 (−0.2 to 0)
Magnesium disorder
Yes	2.1	7.4	0.8	6.6 (5.2 to 7.9)
No	97.9	92.6	99.2	−6.6 (−6.9 to −6.2)
Phosphate disorder
Yes	0.3	1.2	0.1	1.1 (−0.2 to 2.5)
No	99.7	98.8	99.9	−1.1 (−1.3 to −1.0)
Disposition
Routine	32.1	37.9	30.7	7.2 (6.0 to 8.3)
Short-term hospital	<0.1	<0.1	<0.1
Other facility	<0.1	<0.1	<0.1
Home health care	0.4	0.7	0.4	0.3 (−1.10 to 1.7)
Left against medical advice	0.1	0.2	0.1	0.1 (−0.5 to 0.7)
Died in hospital	<0.1	<0.1	<0.1
Alive, destination unknown	67.3	61.2	68.7	−7.6 (−8.4 to −6.7)
Readmission within 30 d
Yes	3.9	11.1	2.3	8.8 (7.4 to 10.2)
No	96.1	88.9	97.7	−8.8 (−9.2 to −8.4)

Abbreviations: HMO, health maintenance organization; MSA, metropolitan statistical area; POS, point of service; PPO, preferred provider organization; RLN, recurrent laryngeal nerve.

^aNot known for all patients.

Presence of Hypocalcemia

Hypocalcemia was present in 19.1% of patients in the initial 30-day postoperative period and was significantly more common in women than men (85.1% vs 80.8%), younger (18-39 years) patients than older patients (33.8% vs 28.4%), and in patients with thyroiditis (11.8% vs 10.2%), thyroid cancer (53.9% vs 49.3%), comorbidities (8.2% vs 6.7%), vitamin D deficiency (6.4% vs 3.1%), and disorders of magnesium (7.4% vs 0.8%) or phosphate (1.2% vs 0.1%) metabolism. Hypocalcemia was also more common in patients who underwent central neck dissection (19.1% vs 15.1%) or lateral neck dissection (10.1% vs 6.2%) and who sustained an RLN injury (3.2% vs 2.0%) compared with those who did not. Parathyroid reimplantation at the time of surgery was performed in 10.1% of cases and was more commonly performed for patients who developed hypocalcemia than for those who did not (14.5% vs 9.0%). Readmission within 30 days was more common among patients with hypocalcemia than among patients without hypocalcemia (11.1% vs 2.3%).

The prevalence of hypocalcemia decreased to 5.3% at 6 months and 4.4% at 12 months after surgery. Because of the low numbers of patients, phosphate disorders were excluded from multivariable analysis. Multivariable random-effect regression analysis controlling for time-invariant and time-variant variables demonstrated that, compared with the initial postoperative period, the odds of hypocalcemia decreased by 90.0% (odds ratio [OR], 0.10 [95% CI, 0.09-0.11]) at 6 months and decreased by 93.0% (OR, 0.07 [95% CI, 0.06-0.08]) at 1 year. The short- and long-term odds of hypocalcemia were significantly higher for women (short-term: OR, 1.39 [95% CI, 1.29-1.50]; and long-term: OR, 1.69 [95% CI, 1.52-1.89]) and for patients who underwent surgery for a malignant neoplasm (short-term: OR, 1.32 [95% CI, 1.05-1.67]; long-term: OR, 1.17 [95% CI, 0.83-1.63]) or thyroiditis (short-term: OR, 1.48 [95% CI, 1.16-1.89]; long-term: OR, 1.60 [95% CI, 1.13-2.26]), were younger than 40 years (short-term: OR for ages 40-64 years, 0.83 [95% CI, 0.78-0.87]; long-term: OR for ages 40-64 years, 0.73 [95% CI, 0.67-0.79]), and who had comorbid conditions (short-term for ≥2 comorbidities: OR, 1.42 [95% CI, 1.11-1.80]; long-term: OR, 1.63 [95% CI, 1.14-2.34]) (Table 2). Central neck dissection (short-term: OR, 1.15 [95% CI, 1.07-1.24]; long-term: OR, 1.25 [95% CI, 1.12-1.40]) or lateral neck dissection (short-term: OR, 1.51 [95% CI, 1.37-1.66]; long-term: OR, 1.95 [95% CI, 1.69-2.26]), intraoperative parathyroid injury (short-term: OR, 1.58 [95% CI, 1.46-1.71]; long-term: OR, 2.05 [95% CI, 1.82-2.31]), and RLN injury (short-term: OR, 1.49 [95% CI, 1.27-1.74]; long-term: OR, 2.04 [95% CI, 1.64-2.54]) were associated with increased odds of both short- and long-term hypocalcemia. Vitamin D deficiency (short-term: OR, 1.96 [95% CI, 1.74-2.21]; long-term: OR, 3.72 [95% CI, 3.30-4.18]) and magnesium disorders (short-term: OR, 8.40 [95% CI, 7.21-9.79]; and long-term: OR, 25.23 [95% CI, 19.80-32.17]) were associated with significantly increased odds of short- and long-term hypocalcemia, whereas menopause was associated with an increased odds of long-term hypocalcemia (OR, 1.66 [95% CI, 1.36-2.04). Magnesium disorders were associated with the highest odds of both short- and long-term hypocalcemia.

Table 2. Multivariable Logistic Regression Model of Variables Associated With Short-term Hypocalcemia and Multivariable Random Effect Logistic Regression Analysis of Variables Associated With Long-term Hypocalcemia.

Characteristic	Odds Ratio (95% CI)
	Short-term Hypocalcemiaa	Long-term Hypocalcemiaa
Pathologic finding
Nodule	1.0 [Reference]	1.0 [Reference]
Goiter	1.13 (0.89-1.43)	1.11 (0.80-1.55)
Thyroiditis	1.48 (1.16-1.89)	1.60 (1.13-2.26)
Cancer	1.32 (1.05-1.67)	1.17 (0.83-1.63)
Age, y
18-39	1.0 [Reference]	1.0 [Reference]
40-64	0.83 (0.78-0.87)	0.73 (0.67-0.79)
Sex
Male	1.0 [Reference]	1.0 [Reference]
Female	1.39 (1.29-1.50)	1.69 (1.52-1.89)
Comorbidity score
0	1.0 [Reference]	1.0 [Reference]
1	1.18 (1.05-1.31)	1.28 (1.09-1.50)
≥2	1.42 (1.11-1.80)	1.63 (1.14-2.34)
Region
Northeast	1.0 [Reference]	1.0 [Reference]
North central	1.01 (0.92-1.11)	0.99 (0.86-1.14)
South	1.01 (0.93-1.10)	0.99 (0.87-1.13)
West	1.03 (0.94-1.14)	1.08 (0.94-1.25)
Census median income quintile
Very low	1.0 [Reference]	1.0 [Reference]
Low	1.17 (1.07-1.29)	1.33 (1.16-1.53)
Medium	1.18 (1.07-1.30)	1.28 (1.10-1.48)
High	1.08 (0.96-1.20)	1.08 (0.92-1.27)
Very high	0.94 (0.85-1.05)	0.94 (0.80-1.11)
Payerb
Comprehensive	1.0 [Reference]	1.0 [Reference]
HMO	0.80 (0.65-0.98)	0.85 (0.63-1.16)
POS	0.78 (0.63-0.97)	0.79 (0.57-1.09)
PPO	0.99 (0.82-1.19)	1.09 (0.82-1.46)
Other	1.11 (0.91-1.37)	1.10 (0.80-1.52)
MSA volume
Low	1.0 [Reference]	1.0 [Reference]
Medium	0.97 (0.90-1.05)	0.94 (0.84-1.05)
High	0.94 (0.86-1.02)	0.90 (0.79-1.03)
Central neck dissection
No	1.0 [Reference]	1.0 [Reference]
Yes	1.15 (1.07-1.24)	1.25 (1.12-1.40)
Lateral neck dissection
No	1.0 [Reference]	1.0 [Reference]
Yes	1.51 (1.37-1.66)	1.95 (1.69-2.26)
Parathyroid reimplantation
No	1.0 [Reference]	1.0 [Reference]
Yes	1.58 (1.46-1.71)	2.05 (1.82-2.31)
RLN injury
No	1.0 [Reference]	1.0 [Reference]
Yes	1.49 (1.27-1.74)	2.04 (1.64-2.54)
Vitamin D deficiency
No	1.0 [Reference]	1.0 [Reference]
Yes	1.96 (1.74-2.21)	3.72 (3.30-4.18)
Menopause
No	1.0 [Reference]	1.0 [Reference]
Yes	1.09 (0.83-1.42)	1.66 (1.36-2.04)
Magnesium disorder
No	1.0 [Reference]	1.0 [Reference]
Yes	8.40 (7.21-9.79)	25.23 (19.80-32.17)
Postoperative radiotherapy
No		1.0
Yes		1.26 (1.08-1.47)
Postoperative radioactive iodine
No		1.0
Yes		1.42 (1.27-1.58)

Abbreviations: HMO, health maintenance organization; MSA, metropolitan statistical area; POS, point-of-service; PPO, preferred provider organization; RLN, recurrent laryngeal nerve.

^aShort-term is the first 30 days after surgery; long-term is 1 year after surgery.

^bNot known for all patients.

Costs of Care

Multivariable generalized linear regression analysis of independent variables associated with overall costs in the 30-day initial treatment period and at 1 year is shown in Table 3 and Table 4. After controlling for all other variables, we found that comorbidity was associated with the greatest increases in both short-term and 1-year costs (short-term for comorbidity score of ≥2, $8332; long-term for comorbidity score of ≥2, $27 936), followed by extent of surgery (short-term for lateral neck dissection, $6618; long-term for lateral neck dissection, $10 342) and RLN injury (short-term, $6309; long-term, $13 286). The 1-year costs of care were highest for patients with comorbidity, cancer-related treatment with neck dissection, postoperative radiotherapy ($14 522), postoperative radioactive iodine ($7137), RLN injury, and magnesium disorders ($14 314). A statistically significant association was observed between hypocalcemia and increased mean incremental costs of care. Magnesium disorders were significantly associated with even greater mean incremental costs of care, exceeded only by the costs associated with advanced comorbidity. High-volume MSA care was associated with lower short-term (–$1882) and long-term costs (–$1647), whereas the high median income quintile was associated with greater short-term ($1713) and long-term costs ($2831) of care.

Table 3. Generalized Linear Regression Analysis of Overall Costs in the 30-Day Initial Posttreatment Period.

Variable	Estimate (95% CI)	Mean Incremental Difference (2018 USD), $
Intercept	9.5261 (9.4316 to 9.6206)	15 203
Aged 40-64 y	0.0163 (0.0011 to 0.0314)	247
Goiter	0.0575 (0.0026 to 0.1123)	880
Thyroiditis	0.0939 (0.0357 to 0.1520)	1482
Cancer	0.1196 (0.0648 to 0.1743)	1819
Female sex	−0.0998 (−0.1202 to −0.0795)	−1518
Comorbidity score
1	0.1680 (0.1314 to 0.2046)	2754
≥2	0.4386 (0.3393 to 0.5379)	8332
Region
North central	0.2204 (0.1953 to 0.2456)	3580
West	0.0670 (0.0401 to 0.0940)	1042
Median income quintile
High	0.1087 (0.0777 to 0.1396)	1713
Very high	0.1351 (0.1061 to 0.1641)	2148
High MSA volume	−0.1272 (−0.1514 to −0.1031)	−1882
Central neck dissection	0.1102 (0.0883 to 0.1321)	1740
Lateral neck dissection	0.3692 (0.3345 to 0.4038)	6618
RLN injury	0.3494 (0.2739 to 0.4249)	6309
Parathyroid reimplantation	0.1055 (0.0839 to 0.1271)	1674
Magnesium disorder	0.1932 (0.1398 to 0.2466)	3227
Hypocalcemia	0.1420 (0.1216 to 0.1624)	2259

Abbreviations: MSA, metropolitan statistical area; RLN, recurrent laryngeal nerve; USD, US dollars.

Table 4. Generalized Linear Regression Analysis of 1-Year Overall Costs.

Variable	Estimate (95% CI)	Mean Incremental Difference (2018 USD), $
Intercept	10.0084 (9.9275 to 10.0892)	25 147
Age 40-64 y	0.1165 (0.1037 to 0.1293)	2894
Goiter	0.0620 (0.0186 to 0.1065)	1590
Thyroiditis	0.0834 (0.0375 to 0.1294)	2193
Cancer	0.1303 (0.0858 to 0.1748)	3314
Female sex	−0.0999 (−0.1168 to −0.0830)	−2541
Comorbidity score
1	0.2153 (0.1906 to 0.2400)	6030
≥2	0.7455 (0.6686 to 0.8223)	27 936
Region
North central	0.1280 (0.1076 to 0.1484)	3379
South	−0.0312 (−0.0498 to −0.0125)	−790
West	0.0400 (0.0182 to 0.0619)	1032
Payer
HMO	−0.1219 (−0.1793 to −0.0644)	−2968
POS	−0.1085 (−0.1680 to −0.0491)	−2637
PPO	−0.1003 (−0.1556 to −0.0450)	−2577
Other	−0.0959 (−0.1554 to −0.0363)	−2340
Median income quintile
High	0.0762 (0.0512 to 0.1013)	1988
Very high	0.1075 (0.0829 to 0.1320)	2831
Medium MSA volume	−0.0195 (−0.0362 to −0.0028)	−494
High MSA volume	−0.06557 (−0.0860 to −0.0454)	−1647
Central neck dissection	0.0792 (0.0618 to 0.0965)	2068
Lateral neck dissection	0.3484 (0.3270 to 0.3698)	10 342
RLN injury	0.4230 (0.3803 to 0.4657)	13 286
Parathyroid reimplantation	0.0464 (0.0288 to 0.0640)	1203
Radiotherapy	0.4628 (0.4353 to 0.4904)	14 522
Iodine therapy	0.2648 (0.2480 to 0.2816)	7137
Magnesium disorder	0.4481 (0.3493 to 0.5470)	14 314
Vitamin D deficiency	0.0993 (0.0754 to 0.1233)	2641
Menopause	0.1239 (0.0877 to 0.1600)	3343
Hypocalcemia	0.1267 (0.1068 to 0.1465)	3392

Abbreviations: HMO, health maintenance organization; MSA, metropolitan statistical area; POS, point of service; PPO, preferred provider organization; RLN, recurrent laryngeal nerve; USD, US dollars.

Discussion

These data demonstrate that postoperative hypocalcemia is common among commercially insured patients after total thyroidectomy, documented in 19.1% of patients, but it resolves in most patients by 1 year after surgery. Similar to other reports, we found that a diagnosis of thyroiditis or cancer, vitamin D deficiency, concurrent neck dissection, intraoperative parathyroid or RLN injury, and magnesium disorders were associated with an increased risk of both perioperative and permanent hypocalcemia. In this study, magnesium disorders were associated with the highest odds of postoperative hypocalcemia at 30 days and 1 year after total thyroidectomy and were associated with increased costs of care.^{1,2,6,7,8,9,10,11,12,20,21} These observations are important at a time when outcomes are increasingly important factors in discussions of value and reimbursement, and they suggest that magnesium disorders may be a potentially modifiable risk factor that can be targeted to reduce the likelihood of postthyroidectomy hypocalcemia.

Current recommendations to reduce the risk of postoperative hypocalcemia include prompt recognition of devascularized or inadvertently removed parathyroid glands with prompt autotransplantation and the use of routine postoperative calcium supplementation.^{22,23,24,25,26} Incidental parathyroidectomy, defined as the presence of parathyroid tissue within the surgical specimen, has previously been associated with higher incidences of postoperative hypocalcemia.²⁷ Although parathyroid autotransplantation is considered standard practice, the success rates are variable.^28,29,30,31 In addition, the practice of routine postoperative oral calcium supplementation has been observed to mitigate the rate of short-term hypocalcemia in some series.^{22,32,33,34,35,36,37,38} Others have proposed selective calcium supplementation based on postoperative parathyroid hormone (PTH) and calcium levels, the postoperative calcium trend, or PTH gradient (between preoperative and 1-hour postoperative levels).^33,37 Selective supplementation, although shown to be associated with higher quality of life, comes at a higher cost per patient than routine supplementation.^35,36,39 Oral calcium supplementation is not reflected in HCPCS or ICD-9 codes from administrative data, limiting evaluation of this practice in this study.

An association between high-volume surgical care and reduced postoperative hypocalcemia has been reported by several authors.^{40,41,42,43,44,45,46} More important, surgeon case volume, rather than hospital case volume, has been significantly associated with surgical outcomes. Surgeons with a high volume of cases, typically defined as those who perform more than 25 to 100 thyroid surgical procedures per year, were associated with lower overall complication rates, with lower rates of permanent hypoparathyroidism and RLN palsy, shorter operative times, and decreased length of hospital stay.^{41,42,43,44,45,46} We did not find an association between MSA volume and hypocalcemia in our study; however, MSA volume is neither hospital or surgeon specific but rather refers to geographical volumes, which can encompass a range of hospital and surgeon volumes within a particular MSA.

In recent years, several studies have demonstrated hypomagnesemia as a risk factor for the development of postthyroidectomy hypocalcemia.^{8,9,10,11,12,21,47} Nellis et al¹² found that the odds of developing hypocalcemia was the greatest for patients with magnesium metabolism disorders. We found similar results in our study, which suggests the hypothesis that selective magnesium supplementation may be an effective prophylaxis against surgical hypocalcemia. Furthermore, postoperative magnesium levels have been observed to mimic calcium levels, with the magnitude of decline, as well as the absolute magnesium level on postoperative day 1 and 2, directly associated with the incidence of both temporary and permanent hypocalcemia.^8,9,10,47 A recent study by Wang et al⁴⁸ found that the risk of postthyroidectomy hypocalcemia in patients with concurrent hypomagnesemia was 4.6 times higher than in patients with normomagnesemia and that the decrease in serum calcium level was more significant in patients who also had a severe decrease in serum magnesium level compared with preoperative levels. Although, to our knowledge, no randomized clinical trials exist to establish causality between hypomagnesemia and hypocalcemia, Fatemi et al⁴⁹ were able to show a significant decrease in serum calcium levels in a group of healthy men subjected to a 3-week low-magnesium diet. These clinical observations regarding the importance of the magnesium level in postoperative hypocalcemia corroborate the large body of basic science research documenting the interdependent association between serum calcium and magnesium.^50,51,52,53 The direct binding of calcium or magnesium ions activates calcium-sensing receptors present on parathyroid cells, leading to calcium-dependent inhibition of PTH secretion. The corollary is that a low magnesium level reduces calcium-sensing receptor activation, promoting PTH release and increasing the level of serum calcium.⁵⁰ However, the paradoxical block of PTH secretion in the setting of severe hypomagnesemia, specifically in patients with magnesium concentrations less than 0.5mM, has been observed clinically and replicated in in vitro and in vivo models.^52,54 This secondary hypocalcemia is resistant to calcium substitution and is restored by magnesium replacement alone.^49,54,55 Some have hypothesized that this is an adaptive phenomenon in chronic hypomagnesemia to prevent the development of secondary hyperparathyroidism.⁵⁶ Quitterer et al⁵⁷ have implicated the increased activity of G_α subunits in the paradoxical block of PTH in vitro, suggesting that patients with magnesium disorders may carry G-protein subunit variations that confer additional susceptibility to PTH blunting in the setting of hypomagnesemia. Taken together, these data suggest that targeting magnesium levels may be efficacious in reducing postthyroidectomy hypocalcemia in some patients.

Limitations

There are several limitations to the use of claims databases in risk adjustment and documentation that may affect our findings. MarketScan contains no information on stage of disease, grade, subtype, race/ethnicity, socioeconomic variables, or survival. Although comorbidity scores were used for risk classification, the ability to adequately control for case mix is limited when discharge diagnoses from claims data are used. Poor outcomes may reflect lower quality or may reflect unobserved patient severity. Metropolitan statistical area–based median income level and volumes may be an imprecise surrogate for true income and hospital volumes. There are limitations to the use of claims data in the identification of postoperative complications because information on outcomes is not collected, and the presence or absence of disease states in claims data may reflect coding practices rather than care provided. Although HCPCS codes for magnesium administration were used to define magnesium deficiency, ICD-9 codes for magnesium and phosphate disorders do not distinguish between deficiency and excess states, and these disorders may be underreported, as may the incidence of vitamin D deficiency and menopause. Laboratory data are not available from claims data. The incidence of complications may be underreported because complications pertaining to hypoparathyroidism may not be evident until after hospital discharge, and many surgeons routinely discharge patients with prophylactic over-the-counter calcium supplementation; in such patients, hypocalcemia may not appear in claims data and thus may be underestimated.^1,2,58 Similarly, low calcium levels in patients with hypocalcemia may prompt additional laboratory tests, such as magnesium levels. In such a setting, hypocalcemia may result in the overidentification of baseline hypomagnesemia in some patients in whom this would have otherwise been asymptomatic. Furthermore, a laryngoscopic examination may not be routinely performed, and RLN injury may be underestimated.^59,60,61,62

Nevertheless, these data demonstrate a strong association between the extent of thyroid disease and surgery with postoperative hypocalcemia, and they confirm an association between magnesium disorders and short- and long-term hypocalcemia that is associated with significant increases in costs. These observations suggest that early identification and treatment of magnesium disorders may provide a potentially modifiable target to reduce the incidence and morbidity of long-term hypocalcemia after total thyroidectomy.

Conclusions

Hypocalcemia is a common complication after total or completion thyroidectomy, but it resolves in most patients within 1 year. Magnesium disorders appear to be an independent factor significantly associated with short- and long-term hypocalcemia and are associated with greater costs of care. This study suggests the hypothesis that perioperative magnesium supplementation after thyroid surgery may potentially improve health care value by reducing the incidence of hypocalcemia and its attendant costs.

Supplement.

eTable 1. ICD-9 and CPT Codes for Included Cases

eTable 2. ICD-9 and CPT Codes for Additional Variables