Risk factors of transient and permanent hypoparathyroidism after thyroidectomy: a systematic review and meta-analysis

Background: Postoperative hypoparathyroidism (hypoPT) is a common complication following thyroid surgery. However, current research findings on the risk factors for post-thyroid surgery hypoPT are not entirely consistent, and the same risk factors may have different impacts on transient and permanent hypoPT. Therefore, there is a need for a comprehensive study to summarize and explore the risk factors for both transient and permanent hypoPT after thyroid surgery. Materials and methods: Two databases (PubMed and Embase) were searched from inception to 2024. The Newcastle–Ottawa Scale was used to rate study quality. Pooled odds ratios were used to calculate the relationship of each risk factor with transient and permanent hypoPT. Subgroup analyses were conducted for hypoPT with different definition-time (6 or 12 months). Publication bias was assessed using Begg’s test and Egger’s test. Results: A total of 19 risk factors from the 93 studies were included in the analysis. Among them, sex and parathyroid autotransplantation were the most frequently reported risk factors. Meta-analysis demonstrated that sex (female vs. male), cN stage, central neck dissection, lateral neck dissection, extent of central neck dissection (bilateral vs. unilateral), surgery [total thyroidectomy (TT) vs. lobectomy], surgery type (TT vs. sub-TT), incidental parathyroidectomy, and pathology (cancer vs. benign) were significantly associated with transient and permanent hypoPT. Preoperative calcium and parathyroid autotransplantation were only identified as risk factors for transient hypoPT, while preoperative PTH was a protective factor. Additionally, node metastasis and parathyroid in specimen were associated with permanent hypoPT. Conclusion: The highest risk of hypoPT occurs in female thyroid cancer patients with lymph node metastasis undergoing TT combined with neck dissection. The key to preventing postoperative hypoPT lies in the selection of surgical approach and intraoperative protection.


Introduction
Postoperative hypoparathyroidism (hypoPT) is the most common complication of thyroid surgery [1] .According to a meta-analysis, the median incidence of temporary and permanent hypoPT following thyroidectomy ranges from 19 to 38% and 0 to 3%, respectively [2] .HypoPT typically arises from intraoperative damage or removal of the parathyroid glands, leading to decreased levels of parathyroid hormone (PTH) in the blood, subsequently triggering symptoms of hypocalcemia [3,4] .Patients may experience muscle spasms, tetany, and cardiac arrhythmias, ultimately diminishing their quality of life [5,6] .Therefore, exploring the risk factors associated with postoperative hypoPT is crucial for providing enhanced healthcare, which can improve surgical safety, enhance postoperative recovery, and reduce long-term health risks for patients.
Recent studies have identified various risk factors for postthyroidectomy hypoPT, including age, operation type, disease type, parathyroid autotransplantation (PA) [7][8][9][10][11] .However, disparities in sample sizes, study designs, outcome definitions, and analysis methods of those studies could result in divergent conclusions.For example, some studies have found that sex was an independent risk factor for hypoPT [7][8][9] , while other studies have failed to yield similar results [10,11] .Central node dissection (CND) is considered an important risk factor for post-thyroidectomy hypoPT [1] , but there were still some negative results [12] .Additionally, the same risk factor may have different effects on temporary and permanent hypoPT, which can affect clinical decision-making [13,14] .
Several meta-analyses have been conducted to explore postthyroidectomy hypoPT [15][16][17] .Koimtzis et al. [15] suggested that variations in permanent hypoPT definitions (diagnosed at 6 or 12 months postoperatively) may not yield statistically significant differences in the overall incidence rate, without delving into the potential risk factors.Besides, Vaitsi et al. [16] confirmed preoperative vitamin D deficiency as a risk factor for both temporary and permanent hypoPT, while Chen et al. [17] identified 12 risk factors predictive of postoperative hypocalcemia.However, above-mentioned studies only focused on individual risk factors [16] or specific symptoms of hypoPT [17] .Therefore, a more comprehensive summary and discussion are still needed for the risk factors of post-thyroidectomy hypoPT.
In this systematic review and meta-analysis, data from 93 studies were synthesized to delineate all risk factors associated with transient and permanent hypoPT following thyroid surgery.The comprehensive identification of risk factors for hypoPT will help surgeon develop strategies for prevention and management of postoperative complication in patients undergoing thyroidectomy.

Protocol registration
This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA, Supplemental Digital Content 1, http://links.lww.com/JS9/C438,Supplemental Digital Content 2, http://links.lww.com/JS9/C439) and Assessing the Methodological Quality of Systematic Reviews (AMSTAR, Supplemental Digital Content 3, http://links.lww.com/JS9/C440)guidelines [18,19] .The protocol of this study has been registered with the International Prospective Register of Systematic Reviews prior to the initiation of data extraction (http://www.crd.york.ac.uk/PROSPERO, registration no.CRD 42023412216 accessed on 21 January 2024).

Eligible criteria
Studies were included if they met the following criteria: (1) published in English; (2) prospective or retrospective cohort of adult patients who underwent open thyroid surgery for the first time; (3) reported the associations between the potential risk factors and hypoPT; (4) provided a precise definition of transient or permanent hypoPT; (5) the odds ratio (OR) and corresponding 95% CIs could be either calculated or extracted directly; Exclusion criteria were as follows: (1) the cohort included children, endoscopic surgery, or second surgeries; (2) studies only reported hypoPT in a short time after surgery; (3) studies that lacked sufficient information to assess the impact of the potential risk factors on hypoPT; (4) unpublished studies and nonpeer reviewed data (e.g.conference abstracts); (5) studies that did not provide a precise definition of hypoPTH (including both timing and criteria) were excluded from consideration.The criteria for including risk factors in the study are as follows: (1) Consistent definition and format across different literature sources.(2) Reported in at least three studies (including permanent and transient hypoPT).(3) Suitable for meta-analysis integration.
The outcomes of all included studies focused on transient or permanent hypoPT during postoperative follow-up, rather than around the perioperative period.The definition of hypoPT included the following criteria: (1) persistent low levels of PTH or calcium after surgery; (2) the need for oral calcium or vitamin D supplementation after surgery; (3) clinical symptoms of hypocalcemia, such as seizures and muscle spasms after surgery; (4) HypoPT that persisted beyond 6 or 12 months postoperatively was classified as permanent, whereas cases resolving within this timeframe were categorized as transient.

Data extraction
Following the elimination of duplicate records, all titles and abstracts underwent a preliminary screening.Full-text articles of potentially eligible studies were retrieved for further assessment.The reference lists of all retrieved articles and relevant reviews were manually searched to identify additional eligible studies.

Quality assessment
A nine-score system of the Newcastle-Ottawa Quality Assessment Scale (NOS) was applied to evaluate the quality of included studies across three domains: selection of study groups (0-4 scores), comparability of groups (0-2 scores), and ascertainment of exposure or outcomes (0-3 scores) [20] .A total score of 0-3, 4-6, and 7-9 was considered to indicate low, moderate, and high quality, respectively.Study selection, data extraction, and quality assessment were independently conducted by two experienced investigators (K.N. and X.Z.) and any discrepancies were resolved through discussions with a senior reviewer (Z.Y.).
The detail results of quality assessment were shown in Table S4A-J (Supplemental Digital Content 4, http://links.lww.com/JS9/C441).Furthermore, we assessed the quality of meta-analysis of each risk factor using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach based on study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias [21,22] .

Statistical analysis
For univariable analysis results of risk factors with the same content and format in the included studies, we conducted a meta-analysis to analyze the combined OR values and 95% CI.
The results were visually presented using forest plots and tables.Given the current existence of two different definitions for transient and permanent hypoPT, which are defined at 6 months and 12 months, we conducted subgroup meta-analyses for these two definitions.Heterogeneity between included studies was assessed using I-squared (I 2 ) statistic.In case of high statistical heterogeneity (I 2 > 50%), random-effect models were employed to pool effect size; otherwise, fixed-effect models were adopted [23] .Publication bias was assessed using Begg's test, and Egger's test.P-value of <0.05 was considered statistically significant.All statistical analyses were performed using the 'meta' package of R version 4.3.0.

Study characteristics
The characteristics and quality assessment of included studies are presented in (TT) vs. sub-total thyroidectomy (sub-TT)], incidental parathyroidectomy, parathyroid in specimen (Fig. 2A&B).In the case of permanent hypoPT, the number of statistically significant risk factors was notably reduced compared to transient hypoPT, but incidental parathyroidectomy and parathyroid in specimen were still important factors (Fig. 2C, D).

Meta-analysis of potential risk factors
After meta-analysis of each potential risk factor, we identified 11 statistically significant risk factors associated with transient hypoPT and 10 risk factors related to permanent hypoPT (Fig. 3 and Figure S1A-E

Subgroup meta-analysis of potential risk factors
Due to the different time-definitions for transient and permanent hypoPT (12 and 6 months), we conducted subgroup analyses for all risk factors (Figs. 4, 5 and Figure S3-6, Supplemental Digital Content 5, http://links.lww.com/JS9/C442).For transient hypoPT with 6-month definition time, the previous analysis revealed that 10 significant risk factors, including sex (female vs. male), preoperative calcium, cN stage, CND, LND, extent of CND, surgery (TT vs. lobectomy), surgery (TT vs. sub-TT), incidental parathyroidectomy, and pathology (cancer vs. benign), maintained their statistical significance in the subgroup analyses (Fig. 4).For transient hypoPT with 12-month definition-time, only surgery (TT vs. lobectomy), surgery (TT vs. sub-TT), incidental parathyroidectomy and PA showed significant association with the outcomes.Surgery (TT vs. lobectomy), surgery (TT vs. sub-TT) and incidental parathyroidectomy were significant risk factors for transient hypoPT regardless of the timing of its definition.
However, there were some differences in the results of the subgroup analysis for permanent hypoPT compared to the previous analysis (Fig. 5).In the analysis of permanent hypoPT with a 6-month definition time, nine factors, namely sex (female vs. male), gross extrathyroidal extension, cN stage, CND, surgery (TT vs. sub-TT), incidental parathyroidectomy, pathology (cancer vs. benign), node metastasis, parathyroid in specimen.Two risk factors exhibited changes: LND and extent of CND (bilateral vs. unilateral) shifted to a negative result.In both the 6-month and 12-month subgroups, CND, incidental parathyroidectomy, pathology (cancer vs. benign), node metastasis were important risk factors for permanent hypoPT.Interestingly, in the analysis of permanent hypoPT with a 12-month definition time, sex (female vs. male) was no longer associated with permanent hypoPT, while PA emerged as a statistically significant risk factor for 12-month permanent hypoPT.

Discussion
HypoPT is a common complication following thyroid surgery, however, current research findings on the analysis of risk factors for post-thyroid surgery hypoPT are not entirely consistent [7][8][9][10][11] .Furthermore, the potential differential impact of the same risk factors on transient and permanent hypoPT requires further exploration and analysis.Despite some meta-analyses discussing hypoPT, there is still a lack of a comprehensive study to definitively identify preoperative risk factors for both transient and permanent hypoPT [15][16][17] .In this study, we reviewed and analyzed 93 studies addressing risk factors for transient and permanent hypoPT, identifying nine common risk factors for both transient and permanent hypoPT, two risk factors specific to Studies on hypoPT predominantly relies on the presence of abnormalities in postoperative PTH and serum calcium or the need for oral supplementation of vitamin D and calcium as the definition for hypoPT [8][9][10][11][12][13][14] . However,distinguishing between transient and permanent hypoPT in different studies varies regarding the timeframes, with some studies employing 6month and others using 12-month [8][9][10][11][12][13][14] .A meta-analysis suggested that the overall incidence of hypoPT did not significantly differ under different time definitions [15] .In our study, we harmonized and performed subgroup analysis for postoperative hypoPT defined at 6 months and 12 months.The definition of time to a certain extent influenced the analysis of risk factors for hypoPT. It altered se (female vs. male), CND, PA for transient hypoPT, and sex (female vs. male), surgery (TT vs. sub-TT), PA in permanent hypoPT.To reduce the disparities reported in various studies, there is still a need to establish uniform and widely applicable clinical criteria for postoperative hypoPT.
This large-sample meta-analysis revealed that female patients are higher risk to experience transient and permanent hypoPT after thyroid surgery compared to male patients.There are several explanations for the observed findings.Firstly, female patients often present with more severe thyroid conditions preoperatively, such as hyperthyroidism or thyromegaly [110,111] .This complexity in female patients undergoing thyroid surgery increases the likelihood of parathyroid injury compared to males.Secondly, sex differences in hormone and vitamin D levels can affect postoperative parathyroid function recovery.Estrogen, for example, influences parathyroid function and enhances calcium absorption in the intestines, helping to maintain stable blood calcium levels [112] .However, hormonal changes during menopause and emotional responses to disease and surgery may disrupt hormone balance, increasing the risk of postoperative hypoPT [113][114][115] .Additionally, females often exhibit stronger immune responses, which may affect postoperative inflammation and healing processes, thereby increasing the risk of hypoPT [116] .Clinically, female patients identified as having a higher risk of postoperative hypoPT should be considered for more intensive treatment and disease management.
Although the relationship between CND/LND and the development of permanent hypoPT remains controversial, it is significantly associated with transient hypoPT after surgery [13,117] .CND/LND aims to clear neck lymph nodes infiltrated by cancer cells and prevent cancer cell spread [118][119][120] .The degree of protection for the parathyroid glands during CND/LND largely depends on the surgeon's experience and skill [121] .Accidental damage, traction, or burning of the parathyroid glands during surgery can lead to postoperative hypoPT [3,122] .Our analysis suggests that surgical approach and the extent of lymph node dissection were the most significant influencing factors for postoperative hypoPT (both transient and permanent).The primary consideration for the surgical approach and CND/LND should be the management of tumor metastasis, with a focus on minimizing the occurrence of transient hypoPT during surgery.The primary cause of postoperative hypoPT is the damage or removal of parathyroid glands during thyroid surgery, and markers related to parathyroid status often exhibit a correlation with postoperative hypoPT [3] .Our analysis indicated that incidental parathyroidectomy was a high-risk factor for both transient and permanent hypoPT.PA is a remedial measure for inadvertent parathyroidectomy during thyroid surgery, and patients undergoing PA may experience transient hypoPT postoperatively, as the reestablishment of blood supply and recovery of parathyroid function require some time [123][124][125][126] .However, the restoration of PTH through PA is limited and may not fully return patients to the same level as those who did not experience incidental parathyroidectomy.Another challenging aspect to assess was parathyroid ischemia, as it may result in only mild or even normal gland discoloration [1] .Nevertheless, study by Promberger suggests that patients with discolored parathyroid glands may experience temporary functional impairment postoperatively [127] .In summary, it is essential to minimize incidental parathyroidectomy during surgery and assess parathyroid ischemia to reduce the incidence of postoperative hypoPT.
The application of novel technologies holds significant promise in reducing postoperative hypoPT.With advancements in medical technology, techniques such as image-guided surgery and microsurgical methods provide surgeons with clearer visualization and finer precision during operations, facilitating meticulous capsular dissection and the identification and preservation of parathyroid glands [128][129][130] .Utilizing appropriate intraoperative strategies for parathyroid identification and preservation is particularly beneficial for surgeons with less experience in the field.The use of carbon nanoparticles enhances the dissection of lymph nodes while safeguarding the parathyroid glands and their function [131] .Near-infrared autofluorescence has also been shown to decrease the risk of transient hypoPT, although its impact on persistent hypoPT requires further validation [132] .A meta-analysis revealed that autofluorescence, indocyanine green fluorescence, and carbon nanoparticles offer superior protection of intraoperative parathyroid glands compared to visual inspection alone [133] .
Several limitations should also be acknowledged in this metaanalysis.Firstly, because there is currently no universally accepted standard for defining postoperative hypoPT, different studies have varying definitions of hypoPT, which can indeed reduce the comparability and persuasiveness of research findings.Secondly, the included criteria were limited to English language studies, potentially leading to exclusion of non-English relevant data and publication bias.Thirdly, our conclusions were drawn based on univariate associations between risk factors and hypoPT rather than multivariable analysis that can account for interactive effects and confounding factors, mainly dure to the heterogeneity in data presentation and absence of consistent multivariable variables across studies.For instance, inconsistencies between PA and permanent hypoPT may stem from the inability to correct for incidental parathyroidectomy and surgical experience across different studies.Finally, based on a limited number of studies, we analyzed some potential risk factors.Some of these factors, such as surgeons' surgical experience and postoperative levels of PTH and Ca, may also be associated with hypoPT.However, due to not meeting inclusion criteria or lacking uniform meta-analysis quantitative indicators, they were not extensively discussed.Therefore, our meta-analysis results should be interpreted with caution.

Conclusion
In this study, we compiled and analyzed 93 studies on risk factors for postoperative hypoPT in thyroid surgery.To sum up, postoperative hypoPT is common in female thyroid cancer patients with lymph node metastasis undergoing TT combined with neck dissection.There are many common risk factors for transient and permanent hypoPT including sex, cN stage, CND, LND, surgery type, incidental parathyroidectomy, and pathology.These findings have important implications for clinical practitioners in thyroid surgery and parathyroid research.A deeper understanding of these risk factors holds promise for developing more effective treatment strategies and postoperative care plans, with the potential to reduce the occurrence of postoperative hypoPT and enhance patient quality of life and treatment outcomes.

Figure 1 .
Figure 1.PRISMA diagram showing screening and selection of studies for systematic review and meta-analysis.hypoPT, hypoparathyroidism.

Figure 3 .
Figure 3. Forest plots showing the meta-analysis results for each potential risk factor.This figure displays the combined results of meta-analysis for both transient and permanent hypoPT, with the specific inclusion details of each study shown in the supplementary figures.CND, central neck dissection; cN, clinical N; hypoPT, hypoparathyroidism; LND, lateral neck dissection; OR, odds ratio; PTH, parathyroid hormone; PGRIS, parathyroid glands remaining in situ; TT, total thyroidectomy.

Figure 4 .
Figure 4. Forest plots showing the subgroup meta-analysis results for each potential risk factor of transient hypoPT.This figure displays the results of subgroup meta-analysis for transient hypoPT with different definition time, and the specific inclusion details of each study were shown in the supplementary figures.cN, clinical N; CND, central neck dissection; hypoPT, hypoparathyroidism; LND, lateral neck dissection; OR, odds ratio; PTH, parathyroid hormone; PGRIS, parathyroid glands remaining in situ; TT, total thyroidectomy.

Figure 5 .
Figure 5. Forest plots showing the subgroup meta-analysis results for each potential risk factor of permanent hypoPT.This figure displays the results of subgroup meta-analysis for permanent hypoPT with different definition time, and the specific inclusion details of each study were shown in the supplementary figures.cN, clinical N; CND, central neck dissection; hypoPT, hypoparathyroidism; LND, lateral neck dissection; OR, odds ratio; PTH, parathyroid hormone; PGRIS, parathyroid glands remaining in situ; TT, total thyroidectomy.
The following research data were extracted from each eligible articles: first author name, publication year, study location, total sample size, number of male participants, average age, study design, number of transient or permanent hypoPT cases, definition of transient or permanent hypoPT, the number of

•
This is the first comprehensive meta-analysis describing the risk factors of hypoparathyroidism (hypoPT) after thyroid surgery.•The highest risk of hypoPT occurs in female thyroid cancer patients with lymph node metastasis undergoing total thyroidectomy combined with neck dissection.

Table 1
Characteristics of included studies.

Table 1 .
The number of participants in these studies ranged from 40 to 192 333, with the percentage of male participants ranging from 0 to 89.5%.The average age of patients varied from 30.7 to 57.0 years, and 30 articles did not mention the average age.In terms of study design, there were 65 retrospective cohort studies, 28 prospective cohort studies included in the analysis.Eighty-five studies reported perma-We systematically screened potential risk factors in each study according to inclusion criteria, ultimately identifying 19 factors for transient and permanent hypoPT (TableS2A-D, Supplemental Digital Content 4, http://links.lww.com/JS9/C441 and S3A-E, Supplemental Digital Content 4, http://links.lww.com/JS9/C441).Among these, sex and PA were the most frequently reported risk factors for both transient hypoPT and permanent hypoPT.More than half of the studies reported five risk factors were significantly associated with transient hypoPT in both univariate and multivariate analyses, which were sex (female vs. male), CND, surgery [total thyroidectomy A C D B Figure 2. Distribution and results of studies considered for systematic review and meta-analysis.(A) Distribution of results from univariable analysis in included studies for transient hypoPT.(B) Distribution of results from multivariate analysis in included studies for transient hypoPT.(C) Distribution of results from univariable analysis in included studies for permanent hypoPT.(D) Distribution of results from multivariate analysis in included studies for permanent hypoPT.cN, clinical N; CND, central neck dissection; LND, lateral neck dissection; PTH, parathyroid hormone; PGRIS, parathyroid glands remaining in situ; Transient hypoPT, Transient hypoparathyroidism; TT, total thyroidectomy; Permanent hypoPT, Permanent hypoparathyroidism.