Comparison Between Surgical and Non-Surgical Management of Primary Hyperparathyroidism During Pregnancy: A Systematic Review

Purpose Primary hyperparathyroidism during pregnancy is an uncommon condition that may have consequences for either the mother, newborn, or both. Treatment options can be surgical or conservative. This study aimed to compare adverse outcomes associated with surgical versus non-surgical treatment to determine the favorable management option. Additionally, the study investigated the correlation between serum calcium values and complication rates. Methods A systematic review of retrospective studies, case series, and case reports. Biochemical parameters, interventions, and outcomes of each pregnancy were recorded. The study population comprised two groups: the non-surgical and surgical groups. Adverse outcomes were categorized as maternal, obstetric, or neonatal. Statistical analysis was conducted to compare outcomes between the study groups.


Introduction
Primary hyperparathyroidism (PHPT) is a relatively common endocrine disorder, as it is the most common cause of hypercalcemia in the non-pregnant population [1].However, it is a relatively rare condition to encounter, with an estimated rate of 7.7 to 50 cases per 100,000 women of reproductive age [2,3].
Pregnancy is characterized by physiological changes in calcium metabolism which must be considered: calcium absorption increases twofold by third trimester, driven by vitamin D and parathyroid hormonerelated protein (PTHrP).The latter is synthesized during pregnancy from the amnion, as well as breasts to lesser extent, and other reproductive tissues [4].PTHrP acts similarly to parathyroid hormone (PTH) by binding to parathyroid hormone 1 receptor (PTH1R), promoting epithelial growth and tissue differentiation in the fetus.Additionally, it acts as the primary stimulus to the active placental calcium pump [4].Total serum calcium values decrease during pregnancy due to the increased intravascular volume, calcium placental e ux, and increased urinary output.Finally, ionized calcium levels remain unchanged, and PTH falls to the low-normal range [5][6][7].
The etiology of gestational PHPT is most often a parathyroid adenoma, which secretes parathyroid hormone, and less commonly parathyroid hyperplasia (5-10%) or parathyroid carcinoma (< 1%) [8,9].PHPT may also occur as part of an inherited syndrome, and genetic counseling has been recommended for patients younger than 40 carrying the disease [10,11].
PHPT may be managed conservatively or surgically.Conservative treatment may include hydration alone in mild to moderate patients or pharmacological therapy in cases of refractory hypercalcemia [15,27].
The de nitive treatment for this condition is parathyroidectomy, which can be performed via cervical exploration or minimally invasive parathyroidectomy (MIP).[9,28] Reports of successful ablation of the gland are also available [29][30][31].
Data regarding pregnancy complication rates from gestational PHPT are variable.Norman et al. reported a signi cant difference in pregnancy loss in gestational PHPT [23], and citations across the literature claim complications of PHPT during pregnancy may reach as high as 67% of mothers and 80% of offspring [18,19,32].However, more recent large cohorts have reported no increased risk of obstetric complications [13,33].Published reviews recommended that normocalcemic patients or those with mild hypocalcemia (less than 1 mg/dL above the normal limits) be managed conservatively [10,15,28,34].Sandler et al. in their research concluded parathyroidectomy should be considered regardless of symptoms [35].Similarly, surgical safety is controversial.While some studies conclude that surgery during pregnancy causes more adverse events than surgery on non-pregnant patients [36,37], others conclude that the risks of non-abdominal surgery are minimal, hence surgery should not be delayed when necessary [38][39][40].
With the aim to shed light on the complication rates and guide management of choice in PHPT during pregnancy, this study has utilized all the relevant published data available, classi ed all complications attributable to gestational PHPT as maternal, obstetric, or neonatal complications, and consequently compared surgical with conservative managements and their outcomes.

Study Design
A literature search on PubMed, ScienceDirect (Elsevier) and Google Scholar was performed using the terms: 'pregnancy' or 'gestation', 'hyperparathyroidism', 'PHPT' and 'parathyroidectomy'.Database included published studies between 1980 and 2023.The study population comprised of women who experienced primary hyperparathyroidism (PHPT) during pregnancy and either underwent parathyroidectomy during pregnancy (surgical group) or were managed conservatively (non-surgical group).Recorded data included the patient's age, biochemical values, obstetric and medical history, time of diagnosis, presenting symptoms, management, and complications, which were subsequently classi ed as maternal, obstetric, or neonatal.We excluded reports involving signi cant comorbidities, such as metastatic non-parathyroid cancer or any condition unrelated to PHPT severe enough to require management in the intensive care unit (ICU) during pregnancy, reports with missing data, and patients treated with alternative management not addressed in this article's scope.We excluded cases with calcium values exceeding 15 mg/dl as these were deemed rare and complex, leading to higher complication rates and outcome bias.Additionally, we excluded records involving ectopic parathyroid adenomas, parathyroid carcinomas, and patients positive for multiple endocrine neoplasia type 1 (MEN1) as these rare cases were correlated with more extended hospital stay, alternative managements, and complicated outcomes.

Data Collection
The initial search yielded 777 articles, manually ltered to identify 259 relevant articles for screening.
Following the screening process for duplications and exclusion criteria,168 publications were selected, comprising 348 cases for data analysis (as depicted in the PRISMA ow diagram in Fig. 1).Each pregnancy was analyzed as a single case.Maternal, obstetric, and neonatal complications were considered as adverse outcomes that occurred solely during pregnancy or shortly after delivery.Reference ranges for calcium and PTH were de ned as 9.5-10.5 mg/dL and 10-65 pg/mL, respectively.Calcium values utilized for analysis represented the average of total serum calcium values measured during pregnancy, as ionized calcium was not consistently reported in a signi cant number of articles.In cases where albumin levels were provided or corrected calcium values were available, the corrected values were utilized for analysis.

Statistical Analysis
Analysis was performed by the Beer-Sheva Faculty of Health Sciences in Israel.Demographic data is expressed as either raw values or medians and interquartile ranges (IQR) when data did not follow a normal distribution.Statistical signi cance was assumed as p < 0.05.Differences in complication rates were calculated using t test was for quantitative data, and chi-square test for categorical data.Correlation between calcium rates and complication rates was calculated using Pearson's correlation.

Results
Out of the 348 cases analyzed, 163 (47%) underwent parathyroidectomy (the surgical group), while 185 (53%) were managed conservatively (the non-surgical group).The mean ages were 31 ± 3 and 31.5 ± 3.5 years, respectively.Average total calcium levels for the surgical group were higher, with a median of 12.3 mg/dL (range:11.5-13.3),compared to 11.1 mg/dL (range: 10.7-11.6) in the non-surgical group.Median PTH levels were 137 pg/mL (range: 94-237) and 123 pg/mL (range:71-224) for the respective groups.61% of the surgical group underwent surgery during the second trimester, 25% during the third trimester, and 7% during the rst trimester.(see Table 1) The etiology of PHPT, when described in the studies, was a solitary adenoma in 125 patients, and hyperplasia in 14 patients.11 cases were excluded due to diagnosis of parathyroid carcinoma.Genetic testing for endocrinologic hereditary syndromes was performed in 49 cases (14%) of the study population.Results were positive for MEN1 in 13 cases, which were subsequently excluded from the study population.
The maternal outcomes for the entire study population revealed that 42% were asymptomatic.however, 102 cases did not describe either symptoms or lack thereof.Gastrointestinal symptoms were the most prevalent in our population, accounting for 37.4%, followed by abnormal lethargy or fatigue at 12.6%, and renal symptoms at 8.5% (Table 2 presents the complete summary).
When treated pharmacologically, most patients received IV uids.17 patients described an addition of furosemide, 5 of which reported a success in reducing calcium levels.An additional 17 patients received calcitonin, with positive results mentioned in 5 patients.A single patient suffered from adverse reaction to the drug.Similarly, cinacalcet was prescribed to 11 patients, with positive results in one patient, and adverse reactions in one patient.
Maternal, obstetric, and neonatal complication rates comparing the study arms are presented in Table 3 with the following results: Maternal complications occurred in 19.5% of the entire study population.No signi cant differences in maternal complication rates were observed between the study arms.The overall obstetric complications were not signi cantly different between study groups as well, however, subcategory analysis revealed higher rates of preeclampsia/eclampsia and preterm labor in the nonsurgical group, and higher rates of hyperemesis gravidarum in the surgical group.Rates of pregnancy loss were higher in the non-surgical group, with 15.3% compared to 1.3% in the surgical group.From a total of 22 cases of pregnancy loss, 10 cases described 1st trimester miscarriage, and the rest did not specify further details.Numbers of neonatal complications were signi cantly higher in the non-surgical group compared to the surgical group.This difference was evident in transient neonatal hypocalcemia (24.4% vs. 2.7%), hypocalcemic tetany (10.7% vs. none), hypocalcemic convulsions (6.9% vs. none), and ICU admissions (9.9% vs. 3.3%), but not neonatal demise.A statistically signi cant positive correlation was observed between serum calcium values and both maternal and obstetric complication rates (p < 0.05), but not neonatal complications.Nevertheless, complication rates in the non-surgical group were signi cantly higher across all calcium levels compared with the surgical group (with p < 0.001, as illustrated in Fig. 2).
Figure 1 PRISMA owchart indicating the process for identi cation and selection of the included studies

Discussion
In the present study, 42% of the population was asymptomatic.Consistent with other publications [41][42][43], gastrointestinal symptoms were predominant, followed by generalized fatigue or lethargy.It is noteworthy that nausea and vomiting are known to affect up to 80% of pregnancies, peaking between 10 to 16 weeks and typically resolving after 20 weeks [44,45].Similarly, a decrease in energy is widely reported during pregnancy [46].These illustrate the diagnostic challenge, which requires a high index of suspicion when encountering "hints" such as hyperemesis gravidarum (de ned as intractable vomiting leading to weight loss and volume depletion [47]) or evidence of renal calcium deposition, which accounted for 6.6% and 11.8% of our study population, respectively [18].
Maternal complications affected 19.5% of the study population in the current study, with no signi cant difference in complication rates between the surgical and non-surgical groups.Interestingly, maternal complications in the surgical group were not elevated despite the higher mean serum calcium levels.The halt in complication rates could potentially be attributable to parathyroidectomy.Schnatz et al. hypothesized that adverse outcomes could stem from underlying long-term untreated disease rather than from surgery itself [14,25].The risk of surgery has been reported to be minimal [39,[48][49][50], with curative results in 95-98% of cases [9,28,51,52].In the present study, the operation was curative in 98% of cases, with postoperative complications occurring in 4.9%.Speci cally, three patients experienced hungry bone syndrome, three suffered from hypocalcemic tetany, one patient had permanent hypoparathyroidism, and one patient experienced transient vocal cord palsy.
Obstetric complications resulted in signi cant differences on a few parameters, namely, preterm delivery, preeclampsia, and pregnancy loss, which occurred at higher rates in the non-surgical group.Additionally, hyperemesis gravidarum occurred at higher rates in the surgical group, most likely due to the early diagnosis of their symptomatic disease and subsequent selection for surgical intervention.Analysis of the data presented in this article suggests that the increase in pregnancy loss arises from losses that occurred in the rst trimester and early second trimester before potential surgical intervention.
Consequently, these instances were categorized under the non-surgical group.The pregnancy loss rate for the entire study population was 7.8%, lower than the documented 15% rate for women in the general population aged 30-34 [53,54].Overall, the current study ndings suggest that parathyroidectomy did not signi cantly alter the overall rates of obstetric complications when compared to non-surgical management, aligning with the conclusions reported previously by Hirsch et al. [33] and Abood and Vestergaard [13], however it may potentially be associated to a reduced risk of preterm delivery and preeclampsia.
Neonatal adverse outcomes were signi cantly more prevalent in the non-surgical group than in the surgical group.The signi cant difference was evident across all maternal mean calcium values.These results are supported by previously reported data by Sandler et al. that revealed that even in asymptomatic PHPT, infant complications were less prevalent in the surgical group [35].These results imply that surgical intervention may yield more favorable neonatal outcomes, regardless of maternal calcium values.The variation in adverse outcomes between the groups primarily consisted of transient postpartum hypocalcemia, hypocalcemic tetany, convulsions, and subsequently, a higher number of ICU admissions.The latter, along with preterm delivery, has previously been reported to be independently linked to hypercalcemia [55] and vitamin D de ciency [56].In some cases, neonatal tetany or convulsions may be the rst signs of asymptomatic gestational PHPT [57][58][59][60][61][62][63].Neonatal hypocalcemia can be severe and prolonged, necessitating long-term calcium supplementation [57].Although a signi cant correlation was observed between calcium values and maternal and obstetric adverse outcomes, no correlation was seen between neonatal complications and mean maternal gestational calcium values, indicating that neonatal adverse outcomes result from more complex interactions than calcium values alone.Neonatal hypocalcemia is attributed to the suppression of parathyroid glands in utero.After birth, the neonate transitions from relying on placental calcium transfer to depending on kidney reabsorption and intestinal absorption.Initially, this process is facilitated by lactose, but it later shifts to an active PTH and calcitrioldependent mechanism [4].However, the suppressed parathyroid glands cannot meet the increased demand, leading to hypocalcemia within the rst days to weeks after delivery.Most calcium reaches the fetus during the third trimester of pregnancy.It is actively transported through the placenta, primarily regulated by PTHrP [64].Notably, PTH itself does not cross the placenta, and it remains uncertain whether the hormone affects the transfer of calcium through the placenta based on animal models [4].In this study, most patients in the surgical group underwent parathyroidectomy during the second trimester, indicating their mean gestational calcium during the third trimester remained within normal values.This observation could potentially account for the reduced risk of postpartum neonatal hypocalcemia and its sequelae in the surgical group.However, due to data unavailability and the retrospective nature of the present manuscript, it was impossible to analyze the relationship between postoperative third-trimester gestational calcium and neonatal complications.Future prospective studies may investigate whether reduced third-trimester calcium values correlate with lower rates of neonatal complications, preferably utilizing ionized calcium, as this marker is more reliable during pregnancy.
Overall, our ndings support the preference for parathyroidectomy over conservative management, even in cases of mild hypercalcemia, due to superior neonatal outcomes alongside non-inferior maternal and obstetric outcomes.This conclusion aligns with several previously published studies [14,35,48,65].
Operation during the second trimester is generally preferable [15,17,22,38,48,49,65,66], although successful operations in the third trimester have been reported on many occasions [11,25,[67][68][69][70][71][72][73].Individuals should maintain adequate vitamin D levels of at least 20 ng/mL [8,74].It should also be considered that conservative management primarily involves oral or IV rehydration and long-term close monitoring.Surgery is recommended postpartum, as it is advised for all individuals under the age of 50 [75].Newborns born to mothers with known PHPT during gestation should be monitored for hypocalcemia for at least two weeks postpartum [56,57].

Conclusions
The present study identi ed a positive correlation between maternal and obstetric outcomes and mean maternal gestational calcium levels, which is consistent with previously published data.Interestingly, adverse neonatal outcomes were signi cantly lower in the surgical group than in the non-surgical group.This difference was evident across all mean maternal gestational calcium values, suggesting that surgical intervention may be associated with superior neonatal outcomes, regardless of maternal calcium values.Maternal and overall obstetric complication rates did not signi cantly differ between the study groups.Based on the overall data presented in this study, it is suggested that parathyroidectomy is favorable over conservative treatment, even in cases of mild primary hyperparathyroidism.

Table 1
Demographic data of the study population

Table 3
Comparison of the maternal, obstetric, and neonatal outcomes between the operated and non-surgical groups.

Table 4
Maternal, obstetric, and neonatal complications in the entire study population, classi ed according to mean maternal gestational calcium values