1. Clinical manifestations and diagnosis of pregnant patients with PHPT
PHPT is characterized by elevated serum PTH concentration and hypercalcemia, with varying degrees of severity from asymptomatic to hypercalcemic crisis [9, 10]. Among pregnant patients with PHPT, 80% develop nausea, vomiting, frequent (nocturnal) urination, which are overlapped with normal physiological reactions during pregnancy, and would be easily overlooked, complicating or delaying the diagnosis of PHPT. Similar findings were also noticed in our series. The high percentage of anemia found in our series was due to either PHPT itself or physiological hemodilution during pregnancy.
The use of the albumin-adjusted serum calcium level[11, 12] is important in patients with low serum albumin levels, especially in pregnant women who may have a 10% decrease in the serum calcium level. However, in our series, all the women with PHPT still had an elevated serum calcium level (median: 3.08 mmol/L). In China, although the clinical and biochemical patterns of PHPT are becoming milder, it is still severer than in western countries[5, 6], this seems to be true also in pregnant women with PHPT.
Postoperative pathology showed one case (case 4)of parathyroid carcinoma with the serum calcium level 4.21 mmol/L and serum PTH 2603.6 pg/ml. Parathyroid carcinoma is a rare cause of PHPT accounting for less than 1% in Western PHPT patients and 6% in Chinese patients.However, in this series, parathyroid carcinoma accounted 11.1% (1/9), we are not sure whether such a high rate in pregnant women has any physiological and pathophysiological relationship with pregnancy. The clinical manifestations of parathyroid carcinoma are mainly moderate to severe hypercalcemia and symptoms of renal and skeletal involvement. Whether malignant tumor is considered at the time of initial diagnosis is critical for the patient's prognosis. Serum calcium and serum PTH levels in patients with parathyroid carcinoma are significantly higher than those in parathyroid adenoma. When serum calcium exceeds 12mg/ dL (3mmol/L), serum PTH levels exceed the normal upper limit of 3–10 times, it is necessary to be fully aware of the possibility of parathyroid carcinoma.The clinical symptoms of parathyroid carcinoma are usually more severe than those in parathyroid adenoma and often involve the kidneys and bones. If the patient has severe renal and skeletal complications, the possibility of malignancy should be considered.
The method to determine the location of parathyroid lesions in pregnancy with PHPT is different from that of ordinary PHPT; the commonly used 99mTc-MIBI and neck CT examinations are limited during pregnancy. The sensitivities of 99mTc-MIBI and color Doppler neck ultrasonography to localize parathyroid lesion(s) are 94.1% and 85.1%, respectively; if they are combined, the sensitivity will increase to 98.9% .
The use of 99mTc-MIBI in pregnant women remains controversial. A case report suggested that pregnancy is not a contraindication to 99mTc-MIBI examination due to the short half-life of the radionuclide, ensuring the safety of 99mTc-MIBI examination, especially when ultrasound cannot accurately localize the lesion during pregnancy. However, in another case series, the authors suggested avoiding the use of radioactive imaging modalities . In our series, 99mTc-MIBI was only used in patients before conception or with no intention to continue pregnancy or after labor, with 100% positive findings. An ectopic lesion was revealed by MIBI fortunately and coincidently in one case (case 1), which was not identified by ultrasound. However, due to the lack of solid clinical data, the use of 99mTc-MIBI in pregnant women with the intention to continue pregnancy should be cautious.
According to our results, neck ultrasonography can localize all the parathyroid lesions in the neck in 8 cases, except an ectopic one. The accuracy of the ultrasound positioning was further confirmed during the operation. From this experience of ours and other similar case reports, it could be recommended that neck ultrasound for pregnant patients with PHPT is the first choice and is effective for preoperative positioning and surgical guidance.
2. Treatment Of Pregnant Patients With Phpt
For pregnant patients with PHPT with asymptomatic mildly elevated serum calcium levels, or not accepting surgery, close observation without surgical intervention is feasible[19, 20]. The first-line medication is oral or intravenous rehydration with or without furosemide, which is safe and can avoid iatrogenic placental hypoperfusion or oligohydramnios caused by dehydration, and it will not increase the risk of obstetric complications such as abortion. However, there is still a need to closely monitor the serum calcium level and disease progression.
PHPT is usually caused by a single parathyroid tumor, and the most effective treatment is surgery. For pregnant women, surgery should be implemented in the second trimester (13 ~ 26 weeks of gestation) because, at this point, the fetal organs have completely developed and the spontaneous abortion rate is the lowest, effectively reducing the risk of maternal and fetal complications. A study of 77 cases of pregnant women revealed that even if the serum calcium is maintained at a median level of approximately 2.67 mmol/L, a 12% risk of fetal death still exists; if the serum calcium level is sustained at 2.70 ~ 2.75 mmol/L, the risk of fetal death will increase. It is suggested that PHPT patients with a history of miscarriage and a serum calcium level exceeding 2.75 mmol/L, even without obvious elevation or symptoms, should undergo surgery and should not wait until postpartum to avoid neonatal hypocalcemia and convulsion .
From our experience and others , parathyroidectomy conducted in the 2nd trimester, especially when guided by experienced MDT, is safe and effective. However, for patients with serious hypercalcemia, such as hypercalcemia crisis(case4)or an uncontrollable elevated serum calcium level ༈case9༉, timely surgery is still needed,even in the 1st trimester༈case9༉in our series.
In non-pregnant PHPT patients, the parathyroid lesion could be confirmed to be removed if the serum PTH level was decreased more than 50% and 60% at 5 and 15 min after the lesion resection. Intraoperative PTH was measured in our series in two cases (case 8 and case 9) showing a 65.53%~78.19% decrease in 10 min after parathyroidectomy.
The surgical therapy is also the most frequent option for the treatment of parathyroid carcinoma. Primary operation is crucial for an adequate local excision. The tumor should be removed in one block with ipsilateral thyroid gland lobectomy. During the operation, the surgeon should avoid the rupture of the capsule. It would be preferable to perform an ipsilateral thyroid gland lobectomy together with parathyroid tissue and neck block dissection.
It should be stressed that, PHPT can be diagnosed biochemically, not necessarily to be confirmed by localization imaging results. For those cases with inconsistent or negative imaging findings, if surgery is indicated, the patient should still be operated. For those with positive pre-operation localizaion, focused parathyroidectomy could be done, while for those with negative imaging result, bilateral cervical exploration (BCE) could be performed, which has a cure rate in excess of 95% in experienced hands[30, 31].
It is noteworthy that there was a case of PHPT in our series (case 2) diagnosed 4 years before pregnancy at our hospital. Surgery was recommended, although her serum calcium level was at the normal upper limit at that time. However, the patient refused the operation. During pregnancy, her serum calcium level increased to 2.95 mmol/L and she had to undergo surgery at 23+ 5 weeks of gestation, with a normal delivery at full term. However, her child was diagnosed with autism at the age of 4.
Because the child’s father had premature Parkinson’s disease, we are not sure whether a relationship exists between this child’s autism and his parents’ diseases.
However, based on our experience with this case, we believe that, for women at reproductive age, whenever the diagnosis of PHPT is made, surgery should be strongly suggested to the patients.
There are other methods to manage parathyroid lesions in pregnant women. Alcohol ablation could be considered in the case of ineffective drug therapy or when a pregnant woman cannot tolerate surgery[32, 33]. This method was not attempted in our series.
3. Timing and method of pregnancy termination of patients with PHPT during pregnancy
Presently, no consensus exists on the timing and delivery method of pregnancy termination in patients with PHPT. Vaginal delivery can be performed under close supervision, but obstetric factors should be considered first. After the diagnosis of pregnancy with PHPT, we fully communicated with the patients and their families during the 2nd trimester and reached a consensus on pregnancy intention (labor induction or continued pregnancy), parathyroid surgery treatment and surgery timing. One patient was fertile and had concerns about the safety of the fetus after parathyroid surgery and requested the termination of pregnancy. There were eight cases of full-term pregnancy, among which three were delivered naturally under close monitoring and four were terminated by cesarean section under lumbar anesthesia at approximately 39 weeks of gestation due to obstetric factors.
4. Screening and perinatal production inspection patterns for pregnant patients with PHPT
Pregnancy with PHPT can lead to severe maternal and infant complications, especially the development of hypercalcemia crisis, which can lead to perinatal maternal death. With our previous experience in PHPT diagnosis and treatment [5–7], we suggest that serum electrolytes should be checked during prepregnancy examination for fertile women. If the serum calcium level is higher than 2.43 mmol/L, serum PTH testing and other tests should be performed for PHPT screening. If any abnormality occurs, an endocrinologist should be consulted as soon as possible.
We have developed an obstetrical screening program for pregnant women. In early pregnancy (< 12 weeks), the serum electrolyte levels are checked at the hospital during the initial diagnosis. If abnormalities in serum calcium occur, serum PTH testing and other tests are performed for PHPT screening. For suspected cases, MDT consultation is made in time to develop a treatment plan. For patients with PHPT during pregnancy, postoperative monitoring of parathyroid function should be strengthened. In addition to routine parameters, serum calcium and PTH concentrations should be checked every 2 weeks and postoperative medication should be adjusted to avoid hypocalcemia. The obstetric MDT process for patients with PHPT is illustrated in Fig. 2.
There are several limitations in this study. Due to the rareness of PHPT in pregnancy, the sample size in this study is small. Some follow-up data regarding patients and their children’s serum calcium levels were obtained through phone interviews. Intraoperative PTH was not routinely measured in all of our patients. PTH monitoring during surgery is helpful to determine the success of the operation, especially for cases with negative preoperative localization or multiple adenomas. We did not test for the MEN-1 gene routinely as in other reports[12, 34]. The test was performed in only one case with a family history in our series, and the result was negative.