Changes And Mechanisms Of Calcium Homeostasis During Pregnancy In Patients With Hypoparathyroidism And Pseudohypoparathyroidis

Part 1.Changes in calcium homeostasis of patients with hypoparathyroidism during pregnancy and lactation periodsBackgroundHypoparathyroidism(HP)is a rare endocrine disorder caused by insufficient synthesis or secretion of parathyroid hormone(PTH).The conventional treatment strategy includes the use of activated vitamin D analogs(or large doses of plain vitamin D)combined with calcium supplements.And the treatment goal is to relieve hypocalcemia-related symptoms.Pregnancy and lactation are two periods in which the levels of many maternal calciotropic hormones change to meet the added calcium demand of fetus and neonate.Since the rarity of HP with pregnancy,studies on the changes in calcium homeostasis of HP patients during pregnancy and lactation are quite limited and with inconsistent conclusion,most of which are case reports.More clinical data are needed.ObjectiveThis study retrospectively analyzed the clinical data of calcium homeostasis during pregnancy and lactation in HP patients collected in out center:1.To explore the change of calcium homeostasis during pregnancy and lactation periods and its influence factor;2.To provide evidence for rational monitoring and management of HP during pregnancy and lactation.Subjects and MethodsHP patients who were diagnosed and followed up at Endocrinology Department of our center and pregnant during January 2003 to February 2023 were enrolled.All patients were classified into different causes according to medical history,laboratory test,and targeted next-generation sequencing combined with multiplex ligation-dependent probe amplification.Data on baseline characteristics,biochemical indices and treatment strategies during pre-pregnancy,pregnancy and lactation periods,and pregnancy outcomes were collected through cases review and telephone follow-up.According to changes in serum calcium and drug adjustment during pregnancy,patients were divided into improved,worsened,stable and unsure group.Clinical characteristics,biochemical indices and pregnancy outcomes were compared among the first three groups.Change of calcium homeostasis during lactation period was also analyzed and was compared with pregnancy period.ResultsA total of 26 HP patients with 34 pregnancies(8 patients developing twice pregnancies)were enrolled.73.1%(19/26)were nonsurgical HP patients and one of them was autosomal dominant hypocalcemia type 1.The mean onset age,diagnosed age,and pregnant ages were 21.4±8.6,24.6±7.0 and 29.4±5.5 years,respectively.80.6%(25/31)got targeted serum calcium level before pregnancy.During pregnancy,71.9%(23/32)developed hypercalciuria while 5.9%(2/34)developed symptomatic nephrolithiasis.Preterm delivery and miscarriage occurred in 25.0%(7/28)pregnancies and cesarean section occurred in 87.0%(20/23)pregnancies.Neonatal average birth weight was 3226±332g(N=21)and one of them developed hypocalcemia.During pregnancy,14.7%(5/34)were classified into improved group,14.7%(5/34)into worsened group,17.6%(6/34)into stable group according to serum calcium and drug dosage changes.Others were classified into unsure group due to variable reasons.Compared to stable group,the onset ages of patients in improved and worsened group were younger(17.0±1.87 vs 18.8±6.42 vs 27.0±6.0 years,P=0.016);the serum calcium levels at diagnosed time were lower(1.52±0.29 vs 1.51 ±0.29 vs 2.01 ±0.11mmol/L,P=0.006);and the serum phosphate levels at diagnosed time were higher(2.53±0.32 vs 2.31±0.08 vs 1.72±0.36mmol/L,P=0.006).The nonsurgical HP ratio was higher in improved group than stable group(5/5 vs 1/6,P=0.001).Before pregnancy,patients in improved group had lower serum calcium and higher serum phosphate level than worsened and stable group(serum calcium:1.73±0.23 vs 2.24±0.16 vs 2.21 ±0.11,P=0.001;serum phosphate:2.07±0.43 vs 1.51 ±0.16 vs 1.56±0.21,P=0.022).The active vitamin D dosage was higher in improved group than stable group both before pregnancy and during the first trimester(pre-pregnancy:0.80±0.33 vs 0.38±0.13;first trimester:0.75±0.25 vs 0.38±0.13;P<0.05).The pregnancy outcomes showed no significant difference among the three groups.During lactation,data on 13 patients with 17 lactation periods were available.The serum calcium levels were higher in lactation than in the third trimester(1.98±0.12 vs 2.60±0.27mmol/L,P<0.001)and 35.3%(6/17)suffered hypercalcemia(serum calcium>2.7mmol/L)within the first 2 month of lactation(40-59d).The urinary calcium excretion also increased in lactation period compared to the third trimester(8.38±2.47 vs 11.83±5.82mmol/24h,n=13,P=0.03)and 76.9%(10/13)suffered hypercalciuria(24hUCa>7.5mmol).82.4%(14/17)of the patients reduced drug dosage significantly.The mean reduced dosage of elemental calcium was 314.3mg/d(1168.0±312.3 vs 853.6±288.5mg/d,P=0.001)while active vitamin D was 0.49μg/d(0.72±0.53 vs 0.23±0.18μg/d,n=11,P=0.006).Conclusion1.The change of calcium homeostasis in HP patients during pregnancy is inconsistent,which might be related to the disease onset age,disease causes,disease severity,and disease condition before pregnancy.HP patients who plan to be pregnant or are in pregnancy should be monitored closely to avoid hypercalcemia or hypocalcemia.2.It is common for HP patients occurring hypercalciuria during pregnancy.And the risk of symptomatic nephrolithiasis increases during pregnancy.24 hour urinary calcium excretion should be monitored and controlled as much as possible to avoid kidney complications.3.The risk of adverse pregnancy outcome increases in HP patients compared to general population and is higher in nonsurgical patients.Besides calcium homeostasis,some other risk factors should be found to improve pregnancy outcome.4.Serum calcium level increases obviously during lactation in most HP patients,especially within the first two month.Some patients even suffer hypercalcemia.After delivery,serum calcium should be monitored closely to reduce drug dosage in time and avoid hypercalcemia.Part 2.Changes in calcium homeostasis of patients with pseudohypoparathyroidism during pregnancyBackgroundPseudohypoparathyroidism(PHP)is a rare endocrine disease characterized by resistance to the action of parathyroid hormone(PTH).Patients show some similar symptoms and biochemical features with HP patients,except for the high serum PTH level.At present,treatment strategies for PHP patients include calcium and active vitamin D(or larger doses of plain vitamin D)supplement to maintain normal serum calcium and phosphate level and reduce serum PTH level to a reasonable range.The study about PHP patients with pregnancy is more rare.A small number of case reports abroad showed inconsistent change of calcium homeostasis in PHP patients during pregnancy.There is no relevant domestic research reported so far.Objective1.To evaluate the change of calcium homeostasis in PHP patients during pregnancy and the possible influence factors;2.To provide evidence for rational monitoring and management of PHP during pregnancy.Subjects and MethodsPHP patients who were diagnosed and followed-up at Endocrinology Department of our center and pregnant during January 2010 to February 2023 were enrolled.Sanger sequencing of GNAS gene combined with methylation specific-multiple ligation-dependent probe amplification were used to classify subjects into different type.Data on baseline characteristics,biochemical indices and treatment strategies during pre-pregnancy and pregnancy periods,and pregnancy outcomes were collected through cases review and telephone follow-up.Changes of calcium homeostasis during pregnancy were analyzed and compared with HP patients reported in the first part.ResultsDate on 7 patients with 8 pregnancies(1 patients experienced twice pregnancies)were enrolled.One patient was PHP 1a,4 were sporadic PHP 1b,1 was autosomal dominant PHP1b,and one with unknown type due to the lack of molecular analysis.The mean onset age,diagnosed age and pregnant age were 13.9±9.4,21.4±7.1,26.6±3.1 years,respectively.Except for 2 patients who did not visit our department before pregnancy,all patients showed normal serum calcium level pre-pregnancy.Most patients showed normal pregnancy outcomes(6/7)and the average neonatal birth weight was 3407±635g.All neonates had normal serum calcium level.According to the serum calcium and drug dosage changes in pregnancy,3 pregnancies were classified into worsened group,1 into improved group,2 into stable group and 2 into unsure group.Serum PTH level in the first trimester significantly decreased compared to pre-pregnancy,and was still at low level in the second and third trimester in stable and improved group,but increased in worsened group.Compared to HP patients,PHP patients showed younger onset age(21.4±8.6 vs 13.9±9.4 years,P=0.051),higher serum calcium level and lower serum phosphate level before pregnancy[sCa:2.09±0.23 vs 2.30±0.14mmol/L,P=0.049;sP:1.65(1.47,1.76)vs 1.40±0.24mmol/L,P=0.032],higher normal serum calcium proportion during pregnancy(0/33 vs 4/8,P<0.001)and lower 24h urinary calcium excretion(9.52±3.34 vs 6.67±2.90mmol/24h,P=0.049).No patient suffered symptomatic nephrolithiasis.Pregnancy outcome showed no significant difference between PHP and HP patients.Conclusion1.The change of calcium homeostasis in PHP patients during pregnancy is variable and related to the change of serum PTH level.The elevation of serum PTH in the second and third trimester might be related to the worsened condition,and the drug dosage might need increase.Serum PTH should be monitored in PHP patients during pregnancy,which might be helpful to guide drug dosage adjustment and maintain normal calcium homeostasis.2.Compared to HP patients,PHP patients have higher proportion of normal serum calcium level and lower urinary calcium excretion during pregnancy.No symptomatic nephrolithiasis is reported.Pregnancy outcome shows no significant difference between the two group,which might be related to the small sample size.PTH might have some effects on maintaining calcium homeostasis in PHP patients during pregnancy.Part 3.Changes in calciotropic and phosphotropic hormones and serum RANKL/OPG、SOST levels in normal pregnant women:an exploratory researchBackgroundNormal calcium and phosphate homeostasis during pregnancy is important for maternal and fetal health.Understanding the physiological change of calcium and phosphate metabolism during pregnancy is fundamental to the analysis of pathophysiological changes in disease conditions.Previous studies have showed that the serum 1,25(OH)2D and PTH related peptide increase progressively during pregnancy while serum PTH is suppressed to low level or increases in the third trimester.Then the intestinal calcium and phosphate absorption increases to meet maternal and fetal demands.In addition,previous studies show increased bone turnover rate during pregnancy,especially in the third trimester,which might be used as a reserve way to guarantee fetal calcium and phosphate supply.However,studies about the changes of fibroblast growth factor-23(FGF23,a major phosphotropic hormone)and other factors such as RANKL,OPG,SOST,which play important role on bone remodeling,during pregnancy are limited.And the conclusions are inconsistent.Also,data on Chinese population is absent.ObjectiveThe study aims to analyze the changes of some calciotropic and phosphotropic hormones and serum RANKL,OPG,SOST level during pregnancy in normal pregnant women who followed up in our center to provide physiological baseline data.Subjects and MethodsThe subjects came from a clinical cohort study conducted by the Nutrition Department of our center.Basic information was collected through questionnaire.Pregnancy related information was collected through the medical records when subjects followed up at the Nutrition Department and Obstetrics Department during pregnancy.Fasting blood samples were collected in three trimesters.Serum 1,25(OH)2D level was tested by mass spectrometry method while serum RANKL,OPG,SOST and FGF23 levels were tested using ELISA method.ResultsA total of 100 subjects were enrolled and 98 finished the study.The average pregnant age was 33.6±4.0 years.88.8%of the subjects were full term delivery while 6.1%were preterm delivery and 5.1%were miscarriage or suffered induced labor.The average birth weight of 95 neonates was 3245±457g.Seven neonates showed low birth weight(5 were preterm delivery neonates,2 were gemellary pregnant neonates)while three neonates were macrosomia.71.1%of the subjects suffered vitamin D deficiency in the first trimester.Serum albumin decreased progressively during pregnancy and was lowest in the third trimester.Serum total calcium level changed similarly while albumin adjusted serum calcium did not decrease.Serum phosphate level was stable and ALP level increased during pregnancy.Serum 1,25(OH)2D level increased progressively and was highest in the third trimester[77.3(62.4,91.4)vs 103.0(83.2,123.5)vs 123.5(99.7,140.3)pg/ml;P<0.01].Serum cFGF23 showed no significant difference during three trimesters[10.462(9.317,12.576)vs 10.928(9.668,12.201)vs 10.386(8.829,13.380)pg/ml].Serum RANKL、OPG、SOST level were tested in all three trimesters in 22 women.Serum RANKL and RANKL/OPG level decreased while OPG level was stable during pregnancy.Serum RANKL in three trimesters were 1.731(1.551,2.971),1.310(1.123,1.527),and 0.985(0.820,1.272)ng/ml,respectively(P<0.001).RANKL/OPG were 5.91(4.26,8.30),3.78(2.57,5.86),2.90(2.05,4.03),respectively(P<0.001).Serum SOST increased progressively and were 0.200(0.188,0.255),0.247(0.196,0.300),0.285(0.230,0.382)ng/ml in three trimesters,respectively(P<0.001).Conclusion1.Serum total calcium decreases during pregnancy due to the dilutional decrease of serum albumin.It is accurate to detect albumin adjusted serum calcium or ionized calcium level to evaluate maternal calcium level during pregnancy.2.Seram phosphate and cFGF23 show no significant change during pregnancy,which supports the stable condition of phosphate metabolism during pregnancy.3.Serum RANKL decreases while SOST increases with the increase of gestational age,which might be related to the net effect of bone resorption(bone resorption overweight bone formation)in the third trimester.Serum OPG is stable during pregnancy.