第一部分 甲状旁腺功能减退症患者妊娠哺乳期钙稳态变化

背景

甲状旁腺功能减退症（hypoparathyroidism, HP，甲旁减）是因甲状旁腺素合成或分泌不足引起的一组罕见的钙磷代谢紊乱性疾病，其常规治疗方案是钙剂联合维生素D制剂，以缓解低钙血症相关症状。妊娠哺乳期是人体钙稳态变化较大的时期，在此期间，母体内多种钙调节激素水平会发生一系列变化以满足胎儿及新生儿钙需求。由于甲旁减合并妊娠罕见，目前关于甲旁减患者妊娠哺乳期钙稳态变化的研究较少且结论不一，多为个例报告，需要更多的临床研究数据。

目的

通过回顾性分析本中心收集的甲旁减患者妊娠哺乳期钙稳态变化相关数据，探讨其妊娠哺乳期钙稳态变化趋势及影响因素，为此类患者妊娠哺乳期合理监测及治疗提供依据。

对象和方法

纳入2003年1月至2023年2月于北京协和医院内分泌科确诊并随访的甲旁减合并妊娠患者，依据病史、实验室检查及靶向目标序列的二代测序联合多重连接探针扩增技术进行病因分类。通过病历复习及电话随访回顾性收集患者甲旁减相关基线数据、妊娠前及妊娠期甲旁减诊疗及妊娠结局相关数据、哺乳期诊疗数据。根据患者妊娠期血钙变化及用药调整将患者分为病情改善组、加重组、稳定组及不确定组，比较前三组患者临床、生化特征及妊娠结局，分析影响患者妊娠期不同钙稳态变化的因素及其对妊娠结局的影响。根据患者哺乳期血、尿钙水平变化及用药调整，分析甲旁减患者哺乳期钙稳态变化及与妊娠期的异同。

结果

共纳入26例甲旁减患者的34次妊娠数据（8例患者经历2次妊娠），73.1%（19/26）为非术后甲旁减，其中1例为ADH1型。平均起病年龄21.4±8.6岁，诊断年龄24.6±7.0岁，妊娠年龄29.4±5.5岁，80.6%（25/31）的患者孕前血钙水平达标。妊娠期间71.9%（23/32）发生高钙尿症，5.9%（2/34）发生症状性肾结石。不良妊娠结局发生率25.0%（7/28），剖宫产比例87.0%（20/23），21名新生儿平均出生体重3226±332g，其中1名（1/7）有低钙血症。

4例患者的5次妊娠期间甲旁减病情改善（14.7%，5/34），归入改善组，5例患者的5次妊娠归入病情加重组（14.7%，5/34），6例患者的6次妊娠归入病情稳定组（17.6%，6/34），余18次妊娠因各种原因无法判断病情转归，归入不确定组。基线特征方面，改善组及加重组患者的起病年龄均较稳定组偏小（17.0±1.87 vs 18.8±6.42 vs 27.0±6.0岁，P=0.016），首诊时血钙水平偏低（1.52±0.29 vs 1.51±0.29 vs 2.01±0.11mmol/L，P=0.006），血磷水平偏高（2.53±0.32 vs 2.31±0.08 vs 1.72±0.36mmol/L，P=0.006），改善组患者中非术后甲旁减比例较稳定组高（5/5 vs 1/6，P=0.001）。孕前病情方面，改善组患者较加重组及稳定组孕前血钙水平偏低（1.73±0.23 vs 2.24±0.16 vs 2.21±0.11，P=0.001），血磷水平偏高（2.07±0.43 vs 1.51±0.16 vs 1.56±0.21，P=0.022）。治疗方面，改善组孕前及孕早期活性维生素D用量均高于稳定组（0.80±0.33 vs 0.38±0.13；0.75±0.25 vs 0.38±0.13；P<0.05）。三组不良妊娠结局（早产/流产）发生率无显著差异。

13例患者的17次哺乳期有数据记录。与孕晚期相比，哺乳期患者血钙水平普遍增加（1.98±0.12 vs 2.60±0.27mmol/L，P<0.001），35.3%（6/17）出现高钙血症（血钙>2.70mmol/L），且均出现在哺乳期前2月内（40-59天）；尿钙排泄明显增加（8.38±2.47 vs 11.83±5.82mmol/24h，n=13，P=0.03），76.9%（10/13）发生高钙尿症（24hUCa>7.5mmol）；82.4%（14/17）的患者药物剂量明显减少，元素钙平均减少314.3mg/d（1168.0±312.3 vs 853.6±288.5mg/d，P=0.001），活性维生素D平均减少0.49μg/d（0.72±0.53 vs 0.23±0.18μg/d，n=11，P=0.006）。

结论

1. 甲旁减患者妊娠期钙稳态变化具有异质性，可能与患者起病年龄、甲旁减病因、病情严重程度、孕前病情控制情况有关。提示对于甲旁减拟妊娠及正在妊娠患者，应增加监测频率，及时调整用药，避免高钙血症或低钙血症。

2. 甲旁减患者妊娠期高钙尿症常见，且症状性肾结石发生风险增加，临床上应注意监测其24小时尿钙水平，及时调整用药，尽量避免肾脏并发症的发生。

3. 甲旁减患者不良妊娠结局发生风险增加，非术后甲旁减患者更高，在维持患者妊娠期钙稳态的同时应积极寻找其他高危因素，改善母婴结局。

4. 大多数甲旁减患者哺乳期血钙水平明显增加，甚至可出现高钙血症。如患者有哺乳计划，需密切监测其分娩后血钙情况，及时减少药量，避免高钙血症。

第二部分 假性甲状旁腺功能减退症患者妊娠期钙稳态变化

背景

假性甲状旁腺功能减退症（pseudohypoparathyroidism, PHP，假性甲旁减）是一组以甲状旁腺素抵抗为主要病理生理改变的罕见内分泌疾病，患者表现为与甲旁减相似的临床症状及部分生化特点，但血PTH水平明显升高。目前其主要治疗方案是对症治疗，对于低钙血症予钙剂联合维生素D制剂治疗，以维持血钙磷正常水平，缓解低钙血症相关症状，同时控制合理的血PTH水平。PHP合并妊娠更为罕见，国外仅有少量病例报道且关于其在妊娠期的钙稳态变化结论不一，国内暂无相关研究报道。

目的

通过回顾性分析本中心收集的PHP合并妊娠患者临床资料，评估患者妊娠期钙稳态变化趋势及可能的影响因素，为PHP患者妊娠期合理监测及治疗提供依据。

对象和方法

纳入2010年1月至2023年2月于北京协和医院内分泌科门诊确诊并随访的PHP合并妊娠患者为研究对象。采用GNAS基因一代测序及甲基化特异性的多重连接探针扩增技术对患者进行PHP分子分型。通过病历复习及电话随访回顾性收集患者PHP相关基线数据、孕前及孕期PHP诊疗及妊娠结局相关数据。根据其妊娠期血钙变化及用药调整将患者分为病情改善组、加重组、稳定组及不确定组。对前三组患者临床及生化特征进行分析，寻找与患者妊娠期病情变化有关的因素，并与第一部分甲旁减患者妊娠期钙稳态变化进行比较。

结果

本研究共纳入7例PHP患者的8次妊娠数据（1例患者经历2次妊娠），PHP1a型1例，散发PHP1b型4例，常显PHP1b型1例， 1例分子分型不明。平均起病年龄13.9±9.4岁，诊断年龄21.4±7.1岁，妊娠年龄26.6±3.1岁。除2例患者孕前未在我科就诊外，所有患者孕前血钙均正常。多数患者妊娠结局良好（6/7），新生儿平均出生体重3407±635g，检测血钙均正常。根据妊娠期病情变化，3次妊娠归入加重组，1次归入改善组，2次归入稳定组，余2次妊娠归入不确定组。患者孕早期血PTH水平均较孕前明显下降，稳定组及改善组患者孕中晚期血PTH水平持续低水平，加重组患者血PTH水平在孕中晚期回升。

与甲旁减患者相比，PHP患者起病年龄有更早的趋势（21.4±8.6 vs 13.9±9.4岁，P=0.051），妊娠前血钙较高（2.09±0.23 vs 2.30±0.14mmol/L，P=0.049），血磷较低[1.65(1.47,1.76) vs 1.40±0.24mmol/L，P=0.032]，妊娠期血钙正常比例较高（0/33 vs 4/8，P<0.001），24小时尿钙排泄较低（9.52±3.34 vs 6.67±2.90mmol/24h，P=0.049），无患者发生症状性肾结石。两组间妊娠结局无显著差异。

结论

1. PHP患者妊娠期钙稳态变化具有异质性，且与血PTH水平变化相平行。血PTH水平在妊娠中晚期的回升可能与患者血钙下降、用药需求增加有关，提示临床上需注意监测PHP患者妊娠期血PTH水平变化，及时调整药物剂量，维持正常钙稳态。

2. 与甲旁减患者相比，PHP患者妊娠期血钙正常比例较高，24小时尿钙排泄较少，高钙尿症发生率低，无患者发生症状性肾结石。两组间妊娠结局无显著差异，可能与样本量较少有关。提示PTH在维持PHP患者妊娠期钙稳态方面可能发挥一定作用。

第三部分 正常女性妊娠期钙磷调节激素及血清RANKL/OPG、SOST

水平变化的探索性研究

背景

妊娠期钙磷稳态的维持对母婴健康至关重要，了解在此期间钙磷代谢的生理变化是分析疾病状态下病理生理改变的基础。既往已有研究显示妊娠期母体血1,25(OH)₂D及PTHrP水平逐渐升高，孕晚期达峰，血PTH水平持续被抑制或在孕晚期回升，主要通过增加肠道钙磷吸收满足母胎钙磷需要。对妊娠期骨转换指标的研究显示，妊娠期尤其孕晚期母体骨转换速率增加，可能作为储备力量保障胎儿钙磷供应。但对于调磷因子FGF23以及在骨形成和骨吸收调节过程中发挥重要作用的RANKL、OPG、SOST在妊娠期的变化，相关研究较少，且研究结论不一，并且缺乏中国人群的数据。

目的

本部分研究旨在分析本中心正常女性妊娠各时期血清部分钙磷调节激素及RANKL、OPG、SOST的变化，提供相关基线数据，为后续病理生理机制研究奠定基础。

对象和方法

本部分研究对象来源于北京协和医院临床营养科《围孕期维生素D营养状态管理对妊娠结局改善的临床队列研究》项目，采用问卷方式收集受试者基本信息，通过受试者在我院营养科及产科的随诊病历收集其妊娠相关资料及生化指标，留取受试者妊娠三期产检时空腹外周血清标本，采用质谱法测定血1,25(OH)₂D，酶联免疫吸附法测定血RANKL、OPG、SOST、FGF23水平，分析受试者妊娠三期上述指标水平变化。

结果

本部分研究共纳入受试者100名，98名随访至妊娠结束。平均妊娠年龄33.6±4.0岁，88.8%足月分娩，6.1%早产，5.1%自然流产或引产。95名新生儿（2名研究对象为双胎妊娠）平均出生体重3245±457g，低出生体重儿7名（5名为早产儿，2名为多胎妊娠新生儿），巨大儿3名。研究对象孕早期普遍存在维生素D缺乏（71.1%，69/97）。

妊娠期血白蛋白水平进行性下降，孕晚期最低，血总钙变化趋势与白蛋白相同，白蛋白校正钙水平无下降趋势。血磷水平在妊娠期保持稳定，血ALP孕晚期达峰。

钙磷调节激素：妊娠期血1,25(OH)₂D水平持续升高，至孕晚期达峰[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]。血cFGF23水平无明显变化[10.462(9.317,12.576) vs 10.928(9.668,12.201) vs 10.386(8.829,13.380) pg/ml]。

22名女性进行了孕早、中、晚三期的血清RANKL、OPG及SOST水平检测：RANKL及RANKL/OPG水平逐渐下降，孕晚期最低，OPG水平无明显变化，其中三个时期血清RANKL水平分别为 1.731(1.551,2.971) 、1.310(1.123,1.527)和0.985(0.820,1.272) ng/ml，P<0.001；RANKL/OPG比值分别为5.91(4.26,8.30)、3.78(2.57,5.86)和2.90(2.05,4.03)，P<0.001。血清SOST水平逐渐升高，孕晚期达峰，三个时期分别为0.200(0.188,0.255)、0.247(0.196,0.300)和0.285(0.230,0.382) ng/ml，P<0.001。

结论

1. 妊娠期母体血白蛋白水平稀释性下降，导致血总钙水平下降，需要检测血白蛋白校正钙或游离钙水平以准确评估母体血钙水平。

2. 妊娠期血磷及血清cFGF23水平无明显变化，支持磷代谢在妊娠期相对稳定。

3. 妊娠期血清RANKL水平逐渐下降，SOST水平逐渐升高，OPG水平维持稳定，前两者可能与孕晚期骨吸收的净效应（骨吸收大于骨形成）有关。

Part 1. Changes in calcium homeostasis of patients with hypoparathyroidism during pregnancy and lactation periods

Background

Hypoparathyroidism(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.

Objective

This 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 Methods

HP 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.

Results

A 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).

Conclusion

1. 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 pregnancy

Background

Pseudohypoparathyroidism(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.    

Objective

1. 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 Methods

PHP 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.

Results

Date on 7 patients with 8 pregnancies(1 patients experienced twice pregnancies) were enrolled. One patient was PHP1a, 4 were sporadic PHP1b, 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.

Conclusion

1. 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 research

Background

Normal 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.

Objective

The 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 Methods

The 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.  

Results

A 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).

Conclusion

1. 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. Serum 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.