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| ORIGINAL ARTICLE |
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| Year : 2021 | Volume
: 6
| Issue : 2 | Page : 58-63 |
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Effect of parity on the serum calcium in the pregnancy: A retrospective study
Nan-Nan Wu, Bin Cao, Jia-Nan Lang, Dong Zhao
Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University; Beijing Key Laboratory of Diabetes Research and Care, Beijing, China
| Date of Submission | 02-Apr-2021 |
| Date of Decision | 14-Jun-2021 |
| Date of Acceptance | 17-Jun-2021 |
| Date of Web Publication | 06-Jul-2021 |
Correspondence Address:
Dr. Dong Zhao
Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China. Beijing Key Laboratory of Diabetes Research and Care, Beijing 101149
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ed.ed_6_21
Background: Maternal hypocalcaemia has adverse outcomes on pregnant women and offspring development. The objective of this study is to test whether parity number is associated with maternal calcium level.
Materials and Methods: According to parity numbers, the pregnant women were divided into never parturition group (NPG) and previous parturition group (PPG). Association between parity number and serum calcium was tested in multivariate linear regression models controlling for age, body mass index (BMI), Vitamin D, and Homeostasis model assessment for insulin resistance (HOMA-IR). The subjects were also subgrouped by recruitment in four seasons and their development of gestational hypertension (GH) and diabetes.
Results: Mean serum calcium was lower in the PPG than that in the NPG (2.15 vs. 2.20 mmol/L, P < 0.001). After adjusted for albumin, adjusted serum calcium was still lower in PPG than that in NPG (2.20 vs. 2.23 mmol/L, P < 0.001). Interestingly, adjusted serum calcium level is consistently lower in the PPG in both the diabetic and hypertension subgroups compared to NPG (2.20 vs. 2.23 mmol/L, P < 0.001). In different seasons, the serum calcium level and adjusted serum calcium level in the PPG were significantly lower than the NPG (P < 0.001). Importantly, adjusted calcium correlated negatively with the parity number (r = −0.044, P < 0.001), when adjusting for age, BMI, Vitamin D, and HOMA-IR. In addition, there was a significant increase in the PPG compared to the NPG including age (29.61 vs. 33.39 years old), BMI (22.80 vs. 23.55), triglyceride (2.27 vs. 2.43 mmol/L), and fasting basal blood glucose (4.73 vs. 4.81 mmol/L), and a significant decrease regarding the albumin (38.72 vs. 37.65 g/L) and Vitamin D (20.98 vs. 18.62 ng/ml). There was no difference in the onset of GH and gestational diabetes mellitus (GDM) between the two groups.
Conclusion: Parity negatively correlated with the serum calcium level. The small but significant difference in the calcium levels indicated that parity may play an intricate role in calcium homeostasis. Timely monitoring of maternal calcium could be clinically beneficial to the multiparous women.
Keywords: Calcium, gestational diabetes, gestational hypertension, parity, season
How to cite this article:
Wu NN, Cao B, Lang JN, Zhao D. Effect of parity on the serum calcium in the pregnancy: A retrospective study. Environ Dis 2021;6:58-63 |
| Introduction | |  |
Pregnancy is a precisely regulated adaptation in the fetomaternal relationship.[1] During pregnancy, mothers strive to meet the fetus's needs of developing skeleton and mineralization by adjusting calcium metabolism and bone mineral status.[2] Accretion of approximately 30 g of calcium takes place in pregnancy, with a peak calcium accretion rate of 250–300 mg/day in the third trimester.[3],[4],[5] Calcium demand is facilitated through doubling of maternal intestinal calcium absorption and mobilization of calcium from maternal bones, as observed through changes in bone biomarkers.[6] Calcium and Vitamin D have well-established associations with bone health and increasing evidence suggests that seasonal variation in 25OHD is associated with bone mass.[7],[8] The study has shown that 25OHD seasonal variation affects the relationship between calcium and skeletal health in pregnant women. It is widely accepted that pregnancy causes transient loss in bone mass.[9] Parity is known to play a role in osteoporosis, higher bone mineral density, age-related degenerative factors in the spine, brain function, stroke, and other diseases.[10],[11],[12],[13],[14],[15] The concentration of calcium ions in serum is maintained within a very narrow range throughout gestation;[16] low maternal calcium increases the risk for gestational diabetes, gestational hypertension (GH), and preeclampsia. Maternal hypocalcaemia has adverse outcomes to pregnant women and offspring development. Therefore, it is important to maintain normal blood calcium levels during pregnancy. With the new policy of 2 or 3 children per family in China, parity became a potential health issue to pregnant women. However, there was no population-based studies demonstrated the role of blood calcium and parity. With the limited understanding of parity and its effect on women's health, we set to understand the association between parity and calcium with other investigated variants including age, body mass index (BMI), Vitamin D, and onset of the gestational diabetes and hypertension. We took into account the season in our research. The present study aimed to demonstrate the effect of parity on the serum calcium in the pregnancy. It is important to explore the serum calcium levels in these women with multiple pregnancies in order to provide evidence-based medical evidence for clinical diagnosis and treatment.
| Materials and Methods | | |
Ethical approval
In our research, all subjects received ethical approval from Beijing Luhe Ethics Committee affiliated to Capital Medical University. Before our analysis, all pregnant women willingly signed the informed consent and procedures in the present study.
Subjects
A total of 1,007 pregnant women were selected from the enrollment in the Department of Obstetrics and Gynecology in Beijing Luhe hospital, Capital Medical University, from January 2017 to December 2017. Their age is from 20 to 49 years old. During the pregnancy, all pregnant women were given 600 mg of calcium element and Vitamin D3 of 125 IU daily. Subjects with high blood glucose and pressure history before pregnancy were excluded in the study; at the same time, pregnant women diagnosed with abnormal parathyroid function during pregnancy and severe hyperlipidemia were excluded. All clinical indicators used in this study were collected at 24–28 weeks during gestation.
The oral glucose tolerance test for testing GDM was performed by giving 75 g oral glucose to subjects after fasting overnight, blood glucose was tested before and after 0.5 and 1 h giving 75 g oral glucose. If the glucose level is higher than 5.1 mmol/L at the basal, 10.0 mmol/L after 0.5 h and 8.5 mmol/L 1 h, the subject is diagnosed as GDM.
The albumin, triglyceride (TG), total cholesterol, and serum calcium were measured by Beckman chemical analyzer AU5800 using Bromcresol Green, single reagent GPO-PAP colorimetric method, and enzymatic CHOD-PAP method. Total calcium in serum was determined by Arsenazo III; Insulin, C-peptide, and Vitamin D were measured by electrocheminescence by Roche Cobas e601. Blood glucose was measured with beta-kinase method. Adjusted calcium level by albumin was done by divide the calcium in serum by albumin to better reflect the calcium change. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated according to the formula: (fasting insulin [μIU/ml] I fasting plasma glucose [mmol/L])/22.5. Homeostasis model assessment β-cell function (HOMA-β) was calculated according to the formula: 20× fasting insulin (μIU/ml)/(fasting plasma glucose [mmol/L]-3.5).
Seasonal groups
Four groups were divided according to the season at 24–28 weeks of gestation. A total of 131 individuals were drawn in spring (never parturition group [NPG]: 65 individuals and previous parturition group [PPG]: 66 individuals), 387 in summer (NPG: 194 individuals and PPG: 193 individuals), 308 in autumn (NPG: 157 individuals and PPG: 151 individuals), and 181 in winter (NPG: 89 individuals and PPG: 92 individuals). Spring started from March 26 Summer started from May 7 Fall started from September 23 and winter started at October 29 in 2017 according to the Beijing Meteorological Bureau.
Statistical analyses
Differences in clinical characteristics and serum calcium between groups were calculated using the Mann–Whitney test for continuous variables and the Chi-square test for categorical variables. Multivariate linear regression was performed to investigate the relationship between parity number and serum calcium when adjusting for age, BMI, Vitamin D, and HOMA-IR. Data analysis and visualization were performed by R software, version 3.6.2 (The R Project for Statistical Computing, Vienna, Austria). A two-sided P < 0.05 was considered statistically significant.
| Results | | |
Clinical characteristics of the studied subjects
Baseline clinical characteristics were shown in [Table 1]. The subjects were subgrouped based on gestational diabetes and hypertension. One hundred and forty-six out of 505 cases in the NPG and 173 out of 502 cases in the PPG developed gestational diabetes. Eight out of 505 cases in the NPG and 11 out of 502 cases in the PPG developed hypertension. There was a statistically significant increase in PPG regarding age (29.61 vs. 33.39 years old), BMI (22.80 vs. 23.55), TG (2.27 vs. 2.43 mmol/L), and fasting blood glucose (4.73 vs. 4.81 mmol/L). Fasting blood glucose was significantly increased in PPG compared to NPG, but insulin and C peptide levels had no difference, ditto for the HOMA-IR and HOMA-β. There was also a significant decrease regarding the albumin (38.72 vs. 37.65 g/L), Vitamin D (20.98 vs. 18.62) in PPG compared to NPG. There was no significant difference in the onset of GH and diabetes between the two groups. | Table 1: Comparisons of clinical characteristics of the study population
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Calcium level in pregnant women in different parities
Compared to NPG, both free calcium level and adjusted level by albumin shows the significantly lowered calcium level in the PPG (2.15 mmol/L vs. 2.20 mmol/L, P < 0.001 and 2.20 mmol/L vs. 2.23 mmol/L, P < 0.001, respectively) in [Figure 1]. Considering the calcium is a very tightly and precisely regulated factor in the circulation, the change is significant enough to cause the physiological difference. Compared to NPG, calcium level was lowered in the PPG in the diabetic subgroup (2.15 vs. 2.20 mmol/L) [Figure 2]a, as well as adjusted calcium (2.20 vs. 2.23 mmol/L) [Figure 3]a. As for hypertension subgroup, calcium level was lowered in the PPG (2.18 vs. 2.27 mmol/L) [Figure 2]b, as well as adjusted calcium (2.22 vs. 2.25 mmol/L) [Figure 3]b. | Figure 1: Comparisons of free calcium levels and albumin regulated calcium levels between NPG and PPG groups
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 | Figure 2: (a) Comparison of free calcium levels in the diabetic subgroup; (b) Comparison of free calcium levels in the hypertension subgroup
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 | Figure 3: (a) Comparison of albumin regulated calcium levels in the diabetic subgroup; (b) Comparison of albumin regulated calcium levels in the hypertension subgroup
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Seasonal change of calcium level in different parity number
The calcium level in the spring and summer indeed was higher than in the fall and the winter [Figure 4] and [Figure 5]. The calcium level in the PPG was significantly lower than the NPG in each season (2.17 vs. 2.22 mmol/L in spring and summer, 2.14 vs. 2.19 mmol/L in autumn, and 2.13 vs. 2.18 mmol/L in winter). Similarly, adjusted calcium was also significantly lower than the NPG in each season (2.21 vs. 2.24 mmol/L in spring and summer, 2.19 vs. 2.22 mmol/L in autumn, and 2.19 vs. 2.21 mmol/L in winter). | Figure 4: Comparison of free calcium levels of the study population in different seasons
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 | Figure 5: Comparison of albumin regulated calcium levels of the study population in different seasons
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Association of parity with other clinical parameters
Univariate and multivariate linear regression analysis is listed in [Table 2] to analyze the relationship between adjusted calcium and age, BMI, HOMA-IR, Vitamin D, and parity number. We found that adjusted calcium level was negatively associated with parity number (P < 0.001) and positively correlated with HOMA-IR and Vitamin D level regardless of the gestational diabetic and hypertension status. | Table 2: Univariate and multiple linear regression analysis to assess the association of plasma adjusted calcium with parity number
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| Discussion | | |
In this study, we analyzed retrospectively two groups of pregnant women. One was NPG (n = 505); the other was PPG (n = 502). Compared with NPG group, PPG group is characterized by younger age, high BMI, high fasting glucose, high incidence of diabetes, and high TG level.
The state of pregnancy is known to increase calcium demands.[17] Normal total serum calcium concentration ranges from 8.8 to 10.4 mg/dl (2.2–2.6 mM) in healthy subjects.[18] For pregnant women, the maternal calcium requirement increases to meet the fetal, neonatal, and maternal needs by increasing the intestinal calcium absorption.[17] Even though calcium homeostasis is finely regulated by a complex mechanism coordinated by a variety of hormones, total serum calcium levels have been described to be consistently low among pregnant women.[19],[20],[21] The serum levels of ionized calcium in recent literature have however been described to remain sensibly unperturbed during pregnancy.[22],[23],[24],[25],[26] In this study, we observed the serum calcium levels of all subgroups ranged from 2.13 to 2.27 mM, showing lower than the normal median line, which supports the former. Importantly, we found that the serum calcium level was negatively correlated with the parity by the single and multiple linear regression assay. We concluded that parity has an impact on the calcium level, and the calcium level lowered with the parity. Our finding on the lowered calcium level in the PPG is consistent with other groups.[27] Surprisingly, all subjects including subgroups of gestational diabetes, hypertension, and the pregnancy in different seasons have lower serum calcium level in the PPG than those in the NPG. Indeed, we found that the pregnancy at 24–28 weeks in the spring and summer has higher serum calcium level than the same pregnancy in the fall and winter due to more ultraviolet exposure. The number of pregnant women with hypertension in the database was small, so the data analyzed in the subgroup with hypertension needed to be validated in a larger population.
Maternal hypocalcaemia has been associated with high blood pressure, pregnancy induced hypertension,[28] preeclampsia,[29],[30] and increased serum lead levels.[31] It has also been associated with fetal morbidities such as neonatal low bone mass,[5] poor fetal growth,[32] and increased risk of small for gestational age.[33] Calcium (Ca) deficiency is associated with preeclampsia and intrauterine growth restriction. Ca supplementation may reduce both the risk of low birth weight and the severity of preeclampsia.[34] Starting from the 18th week of the pregnancy, the fetus teeth and bone started to calcify. A main calcium source for the teeth and bone calcification is from the calcium storage in the mother's bone when the calcium is not sufficient for the pregnant women. It was reported that calcium intake during pregnancy could improve the blood calcium level, dilate the blood vessel, decrease the blood pressor, and lower the risk for GH. It was advocated to take calcium during pregnancy so that to provide the sufficient calcium for the fetus development. In 2016, Chinese Nutrition Association recommended a daily uptake calcium of 800 mg in early pregnancy and 1,000 mg in the midterm and 1,200 mg in the late pregnancy, which includes calcium obtained from the diet and supplemented calcium. Ca supplementation during pregnancy and antenatal care in China is not systematic and the systematic antenatal package of workups does not consider measurements of serum calcium levels at different trimesters for subsequent correction. Therefore, attention should be paid to the maintenance of calcium levels in pregnant women during pregnancy examination.
The new discovery from our study indicated that subjects in the PPG may need more calcium supplement. The small but significant difference we observed between the PPG and NPG will be futured tested in future to confirm its clinical significance with future follow-up and continuous data collection. In addition, the supplemental calcium of 800 mg during pregnancy might confound the serum calcium difference between the two groups. Currently, the calcium supplement for general pregnant women is still practitioner dependent, but it is strategic to prevent the risks for pregnancy hypocalcemia, especially for multipregnancy women, it could lower the incidence of adverse pregnancy outcomes and reduce long-term complications.
The result of low calcium in the second pregnancy prompted us to think of the bone density in pregnant women. To our knowledge, the pregnancy causes the loss of calcium, which affects bone metabolism,[5] in the long term, it will cause the loss of calcium. It is a limitation that we do not have clinical parameters for bone health analysis in this database. In the long term, to better understand the parity and serve the clinical application, we expected to follow-up on these subjects to overcome the current database limitation. The assessment of intake of calcium and Vitamin D and bone metabolism in the context of parity will be the future focus for this continued study.
Conclusion
Parity negatively correlated with the serum calcium level. The small but significant difference in the calcium levels indicated that parity may play intricate role in calcium homeostasis and need to be further investigated. The timely monitoring of calcium could be more clinically significant for the multiparous women. According to our data for multi-pregancy women, we should pay attention to the blood calcium level of mothers and give active intervention.
Financial support and sponsorship
The present study received the Funding support from Beijing Excellent Talents Training Assistance (#2017000082595G244) and the Health and Research Bureau of Tongzhou District (#TWKY-2016-QN-01-58).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]
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