Journal of BMC Nutrition: A randomized controlled trial of calcium supplementation during pregnancy and early postpartum periods

Original: Journal of BMC Nutrition: A randomized controlled trial of calcium supplementation during pregnancy and early postpartum periods

background

Calcium requirements are physiologically upregulated during pregnancy and lactation to meet the needs of developing and lactating babies for bone mineralization and growth [1, 2

Pregnancy and lactation-related bone loss is also confirmed

Biochemical markers of bone resorption (osteoclast activity) and bone formation (osteoblastic activity) have been found to change drastically during pregnancy, indicating a physiological state of high bone transition [12

It is recommended that pregnant and lactating women over the age of 18 should consume at least 1,000 mg of calcium per day [18], but these recommendations are based primarily on studies of non-pregnant women [2

Previously published maternal calcium supplementation and bone conversion tests [23 – 25] were limited by sample size and different study designs, making it difficult to infer from

The objective of this study was to use a double-blind, randomized placebo-controlled trial design to assess the effects

method

Study population and design

From 1 January 2001 to 26 April 2004, pregnant women in the first trimester of the Mexican Institute of Social Security, which serves low-income people in Mexico City, enrolled pregnant women in the first trimester

Overview of the study sample

Calcium carbonate is about 40% elemental calcium by weight [ 26 ]; Therefore, for 1,200 mg of calcium carbonate, the elemental calcium equivalent is: 480 mg

Participants were assessed at four time points: baseline before initiation of treatment (first trimester), and after calcium or placebo at 6 months of gestation (2 months of gestation) and 8 months (3 months of gestation) and 1 month postpartum

The research programme was approved by the Commission of Human Subjects of the National Institute of Public Health of Mexico, the Mexican Institute of Social Security and participating agencies, and complied with all federal guidelines on the use of human subjects

Bone conversion markers

The amount

Bone-specific alkaline phosphatase (BAP) stored in plasma at -70 °C was measured using Ostase® BAP immunoenzyme assay (Immunodiagnostic Systems Inc.

Bone ultrasound measurement

Bone sound velocity (SOS, in m/s) was measured at a distal radius using quantitative ultrasound (QUS) (Sunlight Omnisense 7000, Zicon Ltd.

Dietary intake

Daily calcium intake and total energy were assessed at each visit using a semi-quantitative food frequency questionnaire designed to estimate the usual dietary intake for

Statistical analysis

To assess whether randomization was successfully comparable, baseline features

Use intentional treatment strategies to assess the effects

The secondary strategy is to estimate the efficacy of the supplement by performing a dose response analysis to further evaluate the effect
of the supplement through estimated adherence.
Compliance was analyzed as the proportion of the expected number of pills the subjects took between consecutive visits and then divided into three groups: ≥ 50 percent of tablet consumption, ≥ 67 percent of tablet consumption, and ≥ 75 percent of tablet consumption
.

We also fitted a model with the NTx/BAP ratio as the outcome variable in a subset with two measurements (N = 100 subjects, 270 observations) to see if the relative levels of bone resorption versus bone formation were during pregnancy and to assess whether this change differed
between treatment groups.
All statistical analysis was performed
using STATA for Windows version 12.
0 (StataCorp LP, College Station, Texas).

outcome

A total of 670 eligible women were randomly assigned to either a calcium supplement (N = 334) or a placebo (N = 336) (Figure 1
).
Baseline features were similar in the calcium and placebo groups, except that maternal age was on average in the control group (26.
9 years) than in the supplement group (25.
9 years; p = 0.
02) year higher (Table 1
).
Approximately 35.
4% of women are first-time women, and there are no significant differences in
treatment.
Dietary calcium intake also did not differ significantly between treatment groups, averaging about 1,100 mg
per day.
The geometric mean (and geometric standard deviation (GSD)) before treatment NTx levels in the calcium and placebo groups were 62.
3 (1.
7) and 62.
9 (1.
7) nMBCE/mM creatinine (p = 0.
73),
respectively.

Baseline participants by treatment and follow-up status

A total of 563 women (84%) underwent at least one follow-up evaluation and were included in the analysis
.
Comparing those included in the analysis (placebo N = 275; calcium N = 288) with those not included (placebo N = 61; calcium N = 46) showed no significant difference in treatment allocation, suggesting that those women who remained in the study did not have a systematic difference
with those who did not complete follow-up.
Overall, the proportion of lactating women at the postpartum 1 month was 89.
6%, with no difference between treatment groups (calcium, 89.
9% versus placebo, 89.
3%; p = 0.
8）
。

In unsweeconded treatment-of-intent analysis, calcium was associated with an average decrease of 15.
1%, 16.
4%, and 20.
2% in NTx concentrations during the second and third trimesters and at the first month postpartum period (all p≤ 0.
001).

Estimates of reductions for the corresponding specific visit-specific covariate adjustments are 13.
8, 15.
6, and 19.
2% (all p≤ 0.
001) (table 2
).
The overall covariate adjustment of NTx concentration decreased by an average of 15.
8% compared with placebo (p<0.
001
).

Table 2 Effects of calcium supplementation on NTX (log conversion)

Results from mixed-effect regression models with time-based interactions showed significantly different effects of calcium supplementation on bone resorption with each study evaluation compared to baseline differences
between treatment groups 。 The reduction in the postpartum month of 1 month was more pronounced than in the second and third trimesters of pregnancy, but these reductions were significant for each of the following three assessments: month 2 (decrease -13.
7%, p = 0.
002); Third trimester (decrease -15.
6%, p = 0.
001); and postpartum 1 month: (-18.
6% reduction, p<0.
001) (Figure 2
).

Effect of calcium supplementation on type I collagen [NTx] urinary N-terminal peptide

Since response to treatment may depend on baseline dietary calcium intake, we tested dietary calcium interactions
with treatment groups.
There was no significant interaction
between dietary calcium intake at baseline (as a continuous variable or quartile) and the supplement group.
However, when examining lactation status, supplementation had no effect on non-lactating women (p = 0.
57), while lactating women decreased by 23% (p<0.
0001), indicating that lactation was an effect on
bone resorption of calcium supplementation.

When assessing the effects of calcium supplementation in "post-treatment" women (N = 563) using a model layered by adherence (Table 3), we saw a dose-responsive effect
of calcium on NTx concentrations.
In women taking ≥50% of the pills, calcium was associated with an average 17.
3% decrease in NTx compared with placebo (p< 0.
001
).
For those taking ≥ 67% pills and ≥ 75% pills, this increased to 21.
3% (p< 0.
001) and 22.
1% (p<0.
001).

Effect of calcium supplementation on NTx depending on treatment adherence to b

The subset of women measured by serum BAP (N = 100) did not differ significantly from those who had no available measurements (N = 463), except for the number of school years (BAP was on average 0.
7 years longer, p = 0.
04) and hematocrit (BAP was on average 0.
7 percentage points higher, p = 0.
04).

Calcium alone had no significant effect on BAP at any stage (p-values: 0.
61, 0.
20, 0.
32, stages 2 and 3) at three months and 1 month postpartum) (data not shown).

Adjusting for age, first-trimester, baseline dietary calcium and total energy intake, and baseline NTx/BAP ratios, the calcium group had lower estimates of the NTx/BAP ratio at the 2nd time, but no statistically significant (-10.
1%, p = 0.
32) and third trimester (-13.
4%, p = 0.
20) visits
.
By 1 month postpartum, the NTx/BAP ratio in the calcium group was significantly lower than in the placebo group (-21.
5%, p = 0.
04), indicating a greater
net reduction in bone loss in the calcium supplement group.
Follow up
.

There was no significant difference between women with SOS available (N = 290) and those with no available measurements, except for years of school attendance (0.
6 years more in women with SOS, p = 0.
01) and total energy intake (about 190 kcal less on average SOS consumption in women, p<0.
001).

Although radial SOS decreased during pregnancy in both groups, the decline was relatively weak in the supplement group, and by 1 month postpartum, the radial SOS in the supplement group was higher than in the placebo group, but not significantly
.
p = 0.
13) (data not shown).

Calcium was associated with an average 9.
05 m/s increase in radial SOS relative to placebo, although this difference was not significant (p = 0.
216).

However, in those taking 50% or more of the tablets (N = 251), at 1 month postpartum, calcium was associated with a 26.
3 m/s increase in radial SOS relative to placebo (p = 0.
03).

In those taking at least 75% of the pills, by 1 month postpartum, calcium supplementation was associated with a 59.
0 m/s increase in radial SOS relative to placebo (p = 0.
009).

discuss

In this randomized controlled trial, taking 1,200 mg of calcium carbonate supplementation daily during pregnancy and early postpartum was associated with a decrease in NTx compared with placebo, suggesting that dietary calcium supplementation may help inhibit maternal bone mobilization
.
These effects increased with increased treatment adherence, indicating the presence of dose-response effects, with an average overall reduction of more than 22%
observed in women with the highest adherence.
These results are consistent with previous randomized crossover trials conducted in a small group of women that showed that taking dietary calcium supplements in the third trimester of pregnancy reduced NTx levels by an average of 14 percent [23].

To put the magnitude and direction of these changes in context, this is consistent with the 28% reduction in urine NTx observed in women randomly receiving 0.
625 mg conjugated to equine estrogen after 1 month of hormone replacement therapy (Premarin, Wyeth Ayerst, Philadelphia, Pas.
) [41].

The results of this study are also consistent with a study of 36 Chinese pregnant women with low habitual dietary calcium intake, which found that calcium supplementation was associated with a significant reduction in bone resorption markers; Although contrary to our findings, they also reported an increase in bone formation [ 25 ].

Unlike our study, calcium was provided
by supplementing the "regular diet" with 45 grams of milk powder (350 mg of calcium) or milk powder with a supplement of 600 mg of calcium (950 mg of calcium).
In this study, dietary calcium supplementation during pregnancy was associated with increased spine and systemic BMD measured by DXA at 6 weeks postpartum in a dose-dependent manner (p<0.
05), but not with
hip sites.

In this study, in the most compliant subjects, by 1 month postpartum, calcium was associated
with significantly higher radial SOS (marker of bone density).

While the overall effect, including all subjects, including all subjects, regardless of adherence, was not statistically significant, the direction of the effect was consistent with our hypothesis, and radial SOS measurements were only available in about half of the subjects, so the study was insufficient to detect the effect
of calcium on SOS.
In addition, the effect of calcium on bone density may vary depending on the type of bone
.
We measured SOS at the distal end of the radius, a site dominated by cortical bone, where calcium may act on bone areas
where trabecular bone predominates.

In a study of 125 Gambian women, calcium supplementation of 1,500 mg/day was associated with a decrease in BMD in participants with the distal radius and central axis portion of the DXA measurement, but an increase in the lumbar spine and overall BMD measurements in the body [24].

Like the Chinese study, the Gambia study also measured the effects
of calcium supplementation in women with low dietary calcium intake.
However, it is different
from our study and the study of Liu et al.
[25] The Gambian study did not continue to supplement into the postpartum period, which may be part of the reason they found rebound demineration after stopping breastfeeding [42].

We found that the calcium group had a significantly lower ratio of bone resorption to bone formation at 1 month postpartum, suggesting that calcium was effective in reducing net bone loss
measured after pregnancy.
In our study, the effects observed at 1 month postpartum were driven by lactating women, suggesting that the need to continue calcium supplementation may continue into the postpartum period
.

One limitation of our study was that we used QUS instead of DXA to assess bone quality in pregnant women, and this measurement was only available
in about half of women.
QUS has been shown to predict fracture risk [43] and has been widely used in epidemiological studies to measure bone density, especially in situations where DXA is not available or is not recommended, such as radiation exposure
to the fetus during pregnancy [37 – 39].

In more than 7 years of follow-up, quS was found to have a good correlation with DXA [45]] and provided an advantage for our study that we were able to include repeated measurements
of bone density throughout pregnancy and early postpartum, in addition to biochemical markers of bone transition.

Pregnancy and breastfeeding may affect a woman's peak bone mass, which is an important determinant of subsequent osteoporosis risk [46
].
In addition, calcium may have potential benefits for bone health in children [16 , 17 , 47
].
The possibility that intrauterine planning for fetal bone growth may be an important determinant of osteoporosis and the risk of developing other chronic diseases in later life is being considered
[48].
Emerging evidence suggests that maternal dietary insufficiency during pregnancy may be associated with decreased peak bone mass in offspring [16 , 17 ].

In our trial, women's mean baseline dietary calcium intake was in the currently recommended maternal and lactating female dietary guidelines of 1,000 to 1,300 mg/day [18].

Large amounts of calcium may be required to balance the nutritional needs of the developing fetus [49]; Therefore, previous trials in women with low dietary calcium intake may not have detected an effect
.

Bone mineralization doesn't just depend on the availability of calcium: proteins, energy, and other nutrients are also important
for bone formation and mineralization.
Vitamin D is essential for calcium homeostasis and is now considered an important nutrient for bone health, including moderate support for maternal vitamin D status and increased bone mass in offspring [.
.
.
] 50 ]
。

However, this study was planned and implemented in accordance with the 1997 IOM Guidelines [28
].
Vitamin D and calcium supplementation are not specifically recommended as common practices today
.

Nonetheless, our previous studies of calcium supplementation during pregnancy in adults [23 – 25] did not measure or take vitamin D
.
A small randomized study of Brazilian adolescents with habitually low calcium intake [51] found that 600 mg of calcium carbonate plus vitamin D 3 (200 IU) resulted in higher lumbar bone mass and a lower rate of femoral neck bone loss during lactation, which was consistent
with our results.
Maternal responses to fetal calcium needs may also be highly individualized and may involve other genetic, hormonal, or lifestyle factors [52
].

conclusion

In conclusion, dietary calcium intake may play a modest but important role
in inhibiting maternal bone activity during pregnancy and early postpartum periods.
Calcium supplementation during pregnancy also reduces the risk of hypertensive disorders during pregnancy [53, 54], preeclampsia [55, 56], and lead exposure [57], which in themselves pose a risk
to the mother and fetus.

The risk of calcium supplementation at levels close to the upper recommended daily intake is relatively small [2, 18] and U.
S.
guidelines for pregnancy and lactation calcium are based on studies of non-pregnant adults [2
].
The World Health Organization now recognizes the importance of calcium supplementation during pregnancy [58
].
Therefore, dietary supplementation for calcium intake in pregnant and lactating women should be considered, especially in people with
low dietary calcium intake.

Original link: https://nutritionj.
biomedcentral.
com/articles/10.
1186/1475-2891-13-116

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