Effectiveness of Calcium Supplementation for Improved Outcomes in Hypertensive Pregnancies in Developing Countries: A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-5223949/v1

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Systematic Review

Effectiveness of Calcium Supplementation for Improved Outcomes in Hypertensive Pregnancies in Developing Countries: A Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-5223949/v1

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Background: Hypertensive disorders of pregnancy are common and result in a substantial health burden. Evidence from epidemiological studies have shown an inverse relationship between calcium intake and development of hypertension in pregnancy. This study evaluated the evidence of effectiveness of calcium supplementation for improved outcomes in hypertensive pregnancies in developing countries.

Method: A systematic review was undertaken. Medline, Scopus, Hinari, and Cochrane databases were searched for literature published between 1985 to October 2020. Only RCTs published in English were included. Primary outcomes were pre-eclampsia, eclampsia and gestational hypertension. Secondary outcomes were preterm birth and low birth weight. Data were extracted from 21 selected RCTs for analysis. Meta-analysis was performed where data were available from more than one study for an outcome. Log risk ratio and the 95% confidence interval were estimated for each study. Risk ratios were directly pooled across studies using fixed-effects model if heterogeneity was absent, otherwise a random-effects model was used. P<0.05 was considered statistically significant, except for the test of heterogeneity where P<0.10 was used.

Results: Pooled analysis showed that calcium supplementation significantly reduced the risk of pre-eclampsia and gestational hypertension by 49% [RR: 0.51, (95% CI: 0.38, 0.67), P<0.001] and 53% [RR: 0.47, (95% CI: 0.32, 0.69), P<0.001] respectively when compared with placebo. The best intervention for lowering risk of pre-eclampsia and gestational hypertension was calcium supplement plus other co-supplements. The incidence of preterm delivery was lowered by 48% [RR: 0.52, (95% CI: 0.35, 0.78), P=0.001] in the intervention group.

Conclusion: There is strong evidence that maternal calcium supplementation is associated with improved outcomes in hypertensive pregnancies in developing countries.

Epidemiology

Calcium Supplementation

Hypertensive Pregnancies

Developing Countries

Improved Outcomes

Hypertension disorders of pregnancy (HDP) are a major health problem in the obstetric population (1). They are one of the leading causes of maternal and perinatal morbidity and mortality (1). A pregnant woman is considered hypertensive if her systolic blood pressure (SBP) is greater than or equal to 140 mmHg and/or diastolic blood pressure (DBP) is greater than or equal to 90 mmHg, measured after a period of rest on two consecutive occasions at least six hours apart or SBP ≥ 160 and/or DBP ≥ 110 mmHg on one occasion in a previously normotensive woman (2–5). The International Society for the Study of Hypertension in Pregnancy (ISSHP) has modified the classification of HDP into four categories of disorders namely; 1) pregnancy induced hypertension (PIH)/gestational hypertension (without proteinuria), 2) pre-eclampsia (with proteinuria) and eclampsia (pre-eclampsia with convulsions), 3) chronic hypertension (of any cause), and 4) chronic hypertension with superimposed pre-eclampsia (2).

Hypertension in pregnancy is estimated to complicate 10% of all pregnancies and 11% of first pregnancies, half of which are associated with PIH, pre-eclampsia and eclampsia (6). Pre-eclampsia is characterized by high blood pressure with proteinuria with or without end-organ or utero-placental dysfunction measured after 20 weeks of gestation (7) in an otherwise normotensive woman. It is associated with life-threatening and unfavourable outcomes in both the mother and foetus (6,8). Worldwide pre-eclampsia is one of the major contributing factors for maternal morbidity and mortality (9–13). The prevalence of HDP in developing countries is high (14). In Zimbabwe and Ethiopia for instance, the prevalence of PIH was 19.4% and 19.1% respectively (13,15). In Ghana, PIH contributes between 19–40% of maternal morbidity and mortality, second only to haemorrhage (16). Reducing maternal mortality and morbidity from HDP is a global priority (7,17). Even though the aetiology of HDP is still unclear (17), there is evidence that effective interventions exist at a reasonable cost for prevention and treatment of these complications in pregnancy (18).

Previous evidence showed an inverse relationship between high blood pressure and calcium intake (19). Many epidemiological and clinical studies (20–22), and a series of systematic reviews and meta-analysis (7,23,24) also established this protective association. Results of these studies suggest that routine calcium supplementation during pregnancy could lower the risk of HDP including pre-eclampsia and PIH (6,7,25,26). As a result, WHO has recommended daily calcium supplementation (1.5–2.0g oral elemental calcium) for pregnant women particularly in high-risk populations and those living in areas where dietary calcium intake is low (27). Prominent obstetrics professional organizations have also issued statements about the efficacy of calcium supplementation for prevention of pre-eclampsia in high-risk populations with low dietary calcium intake (10,28). Conversely, calcium supplementation was found to increase the risk of haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome in two (2) systematic reviews (24,29). Also, calcium supplementation during pregnancy is associated with postnatal bone resorption in Gambian women, which persists through subsequent lactation (30). High doses of calcium intake have also been reported to increase the risk of cardiovascular diseases compared with lower doses (31).

Although evidence from RCTs and systematic reviews (23,24,27) suggests daily calcium supplementation (1.5–2.0g) is efficacious to reduce the risk of HDP, its effectiveness is still not clear. To our knowledge, no systematic reviews have specifically evaluated the effectiveness of calcium supplementation for improved outcomes in hypertensive pregnancies. This review therefore aims to evaluate the evidence of the effectiveness of daily calcium supplementation during pregnancy for improved outcomes in hypertensive pregnancies in developing countries.

Settings

This systematic review and metanalysis focused on related studies on calcium supplementation for improved pregnancy outcomes in hypertensive pregnancies in developing countries. This review was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). PICO framework was adopted to underpin the literature search. The studies reviewed were solely published RCTs in which pregnant women received calcium supplementation as compared to placebo or no intervention. This review was carried out on studies conducted in developing countries. “A developing country (or a low and middle-income country) is a country with a less developed industrial base and a low human development index (HDI ≤ 0.450) relative to other countries” (32). Even though not all developing countries are the same, the populations involved in the trials selected for this review had generally low calcium intake at baseline. Studies from developing countries were thus selected because of the high-risk population of pregnant women in these settings.

Searches

Study identification was done in two phases;

In phase one, a comprehensive search of PubMed, Cochrane library, Hinari, and Scopus database was carried out using different search terms to identify relevant keywords contained in the title, abstract and subject descriptors. The search terms and strategies were constructed based on PICO (Patient, Intervention, Comparator, and Outcome) framework as described in detail in appendix A. Synonyms of these search terms were constructed and used to perform an extensive search for literature in the various databases listed above. These strategies were modified to suit each search engine where appropriate. Reference lists of the articles found were screened for more relevant articles. The next stage was exclusion of articles that were not relevant to the topic as well as duplicate articles. The articles left were assessed for eligibility by reading their abstracts. Articles that were not significant for the study were excluded from the fully screened/hand searched articles. In the final stage, published articles that met the specific inclusion criteria were used for the meta-analyses.

In phase two, all previous systematic reviews on calcium supplementation in pregnant women published from 2000 to October 2020 were identified. Individual RCTs included in these previous reviews were selected. Then all individual RCTs on the same topic published between 1985 to October 2020 identified. The reference lists of the retrieved studies were also checked to identify more relevant publications. If more than one study was published by the same authors or institution, the publication year, study quality and sample size were considered, and one study was selected. A library was created for this review using Mendeley desktop (version 1.19.5) referencing software. The primary investigator conducted a comprehensive search and screening of the study titles from the abovementioned databases. All studies with eligible titles were exported to Mendeley library. After that all duplicates were removed before abstract screening. Two reviewers independently conducted the abstract screening. Full texts were retrieved if decisions could not be reached from information provided in the abstract using standardized tools, with guidance from the eligibility criteria. Disagreements regarding selection were resolved by consensus or discussion with a third reviewer. Reporting of findings were done using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Study selection procedure

The review eligibility criteria were defined based on the Participants, Interventions/Exposure, Comparator, and Outcome (PICO) framework. This is shown below;

Population: Thereview focused on pregnant women in developing countries due to their high risk of hypertensive disorders during pregnancy. The study therefore included only RCTs involving pregnant women (especially those in areas with low dietary calcium intake) in developing countries.

Intervention: The primary interest was calcium supplementation or in combination with other supplements among pregnant women. The supplementation must have been administered orally before 32 weeks of gestation to ensure its effectiveness in preventing PIH.

Comparison: The comparator involved pregnant women who received placebo or no calcium supplementation.

Outcome: Improved maternal and perinatal outcomes in hypertensive pregnancies (pre-eclampsia, eclampsia, gestational hypertension or PIH, preterm delivery, low birth weight, and maternal and neonatal mortality).

Eligibility Criteria

Inclusion criteria

The inclusion criteria were based on PICO as follows:

Only RCTs involving healthy pregnant women.
All types of RCTs (being open, single-blind or double-blind).
RCTs in which calcium supplementation and, or any other co-supplement started before 32 weeks of pregnancy at the latest.
RCTs in which calcium supplementation was compared with placebo or no intervention.
RCTs which presented evidence on at least one of the primary outcomes of interest (i.e. pre-eclampsia, eclampsia, gestational hypertension or PIH) in the presence of the intervention.
RCTs which were conducted in developing countries and published in English language between 1985 and October 2020.
RCTs accessible for the reviewers by full-text or abstract.

Exclusion criteria

The following exclusion criteria were used:

RCTs in which the intervention was given as dietary calcium intake.
RCTs which enrolled pregnant women diagnosed with pre-existing hypertension before the trial began.
RCTs which were inaccessible neither by abstract nor full-text for the reviewers.
All ongoing and unpublished RCTs.

Data Extraction

Data was extracted following a standard protocol and using standard data extraction forms by two reviewers. Following assessment of methodological quality, the papers were based on quantitative studies only. A data charting table was used to extract background information and process the information from each utilized study. The data extraction form was developed specifically for quantitative research data extraction based on the work of the Cochrane collaboration and the centre for reviews and dissemination as described in detail in appendix B. Figure 1 explains the multistep process for study selection and inclusion. All variables that focus on answering the research question were included. The research team independently conducted a trial data extraction and later discuss as a group to determine consistency of the data extraction approach with the research questions and objectives. The data extraction form was continually reviewed and updated in an iterative process. This improved the quality applicability, validity and consistency of the chart. Once this was completed, the primary author conducted the data extraction which was reviewed by the other authors. Any and all discrepancies were discussed and agreed upon in the final interpretation. All articles reviewed were assigned a unique code to help track all articles reviewed and those that were excluded during the data extraction/charting process. The data extraction form holds information: 1) General information about the study (author, year, country, study design, sample size, and study period); 2) Intervention and control used in the study (calcium and placebo); 3) General baseline characteristics of participants (age, population of disease risk, dosage of daily calcium intake, mean gestational age at starting calcium, etc.); 4) Outcomes of interest that relate to the meta-analyses (pre-eclampsia, eclampsia, and gestational hypertension). (See appendix D for more details on data extraction form).

The meta-analyses were performed using Stata (Version 16.0) with guidance from high-quality articles from published journals which provided framework for the statistical analysis. The primary outcomes assessed were pre-eclampsia, eclampsia and gestational hypertension while the secondary outcomes were maternal and neonatal mortality, preterm birth, and low birth weight, all due to HDP. Pooled analyses were conducted where data were available from more than one study for an outcome. Log risk ratio (RR) along with its variance and the 95% confidence interval (CI) were estimated for each study. Dichotomous outcomes were analysed using the relative risk (RR) with 95% CI, and continuous outcomes were analysed using the mean difference (MD) with 95% CI. If the literature only provided the median, range, and sample size, the algorithms were utilized to estimate the mean deviation and standard deviation.

The risk ratios were then directly pooled across studies using fixed-effects model (inverse-variance method) if heterogeneity was absent, otherwise a random-effects model was used to pool the data. Statistical heterogeneity was evaluated using Chi-square test (p<0.10 was considered as providing evidence of heterogeneity) and I² statistic (values greater than or equal to 50% indicating significant heterogeneity). If heterogeneity was present (p<0.1 or I²≥50%), a source of heterogeneity was explored by fitting characteristics of subjects (mean age, mean gestational age), clinical data (dosage, and duration of supplement), and methodological characteristics (definition of outcome measurements, and setting of the study) in a meta-regression model one by one. Sensitivity analysis by excluding the outlier studies and/or a subgroup analysis according to that factor was performed.

Bearing in mind the association between the intervention (calcium supplement) and primary outcomes (pre-eclampsia and gestational hypertension) may be modified by different clinical characteristics, the following subgroup analyses were performed where data were available: calcium dose (high dose defined as ≤2.0 g/day and >1.2 g/day; moderate dose defined as ≤1.2 g/day and ≥0.6 g/day; low dose defined as <0.6 g/day); the mean gestational age at which calcium supplementation began and whether combined with other drugs or co-supplements; and risk of disease in population. Study participants at high risk of HDP were defined by the trial authors’ definitions and included as being teenagers, women with previous history of pre-eclampsia, women with increased sensitivity to angiotensin II, women with chronic hypertension, primiparous women, nulliparous women, or obese women. The sub-group analyses were based on evidence that calcium supplementation during pregnancy would be more effective for improved outcomes in hypertensive pregnancies. Publication bias was assessed using Egger’s test. P-values < 0.05 were considered as statistically significant, except for the test of heterogeneity where p < 0.10 was used. Subgroup analyses were limited to the primary outcomes.

Quality appraisal and data management processes

All the included trials were assessed for methodological quality and outcomes of interest using a standardized form. Data were abstracted for study design, study site, methods of sequence generation, allocation concealment, attrition and primary outcomes of interest. Individual studies were evaluated independently for methodological validity by two reviewers according to the Cochrane collaboration’s tool for assessing risk of bias in RCTs (33). Any disagreement that arises between the reviewers was resolved through discussion and with the assistance of a third reviewer where required.

Risk of bias and quality procedures

Study quality was independently assessed by two reviewers using the Cochrane collaboration tool for assessing risk of bias in RCTs (33). The following seven domains were evaluated; 1) selection bias (random sequence generation) 2) allocation concealment), 3) performance bias (blinding of participants and assessors), 4) detection bias (blinding of outcome assessment), 5) attrition bias (incomplete outcome data), 6) selective outcome reporting, and 7) other bias. Each item was classified as low, high, or an unclear risk of bias (if there was insufficient information) (see Appendix B for more details on risk of bias assessment).

Study selection procedures

The initial search for previous systematic reviews identified 18 review studies. Among these, 11 duplicated records were excluded leaving 7 review studies yielding 86 individual RCTs that were retrieved for screening. After screening the 86 individual RCTs, 62 studies were excluded leaving 24 eligible RCTs for further assessment. In searching for individual studies, 797 studies were identified for screening titles and abstracts. Among these, 709 studies were excluded (403 used different interventions, 123 had different outcomes, 102 were not RCTs, 57 were not published in English language, 18 were not conducted among pregnant women, and 6 were review studies) leaving 88 individual RCTs that met inclusion criteria for further assessment. After removing duplicates with searching from systematic reviews, 40 RCTs were eligible for assessing full-text. Of these, 6 studies were excluded due to insufficient data on outcomes of interest. Five (5) studies were excluded because they were conducted in developed countries. Three (3) studies excluded did not present data on interested interventions, 3 not interested comparators, and 2 full-text articles were not accessible. Only 21 RCTs met our inclusion criteria and were included in this meta-analysis. All searches were performed from 10th to 15th October, 2020. The selection process is shown in Fig. 1 above.

Study characteristics

Table 1 presents characteristics of included studies and participants. All studies included were RCTs carried out in developing countries. In all studies, the comparison group received a placebo except in two studies in which participants of comparison group were only observed as controls. A total of 22,759 pregnant women were analysed with 11,275 (49.5%) in the calcium supplement group and 11,484 (50.5%) in the control group. The calcium supplements were in the form of elemental calcium or calcium carbonate, while placebo typically contained starch and lactose. Six (6) included studies began calcium supplementation before the 20th week of gestation and the remaining 15 studies started calcium supplementation from the 20th week of gestation and continued till delivery. Of the 21 studies included, 7 compared calcium supplementation with other drugs (i.e., vitamin D, conjugated linoleic acid, etc.), and 14 compared only calcium versus placebo. Most (66.7%) of the studies employed double blind method to reduce bias in study outcomes. There were four large multicentre trials included in the meta-analysis. Nine (9) of the included trials were conducted in the WHO region of Americas, 8 were carried out in South-East Asia region followed by 6 in Eastern Mediterranean region. Only two trials were found in the WHO African region and one trial each in the European region and Western Pacific region of the WHO. Calcium doses administered to pregnant women ranged from 0.4g/day to 2.0g/day. Sample sizes for individual studies ranged from 30 to 9178 with a median of 190. The duration of included studies ranged from 6 months to 57 months. In more than half (57.1%) of the included studies, participants were defined as being at a higher risk of developing HDP (e.g., elderly pregnancy, teenage pregnancy, nulliparity, previous history of pre-eclampsia, or women with positive roll over test, etc.). The mean age of pregnant women at starting calcium supplement ranged from 16.1 to 38.0 for included RCTs. The year of publication for all studies ranged from 1987 to 2015.

Table 1

Characteristics of studies included in the meta-analysis of calcium supplementation for improved outcomes in hypertensive pregnancies
Authors (year)	Country	Study duration (months)	Disease risk in population	Primary outcome(s)	Dosage of intervention administered (g/day)	Sample size (Ca./Control)	Loss to follow up (%)	Mean age (yrs.) at starting Ca. (Calcium/ Control)	Gest. age at starting calcium (weeks)	Population	Blinding
Calcium versus Placebo trials
Aghamohammadi et al. (2015)	Iran	NA	High risk	Pre-eclampsia	1g of calcium	80 (44/45)	9 (10.1%)	36.9 ± 1.9/ 37.4 ± 2.5	< 20 weeks	NA	Double-blind
Belizán et al. (1991)	Argentina	33	Low risk	Pre-eclampsia GH/PIH	2g of calcium	1194 (593/601)	27 (2.3%)	23.7 ± 5.5/ 23.7 ± 5.7	≥ 20 weeks	Nulliparity	Double-blind
Hofmeyr et al. (2008)	South Africa	NA	High risk	Pre-eclampsia Eclampsia	1.5g of calcium	708 (346/362)	0	22.0 ± 3.7/ 22.1 ± 3.7	< 20 weeks	Nulliparity	Double-blind
Khan et al. (2013)	India	12	High risk	Pre-eclampsia Eclampsia	2g of calcium	262 (127/145)	10 (3.6%)	38.02 ± 1.25/ 38.08 ± 1.26	≥ 20 weeks	Nulliparity	NA
Kumar et al. (2009)	New Delhi	36	Low risk	Pre-eclampsia	2g of calcium	524 (290/262)	28 (5.7%)	21.83 ± 2.51/ 21.91 ± 2.47	< 20 weeks	Primigravida	Double-blind
López-Jaramillo et al. (1989)	Ecuador	30	High risk	GH/PIH	2g of calcium	106 (55/51)	0	18.2 ± 2.2/ 18.7 ± 2.7	≥ 20 weeks	Nulliparity	Double-blind
Lopez-Jaramillo et al. (1990)	Ecuador	30	High risk	GH/PIH	2g of calcium	56 (22/34)	0	19.4 ± 1.8	≥ 20 weeks	Nulliparity	Double-blind
López-Jaramillo et al. (1997)	Ecuador	57	High risk	Pre-eclampsia	2g of calcium	260 (125/135)	0	16.1 ± 0.6/ 15.9 ± 0.7	≥ 20 weeks	Nulliparity	Double-blind
Niromanesh et al. (2001)	Iran	NA	High risk	Pre-eclampsia GH/PIH	2g of calcium	30 (15/15)	0	23.8 ± 4.7/ 22.5 ± 4.9	≥ 20 weeks	Nulliparity Primigravida	Double-blind
Purwar et al. (1996)	India	15	Low risk	GH/PIH Pre-eclampsia	2g of calcium	190 (103/98)	11 (5.4%)	21.78 ± 2.31/ 22.08 ± 2.87	≥ 20 weeks	Nulliparity	Double-blind
Villar et al. (2006)	Argentina Egypt India Peru South Africa Vietnam	21	Low risk	Pre-eclampsia Eclampsia	1.5g of calcium	8316 (4157/4168)	9 (0.1%)	22.6 ± 4.4/ 22.7 ± 4.4	≥ 20 weeks	Nulliparity	Double-blind
Wanchu et al. (2001)	India	NA	High risk	Pre-eclampsia	2g of calcium	100 (50/50)	0	37.4	≥ 20 weeks	Primigravida	Open
Villar et al. (1987)s	Argentina	36	Low risk	PIH	1.5g of calcium	52 (25/27)	0	21.0 ± 3.1/ 21.2 ± 3.6	≥ 20 weeks	Primigravida Nulliparity	Double-blind
Nenad et al. (2011)	Serbia	NA	Low risk	Pre-eclampsia, GH/PIH	2g of calcium	9178 (4590/4588)	0	NA	< 20	Nulliparity	NA
Calcium + other drugs versus Placebo
Asemi et al. (2012)	Pakistan	11	High risk	Pre-eclampsia	0.5g calcium + 200 IU Vit D3	49 (24/25)	0	24.9 ± 4.2/ 24.9 ± 3.7	≥ 20 weeks	Primigravida	Single blind
Bassaw et al. (1998)	Bangladesh	36	Low risk	Pre-eclampsia Eclampsia GH/PIH	1.2g calcium + 0.08g aspirin	331 (81/250)	0	27 ± 1.4/ 26 ± 1.3	< 20 weeks	Primigravida	Single blind
Herrera et al. (2005)	Bangladesh Columbia	36	High risk	GH/PIH Pre-eclampsia	0.6 calcium + 0.45g CLA	48 (25/25)	2 (4.0%)	NA	< 20 weeks	Primigravida	Double-blind
Herrera et al. (1998)	Columbia	12	High risk	Pre-eclampsia	0.6g calcium + 0.45g CLA	86 (43/43)	0	NA	≥ 20 weeks	Primigravida	Double-blind
Marya et al. (1987)	India	NA	Low risk	Pre-eclampsia	0.4g calcium + 1200 IU Vit D	400 (200/400)	0	20 − 35	≥ 20 weeks	NA	NA
Samimi et al. (2015)	Iran	6	High risk	Pre-eclampsia	1g calcium + 3570 IU Vit D3	58 (30/30)	2 (3.3%)	27.3 ± 3.7/ 27.1 ± 5.2	≥ 20 weeks	Primigravida	Double-blind
Taherian et al. (2002)	Iran	36	Low risk	Pre-eclampsia	0.5 calcium + 200 IU Vit D	660 (330/330)	0	21.9 ± 0.28/ 21.2 ± 0.19	≥ 20 weeks	Nulliparity	NA

NA - not applicable yrs – years Ca – Calcium CLA – conjugated linoleic acid IU – international units

Meta-analysis

Impact on pre-eclampsia

The effect of calcium supplementation during pregnancy on risk of pre-eclampsia was pooled across 19 RCTs. There were 11,114 and 11,322 pregnant women in the intervention and control group respectively. Meta-analysis indicates that calcium supplementation during pregnancy is effective to reduce the risk of pre-eclampsia by 49% when compared with placebo [RR: 0.51, (95% CI: 0.38, 0.67), I² = 65.6%, P < 0.001] (Fig. 2). Due to the substantial heterogeneity in the pooled data, the random-effects model was used. The sources of heterogeneity for pooled calcium versus placebo effect were explored in a meta-regression analysis. Results showed that pre-eclampsia risk in population (low risk versus high risk), type of intervention received (calcium only versus calcium plus other drugs), and dosage of calcium supplementation (low, moderate and high dose) could reduce the degree of heterogeneity from 65.6–57.2%, 57.8% and 57.6% respectively. However, the results were not statistically significant.

Subgroup analysis was performed accordingly (Table 2). The protective effect of calcium supplementation was greater in high-risk pregnant women than in low-risk pregnant women with a pooled effect of 57% [RR: 0.43, (95% CI: 0.28, 0.64), I² = 21.9%, P = 0.241] and 40% [RR: 0.60, (95% CI: 0.43, 0.84), I² = 74.0%, P < 0.001] respectively. In addition, the protective effect of calcium supplementation to reduce the risk of pre-eclampsia was higher in the moderate dose group 71% [RR: 0.29, (95% CI: 0.16, 0.52), I² = 0.0%, P = 0.611] compared to low dose 49% [RR: 0.51, (95% CI: 0.32, 0.80), I² = 0.0%, P = 0.481] and high dose group 40% [RR: 0.60, (95% CI: 0.44, 0.82), I².= 68.2%, P < 0.001] Again, the protective effect of calcium supplementation to reduce pre-eclampsia risk was also higher in pregnant women who began calcium supplementation from 20th week of gestation or later 53% [RR: 0.47, (95% CI: 0.32, 0.71), I² = 62.1%, P < 0.001] compared to pregnant women who started calcium supplement before 20th week of gestation 52% [RR: 0.48, (95% CI: 0.26, 0.88), I² = 73.1%, P < 0.001] Finally, subgroup analysis by the type of intervention received showed a more significant protective effects among pregnant women who took calcium with other drugs [RR: 0.40, (95% CI: 0.26, 0.61), I² = 4.3%, P = 0.391] than those who took only calcium supplement [RR: 0.58, (95% CI: 0.43, 0.79), I² = 67.6%, P < 0.001]. Egger’s test, however, did not show any evidence of publication bias for pre-eclampsia (P < 0.001).

Table 2

Subgroup analysis of effect of calcium supplementation in pregnancy on risk of pre-eclampsia
Variable	No. of trials	RR (95% CI)	P-value	I²%
Pre-eclampsia	19
Population risk
High risk	11	0.43 (0.28, 0.64)	0.235	21.9
Low risk	8	0.60 (0.43, 0.84)	< 0.001	74.0
Calcium dose
Low dose	3	0.51 (0.32, 0.80)	0.477	0.0
Moderate dose	5	0.29 (0.16, 0.52)	0.614	0.0
High dose	11	0.60 (0.44, 0.82)	< 0.001	68.2
Gestational age
<20 weeks’	6	0.48 (0.26, 0.88)	0.002	73.1
≥20 weeks’	13	0.47 (0.32, 0.71)	0.002	62.1
Type of intervention received
Calcium plus other drugs	7	0.40 (0.26, 0.61)	0.394	4.3
Calcium alone	12	0.58 (0.43, 0.79)	< 0.001	67.6

Impact on eclampsia

The outcome of eclampsia was reported by two included RCTs with a 33% reduction of risk in the calcium group compared to the control group. However, these results were not statistically significant [RR: 0.67, (95% CI: 0.37, 1.22), I² = 0.0%, P = 0.189]. The included RCTs on eclampsia were made up of a total of 4,479 pregnant women in the intervention arm and 4,478 pregnant women in the control arm. There was no statistical heterogeneity in the pooled data (Fig. 3).

Impact on gestational hypertension/pregnancy induced hypertension

Calcium supplementation was associated with a 53% reduction in gestational hypertension or PIH in 11 RCTs [RR: 0.47, (95% CI: 0.32, 0.69), I² = 93.5%, P < 0.001]. A total of 4,151 pregnant women were in the calcium group versus 4,583 pregnant women in the intervention group. There was a significant statistical heterogeneity in the pooled data (I² = 93.5%) hence the random-effects model was used (Fig. 4). In a subgroup analysis, pregnant women at higher risk of developing PIH had a more prominent protective effect of calcium supplementation [RR: 0.30, (95% CI: 0.10, 0.89), I² = 77.3%, P < 0.001] than those at lower risk [RR: 0.53, (95% CI: 0.34, 0.84), I² = 95.7, P < 0.001] and this difference was statistically significant (P < 0.001). The reduction of PIH risk was also consistent across the following subgroups: pregnant women who began calcium supplementation before the 20th week of gestation [RR: 0.34, (95% CI: 0.08, 1.50), I² = 74.4%, P = 0.021] and pregnant women who started calcium supplementation from the 20th week of gestation [RR: 0.48, (95% CI: 0.35, 0.68), I² = 69.3%, P < 0.001]. Also, subgroup analysis indicated that pregnant women receiving calcium supplement plus other drugs had a higher reduction effect [RR: 0.32, (95% CI: 0.09, 1.06), I² = 53.9%, P = 0.111] compared to pregnant women receiving only calcium supplement [RR: 0.50, (95% CI: 0.33, 0.76), I² = 95.3%, P < 0.001]. Finally, subgroup analysis showed that only high dose of calcium supplement could reduce the risk of PIH [RR: 0.50, (95% CI: 0.33, 0.76), I² = 95.3%] and this was statistically significant (P < 0.001) (Table 3).

Table 3

Subgroup analysis of effect of calcium supplementation in pregnancy on risk of gestational hypertension
Variable	No. of trials	RR (95% CI)	P-value	I²%
GH/PIH	11
Population risk
High risk	4	0.30 (0.10, 0.89)	< 0.001	77.3
Low risk	7	0.53 (0.53, 0.84)	< 0.001	95.7
Calcium dose
Low dose	1	0.67 (0.33, 1.35)	*	*
Moderate dose	2	0.16 (0.05, 0.56)	0.470	0.0
High dose	8	0.50 (0.33, 0.76)	< 0.001	95.3
Gestational age
<20 weeks’	3	0.34 (0.08, 1.50)	0.020	74.4
≥20 weeks’	8	0.48 (0.35, 0.68)	< 0.001	93.5
Type of intervention received
Calcium plus other drugs	3	0.32 (0.09, 1.06)	0.110	53.9
Calcium alone	8	0.50 (0.32, 0.69)	< 0.001	93.5

* = Not applicable because there was only one study in that category

Impact on preterm delivery

Nine (9) RCTs described the effect of calcium supplementation on preterm delivery. There were 4,038 and 4,042 participants in the intervention and control arms respectively. Meta-analysis showed that calcium supplement could reduce the risk of preterm delivery by 48% and this result was statistically significant [RR: 0.52, (95% CI: 0.35, 0.78), I² = 79.3%, P = 0.001] (Fig. 5).

Impact on low birth weight (birthweight < 2500g)

The risk of low birthweight did not show any statistically significant reduction with calcium supplementation compared to placebo in five (5) trials [RR: 0.94, (95% CI: 0.85, 1.04), I² = 36.0%, P = 0.220]. The number of participants in the intervention arm was 3,930 as against 3,935 in the control arm. Due to the evidence of low statistical heterogeneity in the pooled data, the fixed-effects (inverse variance) method was used (Fig. 6).

Impact on maternal and neonatal mortality

In all 21 RCTs included in this meta-analysis, none of them reported evidence on maternal and neonatal mortality due to hypertensive disorders of pregnancy. As a result, meta-analysis could not be performed on these outcomes.

Summary of findings

Meta-analysis indicates that calcium supplementation during pregnancy is effective to reduce the risk of pre-eclampsia by 49% when compared with placebo. For impact on eclampsia, meta-analysis showed a 33% reduction of risk in the calcium group compared to the control group, however, this result was not statistically significant. In addition, calcium supplementation was associated with a 53% reduction in PIH. Also, the risk of preterm deliveries was reduced by 48% in the intervention arm and this result was statistically significant. Calcium supplementation did not show any statistically significant reduction effect on the risk of low birthweight.

Results from the meta-analysis suggested that calcium supplementation could significantly reduce the risk of pre-eclampsia and gestational hypertension or PIH by approximately 49% and 53% respectively, compared with placebo. Even though 33% reduction was recorded by calcium supplementation for eclampsia, the result was not statistically significant. The possible explanation for the effectiveness of calcium supplementation during pregnancy in developing countries could be attributed to the difference in baseline calcium intake. In most of the included trials from developing countries, baseline intake was low, while it was adequate in most of the trials from advanced countries (33). Low calcium levels in the body have been hypothesized to cause an increase in BP by stimulating the release of parathyroid hormone (PTH) and renin-angiotensin pathway which leads to increased intracellular calcium concentration in vascular smooth muscle cells and causes vasoconstriction (34). Sun et al. (2019) emphasised that the pathophysiological mechanism of pre-eclampsia and PIH has not been explained exactly (26). Nevertheless, some scholars believe that calcium deficiency is one of the important factors accounting for these conditions in pregnancy. (Hofmeyr et al., 2007; Villar et al., 2006). Moreover, results of a randomized controlled trial by Carroli et al. (2010) suggested that calcium could increase magnesium levels and have an effect on smooth muscle function of the utero-placental blood flow (55). Furthermore, Desousa et al. (2016) also proposed that calcium supplementation prevented endothelial cell activation induced by trophoblastic debris from pre-eclampsia placentae (56). With regards to the protective effect of calcium in HDP, Chen et al. (2013) maintained that calcium supplementation may prevent the activation of the endothelium in response to activators (57). A quiescent healthy endothelium continuously releases potent vasodilators in response to blood flow, which have the potential to lower vascular resistance directly (58) thereby reducing the risk of hypertension in pregnancy. These findings were corroborated in recently published meta-analysis (7,25,26) in which calcium supplementation was found to consistently reduce the risk of HDP including pre-eclampsia and gestational hypertension.

This study showed that all the three different doses of calcium supplement could reduce the risk of pre-eclampsia. However, calcium supplement given in moderate dose (i.e., 0.6–1.2g/day) was more effective as it could significantly reduce pre-eclampsia risk by 71% compared to low and high dose 49% and 40% respectively. On the other hand, only moderate dose and high dose groups could reduce the risk of gestational hypertension by 84% and 50% respectively. In spite of that, the greater reduction effect in the moderate dose group was not statistically significant, hence, we could not conclude the moderate dose was the best for gestational hypertension. In effect, high dose supplement was regarded most effective for gestational hypertension in this meta-analysis. A plausible explanation for this could be the fact that most studies usually administered high or moderate dose calcium combined with other drugs, such as vitamin D or linoleic acid. In contrast, the low dose calcium tended to be supplemented alone in fewer studies. This may underestimate the effect of low dose calcium supplement in reducing the risk of HDP. The present findings are confirmatory of that of a systematic review and meta-analysis conducted by (Hofmeyr et al., 2018) in which high-dose calcium supplementation with ≥ 1 g/per day during pregnancy reduced the risk of gestational hypertension and pre-eclampsia. Also, according to Imdad et al. (2011) and Khaing et al. (2017) high-certainty evidence suggests high-dose calcium supplementation reduces pre-eclampsia in those at high risk of developing hypertensive disorders.

On the contrary, some literatures reported that high dose calcium supplementation may induce adverse effects such as cardiovascular disease (60,61). Moreover, calcium supplementation in high doses was found to increase the risk of HELLP syndrome in two (2) systematic reviews (23,27). Furthermore, high dose calcium supplementation during pregnancy is associated with postnatal bone resorption in Gambian women, which persists through subsequent lactation (63) but there was no causal inference. Nonetheless, the late effect of high dose calcium supplementation on health is still unclear at present (25). Above all, more in-depth mechanism exploration of this concept is required to help us understand the action mechanism in the various populations. Further research should focus on the different dosing regimen with regards to the amount and timing of supplement per day during pregnancy to reduce the risk of HDP.

Our meta-analysis showed that the best supplementation for lowering the risk of pre-eclampsia and gestational hypertension was calcium supplement plus other co-supplements such as vitamin D and linolic acid. Calcium supplement plus vitamin D might be preferred for reducing pre-eclampsia gestational hypertension risk. This finding could be explained by the fact that adequate vitamin D intake helps maintain calcium homeostasis and in turn has an inverse relationship with blood pressure (33). Christakos et al. (2011) stated that the principal function of vitamin D in calcium homeostasis is to increase calcium absorption from the intestine. This to some extent could explain why calcium supplements taken with vitamin D showed a significant reduction of risk in the intervention arm than only calcium supplements. Nonetheless, this evidence was not enough to make a conclusive statement for using calcium supplement with vitamin D to reduce the risk of HDP. Although supplementation of calcium plus vitamin D supplementation ranked higher than calcium alone, this needs to be confirmed in head-to-head trials (7). Our results are consistent with the updated Cochrane review by Hofmeyr et al. (2018). Our findings were again supported by a meta-analysis performed by Khaing et al. (2017) where they found.

Our meta-analysis demonstrated that calcium supplementation was more effective against pre-eclampsia in high-risk pregnancies (57%) than in low-risk pregnancies (40%). Also, pregnant women at higher risk of developing PIH had a more prominent protective effect from calcium supplementation (70%) than those at lower risk (47%) and this difference was statistically significant. High prevalence of malnutrition in developing countries could account for the greater reduction effect in the high-risk pregnancies. Calcium is regarded as one of the greatest important micronutrients (63). Pregnancy and lactation are periods of high calcium requirement (30,64) because the skeleton of a newborn baby contains approximately 20-30g of calcium. Calcium is largely involved in homeostatic control mechanisms to maintain constant blood pressure levels (65). Consequently, the potential negative effect of a deficiency in calcium intake during pregnancy may affect bone metabolism and may increase the risk of HDP (65,66). Pregnant women at higher risk of gestational hypertension and pre-eclampsia could be those living in either low or middle-income settings, where dietary calcium intake is too low (67). Ross et al. (2012) noted that hormones involved in blood pressure control are altered during micronutrient deficiencies (e.g. lack of calcium) and could result in significant morbidity in malnourished pregnancies (68). Therefore, the WHO has recommended prescribing calcium supplementation in routine antenatal care to those high-risk pregnant women with low calcium intake for prevention of HDP (27). The findings from our study are consistent with the updated Cochrane review by Hofmeyr et al. (2018) in which calcium supplementation showed a significant preventive effect on pre-eclampsia, especially in high-risk pregnancies. Tang et al. (2015) also confirmed that calcium supplementation was more beneficial in high-risk pregnancies. Furthermore, similar findings were reported in previous systematic reviews and meta-analysis in both developed and developing countries (7,25,26,70) that calcium supplement appeared more effective in high-risk pregnancies than in low risk pregnancies.

The WHO in their recommendation stated that “in populations with low dietary calcium intake, daily calcium supplementation (1.5–2.0g oral elemental calcium) is recommended for pregnant women to reduce the risk of pre-eclampsia” (27). In contrast, the WHO (2020) again recommended that “pre-pregnancy calcium supplementation for the prevention of pre-eclampsia and its complications is endorsed only in the context of rigorous research (71). This shows that there is no appropriate timing of initiation of calcium supplementation during gestation in order to improve compliance and reduce the risk of pre-eclampsia in the WHO recommendation. Notwithstanding, this meta-analysis showed that calcium supplementation seemed more effective in reducing the risk of pre-eclampsia in participants who began the supplementation from 20th week of gestation or later. Pooled data from this meta-analysis had mean gestational age of delivery at 38 weeks. This infers that calcium supplement should be given at about 20th week of gestation or later. Patrelli et al. (2012) explained that the bulk of foetal skeletal growth takes place from mid-pregnancy onwards, with maximal calcium accretion occurring during the third trimester (70). The total calcium accretion rate of the foetus increases from approximately 50mg/day at 20 weeks gestation to 330 mg/day at 35 weeks. For the third trimester of pregnancy, 200 mg/day is considered the average accretion rate (70). Therefore, abnormality of the placenta might release secreted factors in mother’s circulations, which could result in clinical manifestation of pre-eclampsia occurring around 20th week of gestation (7). Consequently, increasing calcium concentration during the 20th week of gestation could play a role in decreasing smooth muscle contractility and increasing vasodilation, thus lowering risk of pre-eclampsia (44). These results are consistent with the updated Cochrane review which found a significant preventive effect of calcium supplementation on pre-eclampsia, especially in participants who began supplementation from 20th week of gestation (59). Khaing et al. (2017) found a contrary result to our finding in their systematic review and network meta-analysis. Their result revealed calcium supplementation effect was higher in pregnant women whose supplement durations were 18 weeks’ gestation or shorter but not for longer than 18 weeks’ gestation (7). Further research should therefore focus on the appropriate timing of initiation of calcium supplementation during pregnancy in order to improve compliance to the regimen.

The results of this meta-analysis showed that calcium supplementation had no significant protective effect on low birth weight. However, there was a significant reduction of 48% in preterm delivery in our meta-analysis. This beneficial effect of calcium supplementation in reducing preterm deliveries appears to be related to the reduction in PIH, pre-eclampsia and eclampsia which predisposes pregnant women to the condition. It is worthy to note that maternal calcium supplementation is not only effective in reducing gestational morbidities and preterm deliveries but also morbidities later in childhood and adulthood (72). A systematic review by Bergel and Barros (2007) had reported that offspring of women who were supplemented with calcium during pregnancy had low incidence of hypertension in childhood (72). The present findings were strikingly similar to that of Hofmeyr et al. (2018) who confirmed in their updated Cochrane review that preterm birth was reduced by calcium supplementation to pregnant women during gestation. Further research is recommended on the effects of calcium supplementation on neonatal outcomes not limited to preterm and low birth weight but including small for gestational age and neonatal mortality in developing countries.

This meta-analysis has several strengths. Only RCTs were included in the meta-analysis. Randomized controlled trials and especially, meta-analysis of several of these trials are traditionally the gold standards for judging the benefits of treatments. This is because RCTs are conceptually easier to attribute any observed effect to the treatments being compared. RCTs also minimize bias through the use of blinding and help eliminate, or at least minimize confounding factors through randomization. However, our study also had some limitations. For instance, some relevant records might be missing from our pooling because neither grey literature databases were used for identifying studies, nor non-English studies were considered due to lack of resources and funding. The number of included studies for co-supplements were also small, and thus estimation of supplementation effects was imprecise.

Evidence from this study suggests that calcium supplementation could significantly reduce the risk of pre-eclampsia, gestational hypertension and eclampsia by approximately 49%, 53% and 33% respectively when compared with placebo. Subgroup analysis revealed that calcium supplement given in moderate dose showed a higher reduction effect by 71% in the risk of developing pre-eclampsia, however, this was not statistically significant. In addition, subgroup analysis showed that the best supplementation for lowering the risk of pre-eclampsia and gestational hypertension was calcium plus co-supplements such as vitamin D and linoleic acid. Moreover, the study demonstrated that calcium supplementation was more effective against pre-eclampsia and gestational hypertension in higher risk pregnancies than in lower risk pregnancies. In terms of timing of initiation of the intervention, the results showed that calcium supplementation seemed more effective in reducing the risk of pre-eclampsia in participants who began supplementation from 20th week of gestation or later. However, the results indicated that calcium supplementation had no significant protective effect on low birth weight.

DBP – Diastolic Blood Pressure

HDP – Hypertension disorder of Pregnancy

HELLP – Haemolysis, Elevated Liver Enzymes, and Low Platelet Count

ISSHP – International Society for the Study of Hypertension in Pregnancy

PIH – Pregnancy-induced Hypertension

RCTs – Randomized Controlled Trials

SBP – Systolic Blood Pressure

WHO – World Health Organization

Acknowledgement
I extend my heartfelt gratitude to my co-authors for their invaluable contributions. I would especially like to thank my supervisor, Prof. Paul Amuna, for his exceptional guidance and direction throughout this project.

Author’s contribution

SSA: Conceptualization, Data synthesis, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Writing – original draft; JMG: Formal analysis, Methodology, Writing – review and editing; AA: Formal analysis, Methodology, Writing – review and editing; PA: Supervision, Conceptualization, Data synthesis, Methodology, Project administration, Resources, Validation, Writing – original draft

Funding
Self-funding

Availability of data and materials

No datasets were generated or analysed during the current study.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable

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Effectiveness of Calcium Supplementation for Improved Outcomes in Hypertensive Pregnancies in Developing Countries: A Systematic Review and Meta-Analysis

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Abstract

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Introduction

Methods

Results

Study selection procedures

Study characteristics

Meta-analysis

Impact on pre-eclampsia

Impact on eclampsia

Impact on gestational hypertension/pregnancy induced hypertension

* = Not applicable because there was only one study in that category

Impact on preterm delivery

Impact on low birth weight (birthweight < 2500g)

Impact on maternal and neonatal mortality

Summary of findings

Discussion

Conclusion

Abbreviations

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References

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