Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg) Calcium Supplementation During Pregnancy for Preventing Hypertensive Disorders Is not Associated with Changes in Platelet Count, Urate, and Urinary Protein: a Randomized Control Trial Participant recruitment and retention in longitudinal preconception randomized trials: lessons learnt from the Calcium And Pre-eclampsia (CAP) trial Effect of calcium supplementation in pregnancy on maternal bone outcomes in women with a low calcium intake123 World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: An exploratory, randomized placebo controlled study. The prediction of adverse maternal outcomes in preeclampsia. Lower Rate of Preeclampsia After Antioxidant Supplementation in Pregnant Women with Low Antioxidant Status Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia: a multicentre, double-blind, randomised, placebo-controlled trial
Background It has been suggested that a higher calcium intake might favourably modify cardiovascular risk factors . However , findings of an ultimately decreased risk of cardiovascular disease ( CVD ) are limited . Instead , recent evidence warns that taking calcium supplements might increase myocardial infa rct ion ( MI ) risk . Objective To prospect ively evaluate the associations of dietary calcium intake and calcium supplementation with MI and stroke risk and overall CVD mortality . Methods Data from 23 980 Heidelberg cohort participants of the European Prospect i ve Investigation into Cancer and Nutrition study , aged 35–64 years and free of major CVD events at recruitment , were analysed . Multivariate Cox regression models were used to estimate HRs and 95 % CIs . Results After an average follow-up time of 11 years , 354 MI and 260 stroke cases and 267 CVD deaths were documented . Compared with the lowest quartile , the third quartile of total dietary and dairy calcium intake had a significantly reduced MI risk , with a HR of 0.69 ( 95 % CI 0.50 to 0.94 ) and 0.68 ( 95 % CI 0.50 to 0.93 ) , respectively . Associations for stroke risk and CVD mortality were overall null . In comparison with non-users of any supplements , users of calcium supplements had a statistically significantly increased MI risk ( HR=1.86 ; 95 % CI 1.17 to 2.96 ) , which was more pronounced for calcium supplement only users ( HR=2.39 ; 95 % CI 1.12 to 5.12 ) . Conclusions Increasing calcium intake from diet might not confer significant cardiovascular benefits , while calcium supplements , which might raise MI risk , should be taken with caution Objective . To test the hypothesis that calcium supplementation inhibits the underlying pathological processes in women with preeclampsia . Methods . Seven hundred and eight nulliparous women were enrolled in a WHO r and omized double-blind trial , who received 1.5 g of calcium or placebo from 20 weeks of pregnancy or earlier . Platelet count , serum urate , and urinary protein/creatinine ratio were measured at or near 35 gestational weeks . Results . No difference was detected in rates of abnormal platelet count ( relative risk [ RR ] 1.18 ; 95 % confidence interval [ CI ] , 0.63 to 2.18 ) , serum urate level ( 1.0 ; 0.64 to 1.57 ) or urine protein/creatinine ratio ( 1.01 ; 0.76 to 1.34 ) . This was consistent with the main trial finding of no difference in the incidence of ‘ dipstick ’ proteinuria between women receiving calcium and those receiving placebo ( 8312 women ; RR , 1.01 ; 95 % CI , 0.88 to 1.15 ) . Conclusions . An effect of calcium supplementation in the second half of pregnancy on the rate of abnormal laboratory measures associated with preeclampsia was not demonstrated Background The preconception period has the potential to influence pregnancy outcomes and r and omized controlled trials ( RCTs ) are needed to evaluate a variety of potentially beneficial preconception interventions . However , RCTs commencing before pregnancy have significant participant recruitment and retention challenges . The Calcium And Pre-eclampsia trial ( CAP trial ) is a World Health Organization multi-country RCT of calcium supplementation commenced before pregnancy to prevent recurrent pre-eclampsia in which non-pregnant participants are recruited and followed up until childbirth . This sub- study explores recruitment methods and preconception retention of participants of the CAP trial to inform future trials . Methods Recruiters at the study sites in Argentina , South Africa and Zimbabwe completed post-recruitment phase question naires on recruitment methods used . Qualitative data from these question naires and quantitative data on pre-pregnancy trial visit attendance and pregnancy rates up to September 2016 are reported in this paper . RStudio ( Version 0.99.903 https://www.rstudio.org ) statistical software was used for summary statistics . Results Between July 2011 and 8 September 2016 , 1354 women with previous pre-eclampsia were recruited .  Recruitment took 2 years longer than expected and was facilitated mainly through medical record/register and maternity ward/clinic-based strategies . Recruiters highlighted difficulties associated with inadequate medical records , redundant patient contact details , and follow-up of temporarily ineligible women as some of the challenges faced . Whilst the attendance rates at pre-pregnancy visits were high ( 78 % or more ) , visits often occurred later than scheduled . Forty-five percent of participants became pregnant ( 614/1354 ) , 33.5 % ( 454/1354 ) within 1 year of r and omization . Conclusions In preconception trials , both retrospective and prospect i ve methods are useful for recruiting eligible women with certain conditions . However , these are time-consuming in low-re source setting s with suboptimal medical records and other challenges . Trial planners should ensure that trial budgets cover sufficient on-site research ers with pre-trial training , and should consider using mobile phone and web-based electronic tools to optimize recruitment and retention . This should lead to greater efficiency and shorter trial duration s . Trial registration Pan-African Clinical Trials Registry , Registration Number : PACTR201105000267371 . The trial was registered on 6 December 2016 Background : Mobilization of maternal bone mineral partly supplies calcium for fetal and neonatal bone growth and development . Objective : We investigated whether pregnant women with low calcium intakes may have a more extensive skeletal response postpartum that may compromise their short- or long-term bone health . Design : In a subset of participants ( n = 125 ) in a double-blind , r and omized , placebo-controlled trial ( International Trial Registry : IS RCT N96502494 ) in pregnant women in The Gambia , West Africa , with low calcium intakes ( ≈350 mg Ca/d ) , we measured bone mineral status of the whole body , lumbar spine , and hip by using dual-energy X-ray absorptiometry and measured bone mineral status of the forearm by using single-photon absorptiometry at 2 , 13 , and 52 wk lactation . We collected blood and urine from the subjects at 20 wk gestation and at 13 wk postpartum . Participants received calcium carbonate ( 1500 mg Ca/d ) or a matching placebo from 20 wk gestation to parturition ; participants did not consume supplements during lactation . Results : Women who received the calcium supplement in pregnancy had significantly lower bone mineral content ( BMC ) , bone area ( BA ) , and bone mineral density ( BMD ) at the hip throughout 12 mo lactation ( mean ± SE difference : BMC = −10.7 ± 3.7 % , P = 0.005 ; BA = −3.8 ± 1.9 % , P = 0.05 ; BMD = −6.9 ± 2.6 % , P = 0.01 ) . The women also experienced greater decreases in bone mineral during lactation at the lumbar spine and distal radius and had biochemical changes consistent with greater bone mineral mobilization . Conclusions : Calcium supplementation  in pregnant women with low calcium intakes may disrupt metabolic adaptation and may not benefit maternal bone health . Further study is required to determine if such effects persist long term or elicit compensatory changes in bone structure OBJECTIVE The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces  preeclampsia and preterm delivery . STUDY DESIGN R and omized placebo-controlled , double-blinded trial in nulliparous normotensive women from population s with dietary calcium < 600 mg/d . Women who were recruited before gestational week 20 received supplements ( 1.5 g calcium/d or placebo ) throughout pregnancy . Primary outcomes were preeclampsia and preterm delivery ; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates . RESULTS The groups comprised 8325 women who were assigned r and omly . Both groups had similar gestational ages , demographic characteristics , and blood pressure levels at entry . Compliance were both 85 % and follow-up losses ( calcium , 3.4 % ; placebo , 3.7 % ) . Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia ( 4.1 % vs 4.5 % ) that was evident by 35 weeks of gestation ( 1.2 % vs 2.8 % ; P = .04 ) . Eclampsia ( risk ratio , 0.68 : 95 % CI , 0.48 - 0.97 ) and severe gestational hypertension ( risk ratio , 0.71 ; 95 % CI , 0.61 - 0.82 ) were significantly lower in the calcium group . Overall , there was a reduction in the severe preeclamptic complications index ( risk ratio , 0.76 ; 95 % CI , 0.66 - 0.89 ; life-table analysis , log rank test ; P = .04 ) . The severe maternal morbidity and mortality index was also reduced in the supplementation group ( risk ratio , 0.80 ; 95 % CI , 0.70 - 0.91 ) . Preterm delivery ( the neonatal primary outcome ) and early preterm delivery tended to be reduced among women who were < or = 20 years of age ( risk ratio , 0.82 ; 95 % CI , 0.67 - 1.01 ; risk ratio , 0.64 ; 95 % CI , 0.42 - 0.98 , respectively ) . The neonatal mortality rate was lower ( risk ratio , 0.70 ; 95 % CI , 0.56 - 0.88 ) in the calcium group . CONCLUSION A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity , maternal morbidity , and neonatal mortality , albeit these were secondary outcomes BACKGROUND Epidemiological findings suggest that the link between poverty and pre-eclampsia might be dietary calcium deficiency . Calcium supplementation has been associated with a modest reduction in pre-eclampsia , and also in blood pressure ( BP ) . METHODS This exploratory sub- study of the WHO Calcium and Pre-eclampsia ( CAP ) trial aims to determine the effect of 500mg/day elemental calcium on the blood pressure of non-pregnant women with previous pre-eclampsia . Non-pregnant women with at least one subsequent follow-up trial visit at approximately 12 or 24weeks after r and omization were included . RESULTS Of 836 women r and omized by 9 September 2014 , 1st visit data were available in 367 women of whom 217 had previously had severe pre-eclampsia , 2nd visit data were available in 201 women . There was an overall trend to reduced BP in the calcium supplementation group ( 1 - 2.5mmHg ) although differences were small and not statistically significant . In the subgroup with previous severe pre-eclampsia , the mean diastolic BP change in the calcium group ( -2.6mmHg ) was statistically larger than in the placebo group ( + 0.8mmHg ) , ( mean difference -3.4 , 95 % CI -0.4 to -6.4 ; p=0.025 ) . The effect of calcium  on diastolic BP at 12weeks was greater than in those with non-severe pre-eclampsia ( p=0.020 , ANOVA analysis ) . CONCLUSIONS There is an overall trend to reduced BP but only statistically significant in the diastolic BP of women with previous severe pre-eclampsia . This is consistent with our hypothesis that this group is more sensitive to calcium supplementation , however results need to be interpreted with caution OBJECTIVES ( 1 ) To evaluate whether clinical variables reflecting the multiorgan dysfunctions of preeclampsia can predict adverse maternal outcomes of preeclampsia ; ( 2 ) to determine the usefulness of the mean platelet volume (MPV):platelet ratio as a novel measure of platelet consumption in predicting the severity of preeclampsia . METHOD A retrospective chart review was conducted of cases of preeclampsia seen in 3 tertiary level units from January 2001 to December 2001 . C and i date predictors of adverse maternal outcome were gestational age  ( GA ) on admission to hospital , blood pressure , proteinuria , urine output , uric acid , creatinine , aspartate transaminase ( AST ) , lactate dehydrogenase , bilirubin , albumin , fraction of inspired oxygen : oxygen saturation ( FIO2:SaO2 ) ratio , platelet count , MPV , MPV : platelet ratio , fibrinogen , and seizures . The combined adverse maternal outcomes included maternal death ; 1 or more of hepatic failure , hematoma , or rupture ; Glasgow coma scale < 13 ; stroke ; 2 or more seizures ; cortical blindness ; positive inotrope support ; myocardial infa rct ion ; infusion of any third antihypertensive ; dialysis ; renal transplantation ; > or = 50 % FIO2 for > 1 hour ; intubation ; or transfusion of > or = 10 units of blood products . Descriptive , univariable , and multivariable analyses were performed , with significance set at P < .05 . RESULTS Of a total of 594 women with preeclampsia , 60 ( 10.1 % ) developed at least 1 element of the combined adverse outcome ; 1 of these 60 women died . The most common outcomes were increased oxygen requirements , the use of a third infused antihypertensive , and transfusion > 10 units . In women who developed an adverse outcome , GA and fibrinogen were lower , and total leukocyte count , creatinine , and AST were greater . Multivariable logistic regression revealed that admission GA ( odds ratio [ OR ] , 0.91 ) , dipstick protein ( OR , 1.31 ) , and MPV : platelet ratio ( OR , 391.0 ) independently predicted the outcome . CONCLUSIONS Several promising markers were identified : admission GA , dipstick proteinuria , and the MPV : platelet ratio . MPV : platelet ratio also showed promise as a marker of platelet consumption . A prospect i ve study is required to develop a clinical prediction model for preeclampsia Objective : To investigate maternal and neonatal outcomes after antioxidant supplementation relatively early in pregnancy ( 8 to 12 weeks ) for pregnant women with low antioxidant status . Methods : A r and omized , double-blind , placebo-controlled trial of daily antioxidant supplementation was performed on pregnant women screening positive for low antioxidant status at 8 to 12 weeks of gestation . Low antioxidant status was defined as a superoxidedismutase ( SOD ) level below 1102 U/g Hb or 164 U/mL. The supplementation group received the following antioxidants daily : vitamins A ( 1000 IU ) , B6 ( 2.2 mg ) , B12 ( 2.2 μg ) , C ( 200 mg ) , and E ( 400 IU ) , folic acid ( 400 μg ) , N-acetylcysteine ( 200 mg ) , Cu ( 2 mg ) , Zn ( 15 mg ) , Mn ( 0.5 mg ) , Fe ( 30 mg ) , calcium ( 800 mg ) , and selenium ( 100 μg ) . The control group received Fe ( 30 mg ) and folic acid ( 400 μg ) . Maternal ( preeclampsia , abortion , and hypertension ) and perinatal outcomes were assessed . Results : In the supplementation group ( 29 subjects ) , we observed 2 cases of preeclampsia ( 6.8 % , 1 mild and 1 severe ) , 1 of IUGR ( birth weight 2300 g at 38 weeks ) , and 1 preterm delivery . In the control group ( 31 subjects ) , there were 8 abortions , 9 cases of preeclampsia ( 29 % , 6 mild and 3 severe ) with perinatal outcome : 3 preterm delivery cases and 1 IUGR ( birth weight 2030 g at 39 weeks ) . Preeclampsia was significantly less frequent in the supplementation group when compared to the control group ( 2 vs. 9 cases , p = 0.043 , OR = 0.18 [ 95 % CI : 0.03 , 0.92 ] ) . Finally we focused on the prediction of preeclampsia at 8 to 12 weeks . Combined sensitivity of markers of antioxidant status ( SOD slutathione peroxidase , [ GPx ] , and total anti-oxidant status [ TAS ] ) was 33 % ( false-positive rate of 4.5 % ) . Conclusion : Antioxidant supplementation was associated with better maternal and perinatal outcome in pregnant women with low antioxidant status  than control supplementation with iron and folate alone . In a selected population already screened positive for low SOD , preeclampsia can be detected in 33 % of asymptomatic cases in the first trimester using SOD , GPx , and TAS . It seems feasible that panels of both biochemical and molecular markers may be clinical ly useful in the prediction of this disease Summary Background Reducing deaths from  hypertensive disorders of pregnancy is a global priority . Low dietary calcium might account for the high prevalence of pre-eclampsia and eclampsia in low-income countries . Calcium supplementation in the second half of pregnancy is known to reduce the serious consequences of pre-eclampsia ; however , the effect of calcium supplementation during placentation is not known . We aim ed to test the hypothesis that calcium supplementation before and in early pregnancy ( up to 20 weeks ' gestation ) prevents the development of pre-eclampsia Methods We did a multicountry , parallel arm , double-blind , r and omised , placebo-controlled trial in South Africa , Zimbabwe , and Argentina . Participants with previous pre-eclampsia and eclampsia received 500 mg calcium or placebo daily from enrolment prepregnancy until 20 weeks ' gestation . Participants were parous women whose most recent pregnancy had been complicated by pre-eclampsia or eclampsia and who were intending to become pregnant . All participants received unblinded calcium 1·5 g daily after 20 weeks ' gestation . The allocation sequence ( 1:1 ratio ) used computer-generated r and om numbers in balanced blocks of variable size . The primary outcome was pre-eclampsia , defined as gestational hypertension and proteinuria . The trial is registered with the Pan-African Clinical Trials Registry , number PACTR201105000267371 . The trial closed on Oct 31 , 2017 . Findings Between July 12 , 2011 , and Sept 8 , 2016 , we r and omly allocated 1355 women to receive calcium or placebo ; 331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant , and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks ' gestation . Pre-eclampsia occurred in 69 ( 23 % ) of 296 participants in the calcium group versus 82 ( 29 % ) of 283 participants in the placebo group with pregnancies beyond 20 weeks ' gestation ( risk ratio [ RR ] 0·80 , 95 % CI 0·61–1·06 ; p=0·121 ) . For participants with compliance of more than 80 % from the last visit before pregnancy to 20 weeks ' gestation , the pre-eclampsia risk was 30 ( 21 % ) of 144 versus 47 ( 32 % ) of 149 ( RR 0·66 , CI 0·44–0·98 ; p=0·037 ) . There were no serious adverse effects of calcium reported . Interpretation Calcium supplementation that commenced before pregnancy until 20 weeks ' gestation , compared with placebo , did not show a significant reduction in recurrent pre-eclampsia . As the trial was powered to detect a large effect size , we can not rule out a small to moderate effect of this intervention . Funding The University of British Columbia , a grantee of the Bill & Melinda Gates Foundation ; UNDP – UNFPA – UNICEF – WHO – World Bank Special Programme of Research , Development and Research Training in Human Reproduction , WHO ; the Argentina Fund for Horizontal Cooperation of the Argentinean Ministry of Foreign Affairs ; and the Centre for Intervention Science in Maternal and Child Health
BACKGROUND The hypertensive disorders of pregnancy include pre-eclampsia , gestational hypertension , chronic hypertension , and undefined hypertension .
Pre-eclampsia is considerably more prevalent in low-income than in high-income countries .
One possible explanation for this discrepancy is dietary differences , particularly calcium deficiency .
Calcium supplementation in the second half of pregnancy reduces the serious consequences of pre-eclampsia , but has limited effect on the overall risk of pre-eclampsia .
It is important to establish whether calcium supplementation before , and in early pregnancy ( before 20 weeks ' gestation ) has added benefit .
Such evidence could count towards justification of population -level interventions to improve dietary calcium intake , including fortification of staple foods with calcium , especially in context s where dietary calcium intake is known to be inadequate .
This is an up date of a review first published in 2017 .
OBJECTIVES To determine the effect of calcium supplementation , given before or early in pregnancy and for at least the first half of pregnancy , on pre-eclampsia and other hypertensive disorders , maternal morbidity and mortality , and fetal and neonatal outcomes .