Vitamin D supplementation decreased the risk of preeclampsia by 39% – meta-analysis Feb 2024

Note: 39% reduction is independant of Vitamin D dose.
Study using a high dose found a 70% reduction

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The effect of vitamin D supplementation in pregnancy on the incidence of preeclampsia: A systematic review and meta-analysis

European J. of Integrative Medicine Vol 66, Feb 2024, https://doi.org/10.1016/j.eujim.2024.102343
lZainab Alimoradi a, Farideh Kazemi b, Azita Tiznobeik b, Mark D. Griffiths c, Seyyedeh Zahra Masoumi b, Soodabeh Aghababaei b

Highlights

• Vitamin D may be beneficial in preventing the occurrence of preeclampsia.
• Studies have yielded inconsistent results about the benefits of vitamin D for preeclampsia.
• A new meta-analysis was needed to include recent studies.
• The meta-analysis assessed vitamin D's impact on preeclampsia risk during pregnancy.
• Vitamin D supplementation reduces the incidence of preeclampsia.

Introduction
The results of previous studies regarding the effect of vitamin D on the incidence of preeclampsia are inconsistent. Therefore, the primary objective of the present review was to determine the effect of vitamin D supplementation during pregnancy on the risk of preeclampsia.

Methods
Five major scientific databases were searched from inception to June 10, 2023. Studies with randomized controlled trial designs were identified. To assess the methodological quality of the selected studies, the Cochrane Tool Checklist (CTC) was used. The random effect model was chosen as a combination model. Statistical heterogeneity was evaluated using the standard χ2 test, and the intensity of heterogeneity was calculated using I2. Effect size indicators including risk ratio (RR), risk difference (RD), and number needed to treat (NNT) were calculated with estimated 95 % confidence intervals.

Results
Nineteen studies were included in the systematic review and meta-analysis. The pooled RR of preeclampsia in the intervention group compared to the control group was 0.61 (95 % CI, 0.47 to 0.78; I2=14.4 %; χ2=23.37; p = 0.27; tau2=0.05), and indicated a 39 % reduction in the risk of preeclampsia. The pooled RD of preeclampsia in the intervention group compared to the control group was -0.03 (95 % CI: -0.05 to -0.01; I2=45.5 %; χ2=36.68; p = 0.01; tau2=0.0008) and the difference in the risk of preeclampsia among women who received vitamin D supplements was 3 % less than the control group. The NNT was 29 (95 % CI: 20 to 52).

Conclusion
Vitamin D supplementation significantly reduces preeclampsia during pregnancy.

Introduction
Preeclampsia is one of the most important challenges in midwifery. The disorder is defined based on increased blood pressure and newly started proteinuria after the 20th week of pregnancy. In the absence of proteinuria, high blood pressure with evidence of systemic disease (such as thrombocytopenia or elevated liver transaminases) is also suggestive of preeclampsia [1,2]. In total, preeclampsia and its complications are responsible for 63,000 maternal deaths worldwide each year, accounting for 12 % of all maternal deaths [2]. The disorder affects 3 %−5 % of pregnancies worldwide [1], [2], [3]. The incidence of the disorder in developed countries is approximately 3.4 %, and in developing countries it ranges from 1.8 % to 16.7 % [4]. Differences in incidence among countries reflect, at least in part, differences in maternal age distribution and the proportion of primiparous pregnant mothers in that country's population [3].

Preeclampsia is a multisystem disease with adverse short-term and long-term consequences for both mother and fetus [3]. Pregnant women with pre-eclampsia are prone to pulmonary edema, coagulation defects, and kidney failure in the current pregnancy, as well as being at greater risk of increased blood pressure and cardiovascular diseases in the later stages of life [5]. Fetal consequences of preeclampsia include intrauterine growth restriction and oligohydramnios, as well as increasing the need to terminate the pregnancy in the form of premature birth, which increases perinatal complications and mortality (3). The greatest risk is in pregnancies with the onset of preeclampsia before the 34th week of pregnancy [3].

Various hypotheses have been proposed for the etiology of preeclampsia. Placental dysfunction is accepted as the main cause of preeclampsia because the definitive treatment for preeclampsia is delivery. Placental hypoxia, oxidative stress, vascular endothelial dysfunction, immunity, and genetic factors also contribute to placental dysfunction and vascular abnormalities, which are thought to be the main cause of preeclampsia [6]. Among women at high risk of preeclampsia, an inverse relationship between maternal vitamin D levels in the second trimester and the risk of early preeclampsia has been observed [7,8]. Taking cholecalciferol (vitamin D) supplements can increase glutathione levels and reduce the production of lipid peroxidation products, leading to a reduction in oxidative stress. Therefore, it is possible that early supplements with a high dose of cholecalciferol can be useful in reducing oxidative stress biomarkers as well as improving vascular endothelial function and preventing the occurrence of preeclampsia [9].

Regarding the relationship between the serum level of vitamin D and the occurrence of preeclampsia, a few systematic review and meta-analysis studies have summarized the available evidence from interventional studies on the effect of vitamin D supplementation on the chances of preeclampsia using the odds ratio (OR) [10,11]. In Gallo et al.’s study, the chance of preeclampsia was reduced by 30 % but was not statistically significant [11]. In 2020, Fogacci et al. (10) also found an OR equal to 0.37. Although this was statistically significant, some of the studies included in this meta-analysis were later retracted, Furthermore, in this meta-analysis, the appropriate effect size indices for interventional studies such as RR or RD were not calculated, and only the odds ratios (ORs) were reported. Given that ORs always exaggerate the size of the effect compared to relative risk [12], the results are not reliable. Lo and Lo updated Fogacci et al. study in 2022 and they excluded some studies that were retracted or whose data were not properly extracted, and one study that was found in the manual search was added to the meta-analysis [13]. Therefore, the aim of the present review was to conduct the meta-analysis more accurately. The present review included three studies published in 2021 [14], [15], [16] in the meta-analysis as well as correctly extracting the data of the Sablok et al. [17] study which was excluded from the meta-analysis by Lo and Lo. The RD and NNT were also calculated, in addition to the risk ratio (RR) so that readers can better interpret the results. In other reviews, where the results were analyzed using the RR, two studies reported a reduction in the risk of preeclampsia by 9 % [18] and 53 % [4], and one study also reported a slight increase in the risk of preeclampsia [19].

Due to the explanations given above, and the inconsistent results of previous studies, there is a need to re-conduct a meta-analysis study with a comprehensive and up-to-date search in academic databases, as well as performing analyses using appropriate effect size indicators. Therefore, the present systematic review and meta-analysis were designed with the main goal of investigating the effect of vitamin D supplementation during pregnancy on the risk of preeclampsia.

Section snippets
Methods
The present review was designed based on the stages of systematic reviews using the guidelines for Preferred Reporting Items for Systematic Review and Meta-aAnalyses (PRISMA) [20].

Study selection
The search process led to the retrieval of 1464 potentially relevant papers. Among these papers, 209 papers were removed due to duplication. Then, the title and abstract were checked and 1232 irrelevant papers were removed (such as being non-intervention studies, animal studies, not containing empirical data, and/or not meeting the requirements of the inclusion criteria). Finally, the full text of the remaining 23 papers was studied, of which five were excluded from the analysis due to not . . .

Principle findings
The present review was conducted to investigate the effect of vitamin D supplementation during pregnancy on the incidence of preeclampsia. For this purpose, both risk ratio (RR) and risk difference (RD) indices were examined. Over half of the studies included in the present meta-analysis were conducted in Iran, and except for two studies that were conducted in Ukraine and America, the rest of the studies were conducted in Asian countries. One of the reasons for more studies in Iran may be the . . .

Conclusions
The quality of evidence, based on GRADE ratings, was found to be high in the case of the pooled RR and moderate in the case of the pooled RD. Based on all the studies reviewed, Vitamin D supplementation significantly reduced preeclampsia during pregnancy. More specifically, the pooled RR and RD of preeclampsia in the intervention group compared to the control group were both significant. Moreover, due to the aforementioned limitations, it would be useful to design high-quality interventional . . .

46+ References

• S. Fogacci Vitamin D supplementation and incident preeclampsia: a systematic review and meta-analysis of randomized clinical trials Clin. Nutr (2020)
• A.C.Q. Lo et al. Vitamin D supplementation and incident preeclampsia: an updated meta-analysis of randomized clinical trials Clin. Nutrition (2022)
• A.M. Ali et al. Effect of vitamin D3 supplementation in pregnancy on the risk of pre-eclampsia - Randomized controlled trial Clin. Nutr (2019)
• X. Hua Effect of folic acid supplementation during pregnancy on gestational hypertension/preeclampsia: a systematic review and meta-analysis Hypertens Pregn. (2016)
• P.M. Villa Aspirin in the prevention of pre-eclampsia in high-risk women: a randomized placebo-controlled PREDO Trial and a meta-analysis of randomized trials Bjog (2013)
• P. August, B.S. Sibai, Ch.J. Lockwood, and V.A. Barss. (2022., 1/20). Preeclampsia: clinical features and diagnosis...
• W. Khaing Calcium and vitamin d supplementation for prevention of preeclampsia: a systematic review and network meta-analysis Nutrients (2017)

M. Tabesh et al. Maternal vitamin D status and risk of pre-eclampsia: a systematic review and meta-analysis
J Clin Endocrinol Metab (2013)
M. Xu et al. Selenium and preeclampsia: a systematic review and meta-analysis
Biol. Trace Elem. Res (2016)
A. Gernand et al. Vitamin D, pre-eclampsia, and preterm birth among pregnancies at high risk for pre-eclampsia: an analysis of data from a low-dose aspirin trial BJOG (2017)
X. Zhao, R. Fang, R. Yu, D. Chen, J. Zhao, and J.J.N. Xiao, "Maternal vitamin D status in the late second trimester and...
M. Karamali et al.
Effects of high-dose vitamin d supplementation on metabolic status and pregnancy outcomes in pregnant women at risk for pre-eclampsia
Horm. Metab. Res
(2015)
S. Gallo
Vitamin D supplementation during pregnancy: an evidence analysis center systematic review and meta-analysis
J. Acad. Nutr. Diet
(2020)
M.J. Knol et al.
Overestimation of risk ratios by odds ratios in trials and cohort studies: alternatives to logistic regression
Cmaj
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X.M. Jiang et al.
Effect of vitamin D3 supplementation during pregnancy on high-risk factors - a randomized controlled trial
J. Perinat. Med
(2021)
G.S. Manasova et al.
Supplementation of vitamin D in pregnant women with 25(OH) D deficiency and risk of preeclampsia development improves perinatal outcomes
Pharmacologyonline
(2021)
S. Nausheen
Impact evaluation of the efficacy of different doses of vitamin D supplementation during pregnancy on pregnancy and birth outcomes: a randomized, controlled, dose-comparison trial in Pakistan
BMJ Nutr. Prev. Health
(2021)
A. Sablok
Supplementation of vitamin D in pregnancy and its correlation with feto-maternal outcome
Clin. Endocrinol (Oxf)
(2015)

• F.R. Pérez-López Effect of vitamin D supplementation during pregnancy on maternal and neonatal outcomes: a systematic review and meta-analysis of randomized controlled trials Fertil. Steril. (2015)
• D.E. Roth et al. Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomized trials Bmj-British Med. J. (2017)
• D. Moher Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement Syst Rev (2015)
• Higgins JPT, Churchill R, Chandler J, and Cumpston MS (eds). (2017). Cochrane Handbook for Systematic Reviews of...
• R.P. Heaney Guidelines for optimizing design and analysis of clinical studies of nutrient effects Nutr. Rev (2014)

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VitaminDWiki - Preeclampsia reduced by Vitamin D - many studies contains:

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VitaminDWiki - Pregnancy category contains

918 items in Pregnancy category

 - see also

• Overview Pregnancy and vitamin D
• Number of articles in both categories of Pregnancy and:Dark Skin 29;   Depression 21;   Diabetes 44;   Obesity 17;  Hypertension 44;   Breathing 35;  Omega-3 44;  Vitamin D Receptor 24 Click here for details
• All items in category Infant/Child 852 items
• Pregnancy needs at least 40 ng of vitamin D, achieved by at least 4,000 IU – Hollis Aug 2017
• 38+ papers with Breastfed etc, in the title
• Call to action – more Vitamin D for pregnancies, loading doses are OK – Holick Aug 2019
• 53+ preeclampsia studies
• 94+ studies with PRETERM in the title
• Fertility problem (PCOS) reduced by vitamin D, etc: many studies 15+
• 94+ Gestational Diabetes
• Caesarean birth much more likely if low Vitamin D - many studies 15+ studies
• Post-partum depression and low Vitamin D - many studies 15+ studies
• Stillbirth reduced by Vitamin D, Zinc, Omega-3 - several studies 5+ studies
• Search VitaminDWiki for "Assisted reproduction" 33 items as of Aug 2022
• Fertility and Sperm category listing has 142 items along with related searches
• (Stunting OR “low birth weight” OR LBW) 1180 items as of June 2020
• Less labor pain if higher level of vitamin D – August 2021
• Healthy pregnancies need lots of vitamin D
• Ensure a healthy pregnancy and baby - take Vitamin D before conception
  

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VitaminDWiki – Healthy pregnancies need lots of vitamin D contains

Most were taking 2,000 to 7,000 IU daily for >50% of pregnancy
   Click on hyperlinks for details

Problem	Vit. D Reduces	Evidence
0. Chance of not conceiving	3.4 times	Observe
1. Miscarriage	2.5 times	Observe
2. Pre-eclampsia	3.6 times	RCT
3. Gestational Diabetes	3 times	RCT
4. Good 2nd trimester sleep quality	3.5 times	Observe
5. Premature birth	2 times	RCT
6. C-section - unplanned	1.6 times	Observe
Stillbirth - OMEGA-3	4 times	RCT - Omega-3
7. Depression AFTER pregnancy	1.4 times	RCT
8. Small for Gestational Age	1.6 times	meta-analysis
9. Infant height, weight, head size      within normal limits		RCT
10. Childhood Wheezing	1.3 times	RCT
11. Additional child is Autistic	4 times	Intervention
12.Young adult Multiple Sclerosis	1.9 times	Observe
13. Preeclampsia in young adult	3.5 times	RCT
14. Good motor skills @ age 3	1.4 times	Observe
15. Childhood Mite allergy	5 times	RCT
16. Childhood Respiratory Tract visits	2.5 times	RCT

RCT = Randomized Controlled Trial