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Increased pregnancy problems with COVID-19 – meta-analysis and letter to editor – April 2021

The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis

CMAJ. 2021 Apr 19; 193(16): E540–E548. doi: 10.1503/cmaj.202604
Shu Qin Wei, MD PhD, Marianne Bilodeau-Bertrand, MSc, Shiliang Liu, MB PhD, and Nathalie Auger,

The impact of coronavirus disease 2019 (COVID-19) on maternal and newborn health is unclear. We aimed to evaluate the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and adverse pregnancy outcomes.

We conducted a systematic review and meta-analysis of observational studies with comparison data on SARS-CoV-2 infection and severity of COVID-19 during pregnancy. We searched for eligible studies in MEDLINE, Embase, ClinicalTrials.gov, medRxiv and Cochrane databases up to Jan. 29, 2021, using Medical Subject Headings terms and keywords for “severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR coronavirus disease 2019 OR COVID-19” AND “pregnancy.” We evaluated the methodologic quality of all included studies using the Newcastle–Ottawa Scale. Our primary outcomes were preeclampsia and preterm birth. Secondary outcomes included stillbirth, gestational diabetes and other pregnancy outcomes. We calculated summary odds ratios (ORs) or weighted mean differences with 95% confidence intervals (CI) using random-effects meta-analysis.

We included 42 studies involving 438 548 people who were pregnant.
Compared with no SARS-CoV-2 infection in pregnancy, COVID-19 was associated with

  • preeclampsia (OR 1.33, 95% CI 1.03 to 1.73),
  • preterm birth (OR 1.82, 95% CI 1.38 to 2.39) and
  • stillbirth (OR 2.11, 95% CI 1.14 to 3.90).

Compared with mild COVID-19, severe COVID-19 was strongly associated with

  • preeclampsia (OR 4.16, 95% CI 1.55 to 11.15),
  • preterm birth (OR 4.29, 95% CI 2.41 to 7.63),
  • gestational diabetes (OR 1.99, 95% CI 1.09 to 3.64) and
  • low birth weight (OR 1.89, 95% CI 1.14 to 3.12).

COVID-19 may be associated with increased risks of preeclampsia, preterm birth and other adverse pregnancy outcomes.

Letter to Editor

RE: The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis
William B. Grant, Health research, Sunligth, Nutrition and Health Research Center
22 March 2021

The recent systematic review and meta-analysis by Wei and colleagues found that having COVID-19 during pregnancy was significantly associated with increased risk for preeclampsia, preterm birth, and stillbirth 1. The underlying reason for these findings was not provided.
A likely reason for these findings was an impaired immune system due to low vitamin D status. There is mounting evidence that serum 25-hydroxyvitamin D [25(OH)D] concentration is inversely correlated with both COVID-19 risk and severity 2 and adverse pregnancy outcomes. The mechanisms whereby vitamin D reduces risk of COVID-19 include induction of cathelicidin and defensins to reduce replication of the SARS-CoV-2 virus and reducing risk of developing the cytokine storm, which damages the linings of many organs 2.
A recent meta-analysis using data pooled from 27 RCTs which included overall 4777 participants, of whom 2487 were in the vitamin D-treated arm and 2290 in the control arm. Vitamin D administration in pregnancy was associated with a reduced risk of preeclampsia (odds ratio = 0.37, 95% confidence interval [CI]: 0.26, 0.52). 3.
An open-label study was conducted in South Carolina involving 1064 pregnant women given free vitamin D3 capsules (5000 IU) and counseled on how to achieve 25(OH)D >40 ng/mL (100 nmol/L) 4. The LOESS curve showed gestational age rising with increasing 25(OH)D. Women who achieved 25(OH)D ≥40 ng/mL had a 62% lower risk of preterm birth compared to those with <20 ng/mL (odds ratio = 0.38, 95% CI = 0.23–0.63, p<0.0001). For more information on vitamin D during
pregnancy, see Wagner and Hollis 5

Thus, women who are pregnant or are planning to become pregnant should supplement with vitamin D and measure serum 25(OH)D concentrations to verify that they achieve optimal concentrations in order to reduce risk of both COVID-19 and adverse pregnancy and birth outcomes.

Competing Interests: I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA).

  • Shu Qin Wei, Marianne Bilodeau-Bertrand, Shiliang Liu, et al. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. CMAJ 2021;10.1503/cmaj.202604.
  • Mercola J, Grant WB, Wagner CL. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients. 2020;12:3361.
  • Fogacci S, Fogacci F, Banach M, et al. Vitamin D supplementation and incident preeclampsia: A systematic review and meta-analysis of randomized clinical trials. Clin Nutr. 2020;39:1742-52.
  • McDonnell SL, Baggerly KA, Baggerly CA, et al. Maternal 25(OH)D concentrations >/=40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center. PLoS One. 2017;12:e0180483.
  • Wagner CL, Hollis BW. The Implications of Vitamin D Status During Pregnancy on Mother and her Developing Child. Front Endocrinol (Lausanne). 2018;9:500.

Virus and Pregnancy in VitaminDWiki

Virus and Mortality in VitaminDWiki

Virus and Magnesium (also important to pregnancy)

Virus and Omega-3 (also important to pregnancy)

Virus and Vitamin D Receptor (also important to pregnancy)

Vitamin D Receptor and Pregnancy

A poor receptor will restrict vitamin D from getting to cells

Healthy pregnancies need lots of vitamin D
0. Chance of not conceiving3.4 times Observe
1. Miscarriage 2.5 times Observe
2. Pre-eclampsia 3.6 timesRCT
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 timesObserve
     Stillbirth - OMEGA-3 4 timesRCT - 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
10. Childhood Wheezing 1.3 times RCT
11. Additional child is Autistic 4 times Intervention
12.Young adult Multiple Sclerosis 1.9 timesObserve
13. Preeclampsia in young adult 3.5 timesRCT
14. Good motor skills @ age 31.4 times Observe
15. Childhood Mite allergy 5 times RCT
16. Childhood Respiratory Tract visits 2.5 times RCT

RCT = Randomized Controlled Trial
See Healthy pregnancies need lots of vitamin D for details

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