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- Page navigation anchor for RE: Response to Funk: High risk of bias limits assessment of the association between SARS-CoV-2 infection and adverse pregnancy outcomesRE: Response to Funk: High risk of bias limits assessment of the association between SARS-CoV-2 infection and adverse pregnancy outcomes
Funk et al recently commented on what they perceived was an inadequate evaluation of the quality of studies in our meta-analysis of 42 studies of COVID-19 in pregnancy [1]. Funk et al claimed that our use of the Newcastle-Ottawa Scale failed to identify studies that were “confounded by sociodemographic factors” and “impacted by selection bias”. Their overall premise is that we would not have found the same association between COVID-19 and adverse outcomes had we used a more rigorous approach to evaluate the quality of studies. Below, we respond to Funk et al’s concerns.
Funk et al believe that the relationship between COVID-19 and pregnancy outcomes is confounded by sociodemographic factors. The largest pregnancy cohort study included in our meta-analysis provides quantitative evidence against this claim [2]. In more than 400,000 pregnant women, Jering et al showed that COVID-19 was associated with preeclampsia, preterm birth, and other outcomes after adjusting for age, race/ethnicity, geographic region, comorbidity, and a range of other possible confounders [2]. Associations were either not affected or only weakly attenuated with adjustment. In our study, sensitivity analyses using recommended tools to assess confounding in meta-analysis indicate that sociodemographic confounders would have to be associated with 3 times the risk of COVID-19 and 3 times the risk of preterm birth to eliminate the association between COVID-19 and preterm birth, a highly unlikely scena...
Show MoreCompeting Interests: None declared.References
- 1. Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. CMAJ 2021; cmaj.202604.
- 2. Jering KS, Claggett BL, Cunningham JW, Rosenthal N, Vardeny O, Greene MF, et al. Clinical characteristics and outcomes of hospitalized women giving birth with and without COVID-19. JAMA Intern Med 2021; e209241.
- 3. Mathur MB, VanderWeele TJ. Sensitivity analysis for unmeasured confounding in meta-analyses. J Am Stat Assoc 2020; 115:163-72.
- 4. Savitz DA, Wellenius GA, Trikalinos TA. The problem with mechanistic risk of bias assessments in evidence synthesis of observational studies and a practical alternative: Assessing the impact of specific sources of potential bias. Am J Epidemiol 2019;18
- 5. Smith LH, VanderWeele TJ. Bounding bias due to selection. Epidemiology 2019; 30:509-16.
- Page navigation anchor for RE: High risk of bias limits assessment of the association between SARS-CoV-2 infection and adverse pregnancy outcomesRE: High risk of bias limits assessment of the association between SARS-CoV-2 infection and adverse pregnancy outcomes
In their review on COVID-19 and pregnancy outcomes, Wei and colleagues included 42 comparative observational studies, of which 95% were classified as having a ‘low risk of bias’ based on the Newcastle-Ottawa Scale (NOS).[1] We propose a more critical assessment of the included studies’ weaknesses.
Overwhelmingly, the primary studies included pregnant women in the third trimester, tested for SARS-CoV-2 upon admission to labour and delivery units, with outcomes extracted from medical records during hospitalization. Wei et al perform only unadjusted meta-analysis using these data to evaluate the association between SARS-CoV-2 infection and adverse pregnancy outcomes (e.g. preterm birth); however, these associations are likely to be confounded by socio-demographic factors that predispose women to both. Increased scrutiny of the comparability of the SARS-CoV-2 infected and uninfected women in each study is therefore needed. Although the NOS does not facilitate a robust assessment of confounding, a tailored or supplementary approach to study quality appraisal can be adopted when an intensified bias is suspected.[2, 3]
The review authors included three ‘low risk of bias’ studies that had the primary purpose of comparing placental histopathology for women with and without SARS-CoV-2 infection. Since collection of placental samples is not routine, studies of infection and pregnancy outcomes based on this data are likely to be impacted by selection bias. As illustrati...
Show MoreCompeting Interests: None declared.References
- 1. 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.
- 2. Fell DB, Savitz DA, Kramer MS, et al. Maternal influenza and birth outcomes: systematic review of comparative studies. BJOG 2017;124(1):48-59. doi: 10.1111/1471-0528.14143
- 3. Savitz DA, Wellenius GA, Trikalinos TA. The Problem with Mechanistic Risk of Bias Assessments in Evidence Synthesis of Observational Studies and a Practical Alternative: Assessing the Impact of Specific Sources of Potential Bias. Am J Epidemiol 2019;18
- Page navigation anchor for RE: Response to Cimolai: Quality of systematic reviews and COVID-19RE: Response to Cimolai: Quality of systematic reviews and COVID-19
We thank Dr. Cimolai for commenting on our meta-analysis of COVID-19 in pregnancy.(1) Dr. Cimolai raised a number of concerns with the meta-analysis, including the risk of ‘integrating cumulative disperse data’, ‘heterogeneity in largely unrandomized or especially observational studies’, and ‘confounding variables in diversely accumulated studies’.
The methodology used in this systematic review followed standardized criteria meant to mitigate the problems raised by Dr. Cimolai. The entire purpose of meta-analysis is to integrate disperse data in order to provide more precise effect estimates and settle controversies between studies.(2) The current systematic review followed PRISMA guidelines and provides an accurate picture of the existing literature on COVID-19 in pregnancy. While it is true that Ang et al urged caution in early literature reviews of COVID-19,(3) the limitations raised by Ang et al pertained to case reports and case series and do not apply to the current meta-analysis of cohort and case-control studies.
Dr. Cimolai expressed concern that heterogeneity in unrandomized observational studies is a risk to analysis. Heterogeneity in meta-analysis refers to the variation in outcomes between studies and is not related to the lack of randomization.(2) The explicit advantage of meta-analysis is its ability to quantify and assess heterogeneity between studies. Without meta-analysis, it is not possible to know if heterogeneity even exists. In our study...
Show MoreCompeting Interests: None declared.References
- 1. Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis.CMAJ 2021;10.1503/cmaj.202604.
- 2. Deeks JJ, Higgins JPT, Altman DG. Analysing data and undertaking meta-analyses. Cochrane Handbook for Systematic Reviews of Interventions.Cochrane 2021.
- 3. Ang XL, Chonkar SP, Chua MSQ, Sulaiman S, Lee JCS. Problems with early systematic reviews: the case of coronavirus disease 2019 (COVID-19) in pregnancy. Matern Child Health J 2021; 25:38-41.
- 4. Allotey J, Stallings E, Bonet M, Yap M, Chatterjee S, Kew T, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ 2020;370:m3320.
- 5. Chmielewska B, Barratt I, Townsend R, Kalafat E, van der Meulen J, Gurol-Urganci I, et al. Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis. Lancet Glob Health 2021 Mar 31.
- Page navigation anchor for RE: Quality of Systematic Reviews and COVID-19RE: Quality of Systematic Reviews and COVID-19
Wei et al. are to be commended for their detailed analysis of pregnancy outcomes in the context of the COVID-19 pandemic.(1) Such analyses are needed on an ongoing basis as a plethora of data emerges. The need for solid data became evident very early in the pandemic despite considerable publication becoming available even by that time.(2) Meta-analyses certainly have their place in the furthering of science, but the possible hazards of integrating cumulative disperse data are well-known. That heterogeneity that prevails in largely unrandomized or especially observational studies poses considerable risk to analysis. Risks for confounding variables in such diversely accumulated studies further jeopardizes subsequent analysis.
Undoubtedly, there has been a time-accrued maturation in the quality of individual research that is being embraced for meta-analyses. Ang et al. tactfully raise concern specifically with the systematic reviews of COVID-19 in pregnancy.(3) Their comments are no less relevant in April, 2021. Pre-term birth alone as an outcome has been quite susceptible to the confounding of iatrogenic intervention and Caesarean section. As experience in the pandemic evolves and the severity of disease in pregnancy is better realized, the rates of Caesarean section have proportionately declined.(4) There are many potential other confounders which include clinical versus laboratory-confirmed diagnoses of infection, variability in the diagnostic cycle thresholds or ta...
Show MoreCompeting Interests: None declared.References
- 1. 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.
- 2. Cimolai N. More data are required for incubation period, infectivity, and quarantine duration for COVID-19. Travel Med Infect Dis 2020; 37:101713.
- 3. Ang XL, Chonkar SP, Chua MSQ, Sulaiman S, Lee JCS. Problems with early systematic reviews: the case of coronavirus disease 2019 (COVID-19) in pregnancy. Matern Child Health J 2021;25(1):38-41.
- 4. Cimolai N. A comprehensive analysis of maternal and newborn disease and related control for COVID-19. SN Comprehensive Clinical Medicine 2021 Mar 17;1-23. doi: 10.1007/s42399-021-00836-0.
- 5. Cimolai N. In pursuit of the right tail for the COVID-19 incubation period. Public Health 2021 Mar 26. doi: 10.1016/j.puhe.2021.03.011
- Page navigation anchor for RE: The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysisRE: The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis
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 w...
Show MoreCompeting Interests: I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA).References
- 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.