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Inactivated COVID-19 vaccination and maternal renal function during early pregnancy: A retrospective cohort study of 6397 Chinese pregnant women

  • Yan Zhao
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Yongbo Zhao
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Yicheng Zhou
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Ziyi Zhang
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Yijun Zhang
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Mengyuan Li
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Xin Su
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Liping Jin
    Correspondence
    Corresponding author. Liping Jin, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China.
    Affiliations
    Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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Published:November 22, 2022DOI:https://doi.org/10.1016/j.jinf.2022.11.015
      To the Editor
      The coronavirus disease 2019 (COVID-19) pandemic is still one of the greatest threats to global health.
      • Lal A.
      • Erondu N.A.
      • Heymann D.L.
      • Gitahi G.
      • Yates R.
      Fragmented health systems in COVID-19: rectifying the misalignment between global health security and universal health coverage.
      Rapid and mass vaccination is the pivotal strategy to control the pandemic.
      • Viana J.
      • van Dorp C.H.
      • Nunes A.
      • Gomes M.C.
      • van Boven M.
      • Kretzschmar M.E.
      • et al.
      Controlling the pandemic during the SARS-CoV-2 vaccination rollout.
      The commonly used COVID-19 vaccines are mRNA vaccines, inactivated virus vaccines and adenovirus vector vaccines, which have been found to have excellent safety profile.
      • Ghasemiyeh P.
      • Mohammadi-Samani S.
      • Firouzabadi N.
      • Dehshahri A.
      • Vazin A.
      A focused review on technologies, mechanisms, safety, and efficacy of available COVID-19 vaccines.
      However, the immunologic response following COVID-19 vaccination has been considered as a potential trigger for the development of some renal diseases.
      • Izzedine H.
      • Bonilla M.
      • Jhaveri K.D.
      Nephrotic syndrome and vasculitis following SARS-CoV-2 vaccine: true association or circumstantial?.
      Since global mass-scale vaccination, several new-onset and recurrent cases of glomerulonephritis (GN) manifesting shortly after COVID-19 vaccination have been reported among the general population, which raised concern for the possibility of vaccine-induced renal injury.
      • Izzedine H.
      • Bonilla M.
      • Jhaveri K.D.
      Nephrotic syndrome and vasculitis following SARS-CoV-2 vaccine: true association or circumstantial?.
      • Farooq H.
      • Aemaz Ur Rehman M.
      • Asmar A.
      • Asif S.
      • Mushtaq A.
      • Qureshi M.A
      The pathogenesis of COVID-19-induced IgA nephropathy and IgA vasculitis: a systematic review.
      • Bomback A.S.
      • Kudose S.
      • D'Agati V.D
      De Novo and Relapsing Glomerular Diseases After COVID-19 Vaccination: what Do We Know So Far?.
      • Li N.L.
      • Coates P.T.
      • Rovin B.H.
      COVID-19 vaccination followed by activation of glomerular diseases: does association equal causation?.
      However, no study to date has reported the impact of COVID-19 vaccination on renal function among pregnant women, who may be uniquely susceptible to vaccine-induced renal dysfunction and injury. The aim of this study was to examine the associations of vaccination with inactivated COVID-19 vaccines before conception with maternal renal function during early pregnancy.
      Herein, we conducted a retrospective cohort study at the Shanghai First Maternity and Infant Hospital in Shanghai, China. Participants were pregnant women who were issued with an antenatal card and received routine antenatal care at the hospital between September 2021 and January 2022. A total of 10,832 singleton pregnant women who had no history of SARS‐CoV‐2 infection and received renal function assessment during early pregnancy were screened for eligibility. We excluded women with a known history of renal disease, who did not agree to provide their vaccination information, or received one dose of an inactivated vaccine before this pregnancy. We further excluded women who received adenoviral-vectored vaccine as less than 5% of the participants received such vaccine.
      Vaccination information, regarding vaccine type and manufacturer, number of dosages, and date of vaccination, was obtained from each participant's electronic vaccination record. Participating pregnant women were categorized as having exposure if they received two doses of an inactivated vaccine before this pregnancy. The outcome of interest was maternal renal function, which was quantified by measuring serum levels of urea nitrogen (UN), uric acid (UA) and creatinine (CREA). Serum concentrations of UN, UA and CREA were determined by means of enzymatic methods on Hitachi 7600 chemical analyzer (Hitachi Co., Tokyo, Japan). Additionally, we also calculated the estimated glomerular filtration rate (eGFR), the best indicator of renal function, for each participant using an equation developed by the Chronic Kidney Disease Epidemiology Collaboration.
      • Stevens L.A.
      • Claybon M.A.
      • Schmid C.H.
      • Chen J.
      • Horio M.
      • Imai E.
      • et al.
      Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities.
      According to their vaccination status, all participants were categorized into vaccinated and unvaccinated groups, and their general characteristics were compared using chi-square test or student's t-test. Multivariate linear regression models were conducted to estimate the associations of COVID‐19 vaccination with serum levels of UN, UA, CREA and eGFR. The following potential confounders were adjusted: gestational age at the time of renal function assessment, maternal age and parity, mode of conception, prior abortion history, and pregnancy body mass index (BMI). In multivariate linear regression analysis, the unvaccinated participating pregnant women served as a reference.
      The final analysis included 6397 pregnant women, of whom 3239 (50.6%) received two doses of an inactivated vaccine before this pregnancy and 3158 (49.4%) did not receive any COVID-19 vaccine before and during this pregnancy. The demographic characteristics of the participants were summarized and compared in Table 1. The two groups did not differ in maternal age and pregnancy BMI. However, compared with unvaccinated pregnant women, the vaccinated pregnant women were more likely to be multiparous (27.1% vs 14.9%, P < 0.001) and less likely to have prior abortion history (20.3% vs 26.4%, P < 0.001) and conceive through ART (1.6% vs 6.6%, P < 0.001).
      Table 1Demographic characteristics and renal function parameters of the participating pregnant women.
      CharacteristicsTotal (N = 6397)Vaccinationp-value
      p-values were calculated by chi-square test or student's t-test. Data are present as number (%) or mean ± standard deviation.
      Yes (N = 3239)No (N = 3158)
      Maternal age (year)
       < 355423 (84.8%)2774 (85.6%)2649 (83.9%)0.050
       ≥ 35974 (15.2%)465 (14.4%)509 (16.1%)
      Parity
       Nulliparous5049 (78.9%)2360 (72.9%)2689 (85.1%)< 0.001
       Multiparous1348 (21.1%)879 (27.1%)469 (14.9%)
      Pre-pregnancy BMI (kg/m2)
       < 18.5807 (12.6%)411 (12.7%)396 (12.5%)0.681
       18.5–24.94845 (75.7%)2462 (76.0%)2383 (75.5%)
       ≥ 25745 (11.6%)366 (11.3%)379 (12.0%)
      Mode of conception
       Conceive through ART262 (4.1%)52 (1.6%)210 (6.6%)< 0.001
       Natural conception6135 (95.9%)3187 (98.4%)2948 (93.4%)
      Abortion history
       Yes1493 (23.3%)658 (20.3%)835 (26.4%)< 0.001
       No4904 (76.7%)2581 (79.7%)2323 (73.6%)
      Renal function parameters
       BUN (mmol/L)3.11 ± 0.783.14 ± 0.803.08 ± 0.760.003*
       UA (μmol/L)209.06 ± 45.79206.34 ± 45.28211.86 ± 46.16< 0.001**
       CREA (μmol/L)42.42 ± 7.3842.61 ± 8.5642.22 ± 5.930.032*
       eGFR (mL/min/1.73 m2)138.31 ± 7.68138.31 ± 7.81138.31 ± 7.550.990
      a p-values were calculated by chi-square test or student's t-test.Data are present as number (%) or mean ± standard deviation.
      Analyses of the potential differences in serum renal function parameters between vaccinated and unvaccinated pregnant women showed that serum levels of UN (3.14 vs 3.08, P = 0.003) and CREA (42.61 vs 42.22, P = 0.032) were significantly higher in vaccinated women than in unvaccinated women. In contrast, serum levels of UA (206.34 vs 211.86, P < 0.001) were significantly lower in vaccinated women than in unvaccinated women. However, the two groups did not differ in eGFR (138.31 vs 138.31, P = 0.990) (Table 1).
      The adjusted mean differences in serum renal function parameters associated with COVID-19 vaccination were shown in Table 2. In the main analysis, COVID‐19 vaccination was associated with higher serum UN and CREA levels. Compared with unvaccinated women, the mean serum UN and CREA levels were higher in vaccinated women by 0.04 mmol/L (β=0.04, 95% CI, 0.00, 0.08) and 0.38 μmol/L (β=0.38, 95% CI, 0.01, 0.75), respectively. In contrast, COVID‐19 vaccination was associated with lower serum UA levels. Compared with unvaccinated women, the mean serum UA levels were lower in vaccinated women by 3.80 μmol/L (β=−3.80, 95% CI, −6.05, −1.55). In sensitivity analysis, when restricting the multiple linear regression analysis to nulliparous women (sensitive analysis 2), women who conceived spontaneously (sensitive analysis 1) or women with no history of abortion (sensitive analysis 3), the associations of COVID-19 vaccination with maternal renal function were general similar to those observed in all participants.
      Table 2Adjusted mean difference (95% CI) in maternal serum BUN, UA, CREA and eGFR associated with COVID-19 vaccination before conception.
      Effect estimate (95% CI)
      Main analysis
      Models adjusted for gestational age at the time of renal function assessment, maternal age and parity, mode of conception, abortion history and pre-pregnancy BMI.
      Sensitive analysis 1
      Linear regression analysis performed among women who conceived spontaneously.
      Sensitive analysis 2
      Linear regression analysis performed among nulliparous pregnant women.
      Sensitive analysis 3
      Linear regression analysis performed among women with no history of abortion.
      BUN0.04 (0.00, 0.08)
      P < 0.05.
      0.04 (0.00, 0.08)
      P < 0.05.
      0.04 (0.00, 0.09)
      P < 0.05.
      0.07 (0.02, 0.11)
      P < 0.01.
      UA−3.80 (−6.05, −1.55)
      P < 0.01.
      −4.01 (−6.29, −1.78)
      P < 0.01.
      −4.02 (−6.52, −1.53)
      P < 0.01.
      −3.35 (−5.88, −0.82)
      P < 0.01.
      CREA0.38 (0.01, 0.75)
      P < 0.05.
      0.35 (−0.03, 0.73)0.36 (−0.08, 0.79)0.67 (0.22, 1.11)
      eGFR0.04 (−0.32, 0.40)0.09 (−0.28, 0.46)0.18 (−0.23, 0.59)−0.22 (−0.63, 0.20)
      a Models adjusted for gestational age at the time of renal function assessment, maternal age and parity, mode of conception, abortion history and pre-pregnancy BMI.
      b Linear regression analysis performed among women who conceived spontaneously.
      c Linear regression analysis performed among nulliparous pregnant women.
      d Linear regression analysis performed among women with no history of abortion.
      low asterisk P < 0.05.
      low asterisklow asterisk P < 0.01.
      This study, to our knowledge, is the first study to examine the impacts of COVID-19 vaccination on renal function in pregnant women. We found that pregnant women who vaccinated with two doses of an inactivated vaccine before conception had higher serum UN and CREA, and lower UA than women with no such exposure. Considering that the estimated increase in serum levels of UN and CREA was relatively small, it was difficult to conclude that COVID-19 vaccination had a detrimental effect on maternal renal function. Our findings contributed to the mounting evidence that support the safety of inactivated COVID-19 vaccine in pregnant women.
      In summary, our study provided the first evidence that vaccination with inactivated COVID‐19 vaccines before conception might result in a small change in maternal renal function, but this did not reach clinically significant levels.

      Declaration of Competing Interest

      The authors report no conflict of interest.

      Acknowledgments

      This study was supported by the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine, Ferring Pharmaceuticals and Chinese Academy of Sciences ( FIRMSCOV02 ), the National Key Research and Development Program of China ( 2022YFC2702204 ), the National Natural Science Foundation of China ( 81730039 , 82071653 , 82271701 , 82173533 ), and the Shanghai Rising-Star Program ( 21QA1407300 ).

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