Safety of COVID-19 vaccination in women undergoing IVF/ICSI treatment - Clinical study and systematic review

Background: It was suggested that vaccination in general might affect reproductive health. Safety of COVID-19 vaccination in women undergoing assisted reproductive techniques (ART) treatment is not well established.

Methods: We performed a retrospective study including 536 women undergoing fresh embryo transfer after IVF/ICSI treatment in a huge IVF center in southern China to investigate the effect of COVID-19 vaccination on oocyte maturation, fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate and miscarriage rate. In addition, we performed a systematic review of existing studies on the safety of COVID-19 vaccination in women undergoing ART treatment.

Results: In our study, 268 women received inactivated or recombinant COVID-19 vaccination and 268 controls were enrolled based on propensity score matching. We observed a decreased fertilization rate and signs for impaired oocyte maturation in vaccinated women. Besides our study, there were 15 studies analyzing the safety of COVID-19 vaccination in women undergoing ART treatment. For the mRNA vaccines, no adverse signals were reported concerning oocyte maturation, fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate and miscarriage rate. In women being vaccinated with an inactivated vaccine, implantation rate, clinical pregnancy rate and miscarriage rate were not affected, whereas oocyte maturation and fertilization rate were impaired.

Conclusions: Vaccination against COVID-19 in women undergoing ART treatment seems to be safe especially for women getting mRNA vaccines. The effects on oocyte maturation and fertilization rate of inactivated and recombinant COVID-19 vaccinations might be a safety signal and need further investigation and independent confirmation.

Introduction

The appearance and rapid spread of the novel coronavirus disease 2019 (COVID-19) in 2020 have caused loss of life and poorer health outcomes also in pregnant women and their newborns. The SARS-CoV-2 virus belongs to the β-corona virus family as the other human pathogenic corona viruses. In patients with a more severe upper respiratory tract infection, the SARS CoV-2 infection often causes a mild and/or severe acute respiratory syndrome (SARS) with subsequent release of cytokines/mediators such as: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8 (CXCL8), IL-10, IP10, IL-12, IL-13, IL-17, IL-33, IL-25, IL-37, IL-38, GCSF, GM-CSF, HGF, IP-10, MCP-1, MIP-1α, IFN-γ, IFN-α, TRAIL, MCSF, and TNF-α (1). There is clear evidence suggesting that SARS-CoV-2 may infect the ovary, uterus and vagina because these organs do express angiotensin converting enzyme 2 (ACE2), the key host factor for SARS-CoV2 infection (2, 3). SARS-CoV-2 infection was shown to adversely affect female reproductive functions (luteal angiogenesis and degeneration, regular changes in endometrial tissue, and embryo development) and increased the risk of infertility and menstrual cycle disorder (4–6). Infection with SARS-CoV-2 results in a down-regulation of ACE-2 expression, subsequentially leading to reduced conversion of angiotensin (ANG)-II to Ang 1–7 and excessive accumulation of ANG-II which causes for example reactive oxygen species (ROS) production. This alters ovarian steroidogenesis, follicular development, oocyte maturation, ovulation, and atresia (7). Moreover, SARS-CoV-2 infection, often causing an excessive production of proinflammatory cytokines, including IL6, IL1β, TNFα, and MCP-1/CCL2, impairs reproductive physiology, such as ovulation and endometrial receptivity (7). It was suggested that Ang II mediated excessive ROS production might reduce female fertility (8). Moreover, pregnant women with symptomatic COVID-19 were more likely to experience ICU admission, intubation, and death (9). SARS CoV-2 infection seems to be associated with oligohydramnios, fetal growth restriction, preterm birth, and stillbirth (10–14) and potential long-term adverse health outcomes (15). Since there is no precise cure for the disease in pregnant women approved so far, mass vaccination is a key method by which countries are aiming to control the pandemic for this special population (16).

Due to safety reasons, however, pregnant and breastfeeding women were not included in the initial Phase III clinical trials of the COVID-19 vaccine developmental programs, resulting in limited data on the efficacy and more important safety of the COVID-19 vaccine in pregnant and breastfeeding women (17). Since the end of 2020, key national and international health institutions like the WHO as well as academic associations guided the COVID-19 vaccine, including women who are pregnant, breastfeeding, or planning pregnancy (naturally or with the help of assisted reproductive technology) (18). Antibody titers after vaccination are similar in pregnant and non-pregnant women (19). A large prospective cohort study including 7809 pregnant women found that COVID-19 vaccines were well tolerated in pregnant and lactating women (20). A systematic review including 26 studies analyzing perinatal outcomes after COVID-19 vaccination in pregnancy showed that the overall rates of adverse perinatal outcomes were not increased after maternal vaccination (21). However, there is still an ongoing controversial debate on the safety and efficacy of COVID-19 vaccination in this population (22).

Bentov et al. assessed the follicular steroidogenesis and oocyte quality in women undergoing mRNA vaccination and did not see any difference when compared with unvaccinated women (23). For in-vitro fertilization (IVF) treatment, a study reported that COVID-19 infection could lead to a significantly lower proportion of top-quality embryos while no difference in the number of oocytes and mature oocytes retrieved, and fertilization rate was seen. However, the sample size in this study was small and for sure beyond the power to seriously address safety concerns (24).

For the prevention of COVID-19, several vaccine types have been developed and approved so far (inactivated virus vaccine, mRNA vaccine, live attenuated vaccine, recombinant protein subunit vaccine, and vector vaccine) (25). Whether a different type of vaccine affects reproduction outcomes is unknown. Since the IVF procedure is a unique controlled process of human reproduction, the effects of vaccination on the different steps of human reproduction (oocyte maturation, fertilization, embryo development, implantation, biochemical pregnancy, clinical pregnancy, early and late abortion, and finally life birth rate) can be distinguished. We thus compared in a retrospective study the effects of two main types of vaccination on pregnancy outcomes. We compared inactivated and recombinant COVID-19 vaccines:

A) Inactivated vaccine, which used Vero cells to culture and grow COVID-19 virus and β-propionolactone to inactivate the virus while retaining antigenic components that induce immune responses (26).

B) Recombinant protein vaccine, which is based on recombined coronavirus S protein receptor-binding region (RBD) gene expression in Chinese hamster ovary (CHO) cells. The CHO cells make RBD protein dimers that are purified and concentrated for use as a vaccine. Aluminum hydroxide adjuvant is added to improve immunogenicity (26).

In addition, we performed a systematic review of all available information’s on the safety of the different COVID-19 vaccines during pregnancy with a focus on reproductive medicine safety endpoints.

Materials and methods

Study design and setting

This is a retrospective analysis of women who received ART treatment from June 2021 to September 2021 in the Reproductive and Genetic Hospital of CITIC-Xiangya. 536 women were enrolled in the analysis by propensity score matching (PSM): women received COVID-19 vaccination (n = 268) and control group (n = 268). (for more details see: Supplementary Figure S1). The vaccines used are described in detail in Supplementary Table S1. Based on the vaccine type we build two vaccination groups and a control group without any COVID-19 vaccination.

The study was approved by the Ethics Committee of the Reproductive and Genetic Hospital of CITIC-Xiangya (approval number: LL-SC-2022).

Participants

The participant’s inclusion and exclusion criteria were as follows:

Inclusion criteria: (1) age: 20-45 years, (2) women received ovarian stimulation and oocyte retrieval due to any type of infertility. Exclusive criteria: (1) women receiving oocyte donation, (2) women undergoing frozen embryo transfer cycles, and (3) prior SARS-CoV-2 infection. (4) male partners received any COVID-19 vaccination or had SARS-CoV2 infection.

Outcome measurement

The primary study endpoints were: normal fertilization rate and clinical pregnancy rate, For the primary study endpoints multivariant linear regression analysis considering confounding factors were done.

All other study outcomes such as laboratory values, oocyte and embryo quality data were analyzed as described recently (27). Normal fertilization rate was defined as

Normal fertilization rate was defined as the presence of two pronuclei (2PN) 16-18 hours after fertilization, basically one from sperm and the other from oocyte. Clinical pregnancy was defined as the existence of gestational sac(s) with fetal heart activity by ultrasound at week 4 after ET. Implantation rate was defined as the total number of embryos transferred divided by the number of sacs. Miscarriage was defined as intrauterine pregnancy loss after confirmation of gestational sacs.

Data analysis

We applied Statistical Package for Social Sciences for Windows, version 25.0 (SPSS Inc, Chicago, IL, USA) to perform data analyses. Homogeneity of variance and normality of data was estimated using the Levene and Kolmogorov-Smirnov tests, respectively. Values were expressed as means ± standard deviation or frequency (%). A comparison of quantitative variables between groups was performed using the Mann-Whitney U test or T-test. Qualitative variables were compared by the Chi-square test or Fisher’s exact test. Multivariate logistic regression analysis (enter model) and multiple linear regression analysis (kick-out model) were performed to figure out the impact factor on pregnancy and fertilization rate. Baseline clinical factors related to fertility were considered confounding factors. Statistically significant data was indicated with p < 0.05.

Systematic review

The systematic review of the safety of COVID-19 vaccines in embryo transfer included studies published from January 1^st, 2021 to December 1^st, 2022. We focused on studies published in English. We used the following sources: PubMed, Google scholar, Embase and Scopus. The search terms were ‘COVID-19 vaccine’ OR ‘COVID-19 mRNA vaccine’ OR ‘COVID-19 inactivated vaccine’ AND ‘embryo transfer’ OR ‘IVF outcomes’ OR ‘ICSI outcomes’ OR ‘pregnancy outcomes’. Our literature searches yielded 197 studies, from which 23 duplicates were removed. After a review of the titles and abstracts, 23 studies were identified as potentially eligible for inclusion. 7 studies focused on men instead of women and 1 study focused on the antibody after COVID-19 vaccination. Finally, 15 studies were included in the systematic review. See details in Figure 1.

FIGURE 1

Figure 1 Flow chart of screening studys into systematic review.

Results

Clinical findings

We matched the vaccinated women and controls by PSM (propensity score matching) (Supplementary Figure S1). Next, we analyzed the different types of vaccines separately. In the present study, most of our participants (n=223) received an inactivated vaccine, 44 women received a recombinant vaccine and only 1 woman received an adenovirus vector vaccine, which was excluded from further analysis. Information’s of the used vaccine is shown in Supplementary Table S1. For women who received the inactivated vaccine, baseline anti-Müllerian hormone (AMH) concentrations were lower as compared to the controls and those who received the recombinant vaccine (Table 1). No other differences were observed in other baseline characteristics among groups, see Table 1.

TABLE 1

Table 1 The demographic and clinical characteristics of participants.

The primary study endpoints of our single center study were normal fertilization rate and clinical pregnancy rate.

In women received inactivated vaccine, there was no significant difference in both normal fertilization rate and clinical pregnancy rate compared to controls (Tables 2, 3; Figure 2). Concerning the secondary outcomes, only the number of MI phase oocytes (immature oocytes) was higher than controls (Table 2). Since there is no consensus on the time interval after vaccination to receive ART treatment, we regrouped the participants according to a time cut-off determined by Receiver Operating Characteristic (ROC) analysis. The time cut-off value was six weeks. Hence, we grouped our participants into two groups: <six weeks and ≥ six weeks. Analysis of time-dependency (<six weeks versus ≥ six weeks) of potential effects of inactivated vaccine revealed no difference with regard to oocyte-, zygote- and embryo-quality and pregnancy outcome (Supplementary Table S2, S4). Multivariant linear regression analysis (normal fertilization rate) and logistic regression analysis (clinical pregnancy rate) considering confounding factors were performed. The results showed that inactivated vaccination had a negative impact on the normal fertilization rate (Table 4) but not on the clinical pregnancy rate (Table 5). There was no time dependency of the adverse effects of inactivated vaccination on normal fertilization rate and clinical pregnancy rate (Tables 4, 5).

TABLE 2

Table 2 Laboratory outcomes in women received different type of vaccines and controls.

TABLE 3

Table 3 Pregnancy outcomes in women received embryo transfer.

FIGURE 2

Figure 2 Preganncy outcomes in different vaccine type. * P<0·05.

TABLE 4

Table 4 Multi liner regression analysis on normal fertilization rate (kick-out model).

TABLE 5

Table 5 Multivariate regression analysis on clinical pregnancy rate (only women received embryo transfer).

In women receiving recombinant vaccine, normal fertilization rate was lower as compared to controls (Table 2; Figure 2). Concerning the secondary outcomes, Women with recombinant vaccination received more retrieved oocytes, MI phase oocytes (immature oocytes) and one pronucleus (1PN) than controls (Table 2). Analysis of time-dependency (<six weeks versus ≥ six weeks) of potential effects of recombinant vaccine showed that the number of 1PN zygotes was significantly higher while the day five (D5) blastocyst formation rate and the day six (D6) good quality blastocyst rate were lower in women who received ART treatment less than six weeks after recombinant vaccination (Supplementary Table S3). Univariant not adjusted analysis showed that clinical pregnancy rate was higher in women received ART treatment more than six weeks after recombinant vaccination (Supplementary Table S5). Multivariant regression analysis showed that recombinant vaccination had a negative impact on the normal fertilization rate (Table 4) but had no impact on clinical pregnancy rate (Table 5). Time interval after recombinant vaccination to receive ART treatment had no effects on normal fertilization rate and clinical pregnancy rate (Tables 4, 5).

Taken together, it appears that the inactivated vaccine might have adverse effects on oocyte maturation. This, however, does not substantially affect the primary study endpoints of our single center study: normal fertilization rate and clinical pregnancy rate

Systematic review

We compared existing studies on the safety of COVID-19 vaccines in embryo transfer published from January 1^st, 2021 to December 1^st, 2022. According to the searching and screening criteria described in the method section, 15 studies were taken into account finally.

In these 15 studies, 2 studies from America reported the safety of mRNA vaccination and one of which involved adenovirus vector vaccines (29, 30), 1 study from Spain (31) and 7 studies from Israel (24, 32–37) mainly reported the safety of mRNA vaccination and 5 studies from China (38–42) reported the safety of inactivated vaccination and one of which also involved adenovirus vector vaccines and recombinant subunit vaccines.

Oocyte maturation

Nine studies analyzed oocyte maturation and there was no difference in oocyte maturation in all these studies (24, 30, 33–37, 40, 42). However, there are more MI oocytes in vaccinated women, especially in those who received the recombinant vaccine in our study.

Fertilization rate

Twelve studies analyzed the fertilization rate. One study (29) reported a higher fertilization rate in vaccinated women while other studies found no difference (24, 30, 32–36, 38–40, 42). In our present study, a lower fertilization rate was observed in vaccinated women, especially in those who received recombinant vaccine

Blastulation rate

Nine studies reported blastulation rate, no difference was observed in all the studies (29, 30, 33, 36, 38–42) and also in our study.

Implantation rate

Five studies reported implantation rate, no difference was observed in all the studies (31, 32, 39, 40, 42) and also in our study.

Clinical pregnancy rate

Twelve studies analyzed clinical pregnancy rate, no difference was observed in all the studies (30–34, 36–42) and also in our study.

Ongoing pregnancy rate

Six studies analyzed ongoing pregnancy rate. One study showed that ongoing pregnancy rate was significantly lower in women who received the first inactivated COVID-19 vaccine dose 60 days or less before fertilization treatment. However, no reduced risk for ongoing pregnancy in the 91 days or more subgroup was observed (42). No difference was observed in the other studies (29, 30, 32, 39, 41) and also in our study.

Miscarriage rate

Four studies analyzed miscarriage rate, no difference was observed in all the studies (29, 30, 39, 41) and also in our study.

In summary, almost all of these studies stated that vaccination had no detrimental effect on cycle characteristics or other laboratory and pregnancy outcomes in women undergoing ART treatment except that one study observed that vaccinated patients had higher fertilization rates than unvaccinated patients. However, in the current study, more MI oocytes and lower fertilization rate were observed in vaccinated women, especially in those who received recombinant vaccine. See more details in Table 6.

TABLE 6

Table 6 Systematic review of COVID-19 vaccination studies in women undergoing IVF/ICSI treatment.

Discussion

The safety of vaccines against COVID-19 in women undergoing IVF/ICSI treatment is not well established. There were no placebo-controlled studies in women being vaccinated against COVID-19 in women undergoing IVF/ICSI treatment with regard to relevant safety endpoints for human reproduction. Only observational studies were reported. In addition, a comparison of the different vaccine types (mRNA vaccine, Adeno-viral based vaccine, inactivated vaccine types) is missing. We thus systematically analyzed safety data from our center and data coming from so far published observational studies. Oocyte maturation, fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate, and miscarriage rate were the criteria to evaluate reproductive safety. Two types of vaccines against COVID-19 were mainly analyzed. For the mRNA vaccine no adverse signals were reported concerning fertilization rate, blastulation rate, implantation rate, clinical pregnancy rate, and miscarriage rate. Data on life birth rate – probably the most important hard clinical endpoint – and oocyte maturation, however, after mRNA vaccination were not reported so far. Thus, as of today, mRNA vaccines seem to be safe for women undergoing IVF/ICSI treatment, see Table 6.

In women being vaccinated with the Chinese inactivated vaccine, implantation rate, clinical pregnancy rate, and miscarriage rate were not affected. However, we saw a decreased fertilization rate and signs for impaired oocyte maturation in vaccinated women in women with recombinant and inactivated vaccine. Until now, the effect of COVID-19 vaccination on oocyte maturation was reported in nine studies testing mRNA vaccination and there was no difference in oocyte maturation between vaccinated and unvaccinated patients in all these studies (24, 30, 33–37, 40, 42). Safety data on adenovirus vector vaccines and recombinant subunit vaccines of COVID-19 in women undergoing ART treatment were limited. Only our study observed a sign of impaired oocyte maturation in women with recombinant vaccine especially, hence, further confirmation on this safety endpoint is required. The folliculogenesis process is complex and dynamic, which involves multiple endocrine cells and numerous signals that have been estimated to span > three months (43). Follicular cytokines in folliculogenesis are keys to reproductive success. They induce an immune-permissive, embryotropic environment that supports gametogenesis, fertilization, implantation, embryo development, and fetal growth (44). Anti-Müllerian hormone (AMH), produced by the granulosa cells of the ovarian follicles, is an indicator of a patient’s ability to respond quickly and efficiently to ovarian reserve (45). Being a member of transforming growth factor b (TGF-b) superfamily, AMH is involved in cytokine and growth factor network in the human body and responsible for the intercellular communications and immunological responses including inflammation. AMH may protect the ovary from inflammation by decreasing its own production in response to a rise in cytokines (46). The COVID-19 infection could activate a pro-inflammatory response and lead to cytokine storm (such as interferons, interleukins, chemokines, colony-stimulating factors, and TNF-alpha) and systemic inflammation (47). Vaccination might cause some of these inflammatory responses, which might also interfere with folliculogenesis, resulting in abnormal oocytes and fertilization (24). Clear evidence shows that after vaccination (for example, influenza vaccine), the “innate immune system”/”innate immunity” is activated and the vaccine is processed by antigen-presenting cells, which include macrophages and dendritic cells. Macrophages can produce some inflammatory molecules (cytokines), which is one of the important reasons why there is a local reaction after the vaccine at the site of injection. Mature dendritic cells migrate into regional lymph nodes, where they induce activation and clonal expansion of naïve CD4+ T-helper and CD8+ cytotoxic T cells. The activation and differentiation of naïve B cells are induced by antigen and CD4+ T-helper cells. Naïve B cells differentiate into memory B cells and antibody-secreting B cells. Long-term immunity is assured by memory B and T cells in the blood and lymph nodes as well as by long-living plasma cells and memory T cells in the bone marrow (48). These early inflammatory processes after vaccination might have an effect on folliculogenesis in the stimulated ovaries. Basic science studies are needed to confirm this hypothesis coming from our clinical data.

Vaccinating women in the third trimester of pregnancy offers the opportunity to provide early protection to infants through the transplacental transfer of maternal antibodies (49). Many studies have demonstrated the efficient transfer of pertussis antibodies across the placenta (50, 51). The WHO has recommended influenza vaccination during influenza season for all pregnant women since 2005 (3). Min Seo Kim et al. compared the safety of mRNA COVID-19 vaccines to influenza vaccines and demonstrated that the overall safety profile pattern suggests a lower risk of serious adverse events following immunization by mRNA vaccines compared to influenza vaccines (52).

However, limitations also exist in our single center observational study as well as in all other vaccination studies. We cannot fully exclude potential bias even though we made PSM before the study. Moreover, all studies only did first-term trimester follow-ups, whether long-term pregnancy complications and neonatal outcomes are affected needs to be investigated. Since all studies in the field are just observational studies, none of the studies can control for yet unknown confounding factors.

Conclusion

Vaccination against COVID-19 in women undergoing ART treatment seems to be safe especially for women getting mRNA vaccines. The effects on oocyte maturation and fertilization rate of inactivated and recombinant COVID-19 vaccinations need further investigation and independent confirmation.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving human participants were reviewed and approved by Reproductive and Genetic Hospital of CITIC-Xiangya (approval number: LL-SC-2022). The patients/participants provided their written informed consent to participate in this study.

Author contributions

BH and HC designed the study. HC collected the data. HC and XZ analyzed the data. HC, XZ, and BH wrote the manuscript. HC, GL, FG, and BH revised the manuscript. All authors contributed to the article and approved the submitted version

Funding

China Scholarship Council supported HC and XZ.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2022.1054273/full#supplementary-material

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