The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) causes coronavirus disease 2019 (COVID-19) and an ongoing severe pandemic. As of May 16, 2021, confirmed infections have amounted to 162,177,376, with casualties reaching an alarming number of 3,364,178 (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). SARS-CoV-2, a novel enveloped RNA beta-coronavirus, infects host through angiotensin II-converting enzyme 2 (ACE2), a membrane-bound aminopeptidase that functions as its putative receptor predominantly expressed within type II alveolar cells of the lung. In addition to ACE2, SARS-CoV-2 requires the cellular protease, TMPRSS2, to cleave viral spike protein and facilitate fusion of viral and cellular membranes (Hoffmann et al., 2020; Zhou et al., 2020). Judging from sequencing data, SARS-CoV-2 shares more than 80% similarity with the SARS-CoV (Gralinski and Menachery, 2020; Xu et al., 2020; Zhou et al., 2020), which caused an outbreak in 2002 and shares 50% sequence similarity with Middle East respiratory syndrome (MERS) coronavirus that erupted in 2012 (Wang et al., 2020).

Previous studies have shown that pregnant women are at greater risk of morbidity and mortality due to many of the fatal viral infections, including hepatitis E virus, influenza A virus, SARS-CoV, and MERS-CoV (Rasmussen et al., 2020). Among those cases related to SARS-CoV and MERS, a high rate of adverse pregnancy outcomes including abortion, preterm birth, fetal growth restriction, and maternal or neonatal death had been presented (Wong et al., 2004; Alfaraj et al., 2019; Rasmussen et al., 2020). Considering the resemblance to SARS-CoV and MERS, researchers proposed that COVID-19 has the potential to result in maternal or perinatal adverse outcomes for pregnant women (Favre et al., 2020). As a matter of fact, until now, increasing cases and studies have been exhibited, recounting occurrences of adverse pregnancy outcomes during COVID-19. Through digging those data, it has been concluded that COVID-19 infection is associated with a higher rate of preterm birth, preeclampsia, cesarean, and perinatal death (Di Mascio et al., 2020; Juan et al., 2020; Rasmussen et al., 2020). However, the mechanism related to those clinical manifestations has not been well elucidated. There are studies claiming a high expression of ACE2 in the endometrium, and its protein abundance increased during decidualization (Chadchan et al., 2020). ACE2 also exists in maternal–fetal interface cells including stromal cells and perivascular cells of decidua, cytotrophoblast (CTB), and syncytiotrophoblast (STB) in placenta with a dynamic fluctuation over time (Li et al., 2020), thus providing a target receptor for SARS-CoV-2 entering endometrial stromal cells and eliciting pathological manifestations in women with COVID-19. Unified with this theory, a study comprising 11 SARS-CoV-2-positive pregnant women reported the presence of SARS-CoV-2 in placental and fetal membrane swabs of three patients (Penfield et al., 2020). Furthermore, localization of SARS-CoV-2 spike protein and RNA was found in the villi and peri-villous fibrin, and infiltration of macrophages was reported in placental sections (Hosier et al., 2020).

More conjectures about the pathogenesis of adverse pregnancy outcomes are based on the immunological status of pregnant women, picturing as inflammation alteration and cytokine storm related to infection. Pregnancy is an immunological condition in which the semi-allogeneic fetus grows in the mother’s uterus. The immunological environment during pregnancy changes as pregnancy proceeds initially through Th1 (pro-inflammatory response) during the first trimester, then changes to Th2 (anti-inflammatory response) by the second trimester, and again alters toward a Th1 phenotype at the end of third trimester concomitant with initiation of parturition (Weetman, 2010; Verma et al., 2020). Break of the immunological status during pregnancy will definitely do harm to successful delivery.

Virtually all organs and biological systems possibly suffer from this new coronavirus infection by either direct virus-targeted damage or indirect effects. As the pandemic rapidly spread, thyroid dysfunction associated with COVID-19 has been gradually reported (Brancatella et al., 2020; Ruggeri et al., 2020; Marazuela et al., 2020). However, there is conflicting evidence regarding the effects of COVID-19 on thyroid function. COVID-19 has been reported to cause subacute thyroiditis manifesting as marked thyrotoxicosis, as in Graves’ disease (Brancatella et al., 2020; Lania et al., 2020; Muller et al., 2020). It has been found that SARS-CoV-2 causes an overactivation of the immune response through different T-cell lymphocytes (Th1/Th2/Th17), which leads to the activation and release of various pro-inflammatory cytokines including interleukins (IL-1–IL-6) and tumor necrosis factor (TNF-α), culminating in a “cytokine storm” (Lania et al., 2020). The shift in the immune balance between Th1 and Th2 in the body toward Th2 is intrinsic to the pathogenesis of Graves’ disease (Kocjan et al., 2000). Moreover, IL-6, which is elevated in the acute phase, is a specific marker of thyrotoxicosis (Lania et al., 2020). On the other hand, in Chinese studies of COVID-19 patients, general reductions in thyroid-stimulating hormone (TSH), total thyroxine (T4), and triiodothyronine (T3) were more consistent with a non-thyroidal disease pattern (Chen et al., 2021). The degree of decrease in TSH levels correlates positively with the clinical severity of COVID-19 (Khoo et al., 2021). As widely recognized, thyroid hormone (TH) acts as a pleiotropic regulator of growth, differentiation, proliferation, and other physiological processes and is required to maintain the metabolic rate and oxygen consumption in almost all tissues (Chen et al., 2013). For pregnant women, more TH is demanded to maintain the hemostasis concentration during gestation due to the physiological change of thyroid economy (Glinoer et al., 2010). Although it is unclear how SARS-CoV-2 virus affects pregnancy given that pregnancy outcome is influenced by TH levels and the mechanism of SARS-CoV-2 invasion of the thyroid has been well documented. Here, we review previously documented changes in SARS-CoV-2-associated thyroid disease and pregnancy and further discuss various potential mechanisms to help clinicians better understand the impact of SARS-CoV-2 on pregnancy and to facilitate diagnosis and rational treatment of COVID-19.

In the first and early part of the second trimester, fetuses entirely rely on maternal supply of TH (Chen et al., 2015). While from the middle of the second trimester and onward, both maternal and fetal original THs are present in the fetus (Chan et al., 2009). Apparently, the process of transplacental TH exchange involves a cascade of events and masses of TH-related proteins, any impaired link or key protein deficiency during the course will contribute to the reduction of TH exchange, further damaging placenta function and fetal development, leading to adverse pregnant events. T3 and T4 exert effects not only in fetal development but also in placenta function (Landers et al., 2009; Li et al., 2010; Chen et al., 2015). It has been concluded that the possible consequences of hypothyroidism during gestation include spontaneous abortion/miscarriage, gestation-induced preeclampsia, placenta abruption, preterm delivery, congenital anomalies, fetal distress in labor, stillbirth or perinatal death, and increased frequency of cesarean sections (Glinoer et al., 2010). As we can see, outcomes caused by insufficient TH during gestation are highly consistent with those happening in the context of SARS-CoV-2 infection. Consistent to our thesis, there has already been a trial of using T3 for the treatment of critically ill patients with COVID-19 infection (Pantos et al., 2020).

TH enters and exit the placental cells through six TH membrane transporters: large amino acid transporter-1 (LAT1), LAT2, organic anion transporting polypeptide-1A2 (OATP1A2), OATP4A1, monocarboxylate transporter-8 (MCT8), and MCT10 (Adu-Gyamfi et al., 2020). As mentioned above, TH transporters may be altered during inflammation, such as MTC-10. Interestingly, in severe IUGR villous placentas, MCT8 expression is significantly increased, while MCT10 expression is significantly decreased (Loubiere et al., 2010). Although MCT-10 may not serve as the most essential TH transporter in the placenta, at least it suggests that the abnormalities of TH transporters during inflammation are not purely innocent in pregnant complications.

Within the placenta, TH is mostly acted on by D2 and D3. As clarified above, during inflammation, cytokines are able to suppress D2 activation, thus inhibiting T3 generation. That means inflammation caused by SARS-CoV-2 can become a risk factor for pregnancy, leading to lack of T3 in placenta and fetus. Furthermore, the main regulator of TH homeostasis in the placenta is D3 (Adu-Gyamfi et al., 2020), which protects the fetus from an overexposure to T3. D3 activity possibly alters in the context of inflammation. During acute and chronic inflammation and during sepsis, liver Dio3 mRNA expression and activity levels are decreased (de Vries et al., 2015). If it is a similar case within the placenta during SARS-CoV-2-induced inflammation, that can negatively affect fetus because of overexposure to T3. Notably, there is an observation suggesting a possible blunting of D3 activity in preeclampsia (Kurlak et al., 2013). Abnormal upregulation of the placental D3 gene is a potential contributor to fetal hypothyroidism because the more D3 remains active, the less active TH will be transferred to the fetus (Wilcoxon and Redei, 2004). The upregulation of D3 is rarely seen and usually occurs in conditions of prolonged critical illness or inflammation (de Vries et al., 2015), but further study indicated that the prolonged reduction of food intake during illness may be the dominant trigger for D3 upregulation (de Vries et al., 2014). Hence, it may serve as a reminder that during SARS-CoV-2 infection and treatment, pregnant women should better avoid fasting for too long.

Significant physiological changes in the THs of pregnant women occur during pregnancy (Fan et al., 2019). Around the fifth or sixth week of pregnancy, although the fetal thyroid is beginning to develop, the fetus is not yet able to synthesize its own THs at this time (Patel et al., 2011). Therefore, the fetal TH required for normal neurodevelopment comes exclusively from the mother. Current studies suggest that SARS-CoV-2 infection alters thyroid function in early pregnancy and that there is an increased risk of adverse pregnancy outcomes (Lin et al., 2020). The relationship between ACE2 expression levels during SARS-CoV-2 infection is intricate, with high ACE2 expression favoring the entry of SARS-CoV-2 host cells, while reduced ACE2 expression following infection may lead to severe disease (Ni et al., 2020). THs play a key role in determining ACE and ACE2 expression in plasma and different tissues, which in turn may play a role in the severity of SARS-CoV-2 infection and disease (Kumari et al., 2020). Therefore, TH levels in COVID-19 pregnant women are of interest. However, further research is needed to determine whether such monitoring and treatment will lead to safe and effective outcomes.

Vaccines are currently one of the most promising preventive measures against COVID-19 (Iqbal Yatoo et al., 2020). Vaccination during pregnancy is a promising strategy to protect mothers and newborns from SARS-CoV-2 infection (Saxena et al., 2020). However, live or live attenuated vaccines may not be safe because of the risk of disease in the immune-regulated gestational state (Kumar et al., 2021). Recently, there have been some reports of thyroid problems following vaccination (Joob and Wiwanitkit, 2021; Vera-Lastra et al., 2021). For example, Vera-Lastra et al. (Vera-Lastra et al., 2021) noted that SARS-CoV-2 vaccination may induce hyperthyroidism. Furthermore, adjuvants may cause alterations in the immune system and cause thyroid problems. In terms of pathophysiology, COVID-19 vaccination causes an increase in blood viscosity (Joob and Wiwanitkit, 2021). High blood viscosity is an important factor in abnormally high TH levels (Tamagna et al., 1979). On the other hand, inactivated or nucleic acid vaccines may be safer because there is no risk of disease from this kind of vaccine (Vora et al., 2020). Overall, we considered that the selection of a reasonable COVID-19 vaccine is essential to induce a balanced humoral and cell-mediated immune response without overactivating the maternal immune system (Vora et al., 2020). An inappropriate vaccine will lead to TH disorders, thereby inducing an adverse pregnancy.

We provide a plausible overview relating to COVID-19, TH, and pregnancy, elucidating the possible mechanism that COVID-19 would give rise to adverse pregnancy outcomes. SARS-CoV-2 causes an overactivation of the immune response and culminates in a “cytokine storm,” which, on one hand, leads to a disturbance in maternal TH, and on the other hand, causes dysfunction of TH transporter and deiodinase in placenta. The overall TH disturbance in pregnant women eventually induces placenta dysfunction, including disturbance of EVT invasiveness and angiogenesis, and alteration of immune status. Therefore, physicians should raise alertness on TH abnormality when treating pregnant COVID-19 patients.

Conceptualization: PH and SC. Resources: QS, PC, MW, and BW. Data curation: PC, MW, and BW. Writing: QS, MW, and PH. Supervision: PH and SC. Funding acquisition: PH and SC. TH’s contribution to this article is in the manuscript writing. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the National Natural Science Foundation of China (81974423, 81902729), the Key Research and Development Programme of Hunan Province of China (2019SK2031), the Natural Science Foundation of Hunan Province (2020JJ5904), and China Postdoctoral Science Foundation (2020M672517, 2021T140749).

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.

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