European Journal of Clinical Microbiology & Infectious Diseases

https://doi.org/10.1007/s10096-020-03897-6

REVIEW

Analysis of the susceptibility to COVID-19 in pregnancy

and recommendations on potential drug screening
Xiaoxuan Zhao 1 & Yuepeng Jiang 2 & Yang Zhao 3 & Hongyan Xi 1 & Chang Liu 2 & Fan Qu 4 & Xiaoling Feng 5

Received: 11 March 2020 / Accepted: 2 April 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
To analyze the susceptibility of SARS-CoV-2 in pregnancy and the drugs that can be used to treat pregnancy with
COVID-19, so as to provide evidence for drug selection in clinic. By reviewing the existing literature, this paper
analyzes the susceptibility of pregnant women to virus, especially to SARS-CoV-2, from the aspects of anatomical,
reproductive endocrine and immune changes during pregnancy and screens effective and fetal-safe treatments from
the existing drugs. The anatomical structure of the respiratory system is changed during pregnancy, and the virus
transmitted by droplets and aerosols is more easily inhaled by pregnant women and is difficult to remove.
Furthermore, the prognosis is worse after infection when compared with non-pregnancy women. And changes in
reproductive hormones and immune systems during pregnancy collectively make them more susceptible to certain
infections. More importantly, angiotensin-converting enzyme (ACE)-2, the SARS-CoV-2 receptor, has been proven
highly increased during pregnancy, which may contribute to the susceptibility to SARS-CoV-2. When it comes to
treatment, specific drugs for COVID-19 have not been found at present, and taking old drugs for new use in treating
COVID-19 has become an emergency method for the pandemic. Particularly, drugs that show superior maternal and
fetal safety are worthy of consideration for pregnant women with COVID-19, such as chloroquine, metformin,
statins, lobinavir/ritonavir, glycyrrhizic acid, and nanoparticle-mediated drug delivery (NMDD), etc. Pregnant women
are susceptible to COVID-19, and special attention should be paid to the selection of drugs that are both effective
for maternal diseases and friendly to the fetus. However, there are still many deficiencies in the study of drug safety
during pregnancy, and broad-spectrum, effective and fetal-safe drugs for pregnant women need to be developed so as
to cope with more infectious diseases in the future.

Keywords New coronavirus disease . Pregnancy . Virus susceptibility . Antiviral treatment . Fetal safety

Introduction

* Fan Qu
Since the end of 2019, the 2019 new coronavirus disease
[email protected] (COVID-19) that occurred in Wuhan, Hubei Province has
* Xiaoling Feng
posed a serious threat to China and even the world. In
[email protected] January 30, 2020, COVID-19 was declared a public health
emergency of international concern (PHEIC) by WHO. The
1
Heilongjiang University of Chinese Medicine, Harbin 150040, China novel coronavirus is officially classified as SARS-CoV-2,
2
Zhejiang Chinese Medical University, Hangzhou 310053, China known as “severe acute respiratory syndrome coronavirus 2”
3
Hebei College of Traditional Chinese Medicine,
[1]. So far, 77,262 cases have been confirmed in China and
Shijiazhuang 050000, China nearly 2000 cases of infection in other countries. Although the
4
Women’s Hospital, School of Medicine, Zhejiang University,
isolation, gene sequence, and structural analysis of the virus
Hangzhou 310006, China have been completed, there is still no specific drug against it.
5
First Affiliated Hospital of Heilongjiang University of Chinese
Since drug development needs a long period, it cannot meet
Medicine, Harbin 150040, China the urgent needs of the moment. Therefore, using the existing
drugs to cut off the above process of the virus is expected to
 Eur J Clin Microbiol Infect Dis

make a breakthrough in a short time, on the premise of under-

standing the invasion, replication, and release mode of the
virus. There is a special group in this outbreak, pregnant wom-
en, which deserve our great attention because of the physio-
logical changes during pregnancy that make them more sus-
ceptible to virus. Previous epidemiological evidence strongly
suggests that pregnant women have a higher risk of serious
illness and death from viral infections [2] during pandemics
such as influenza and ebola [3, 4]. In addition, viral infections
tend to result in miscarriage, preterm, and so on. And because
of the existence of fetus and placenta, pregnancy brings us
unique pharmacological challenges. As discussed in the liter-
ature of the past two decades, pregnant women are indeed
“drug orphans” [5]. The number and efficacy of drugs that
can be used to treat pregnant women who are afflicted with
other diseases are extremely limited. And it is often difficult to Fig. 1 Schematic diagram of the structure of coronavirus
quantify the passing degree of a drug between mother and
fetus and its side effects on fetus. Therefore, it is of great
significance to understand why pregnant women are at higher
risk during outbreaks of infectious disease, and then design is only one complete 2019nCoV genome (29,870 bp, exclud-
appropriate prevention methods and treatment on due consid- ing poly (a) tail) (No. mn908947) in GenBank [11]. Lu and his
eration of pregnancy. Thus, we reviewed the existing literature colleagues [12] found that although SARS-CoV-2 is more
and summarized the etiological features of SARS-CoV-2; an- similar to bat-sl-covzc45 and bat-sl-covc21 (about 88% of
alyzed the susceptibility of pregnant women to virus from the genome sequence homology) derived from two bat-like
respiratory, immune, and endocrine system changes; and pro- coronaviruses, compared with SARS-CoV-1 (about 79%).
posed the therapeutic drugs that could be used to treat preg- And the homology model showed that the structure of recep-
nant women with COVID-19, so as to provide information for tor binding region of SARS-CoV-2 and SARS-CoV-1 is more
the selection of drugs for clinical treatment. similar, suggesting a similar pathogenesis of the two viruses.
Scholars have confirmed that both SARS-CoV-2 and SARS-
CoV-1 enter the host cell by binding their S proteins to ACE2
Etiological features of SARS-CoV-2 receptors located on the surface of the host cells. On February
19, 2020, researchers from the University of Texas and NIH
Coronavirus is a plus-stranded linear RNA virus with an en- used cryoelectron microscopy to demonstrate the molecular
velope (or capsule) and is the largest RNA virus. Belonging to structure of the neocoronavirus S protein for the first time, and
the order Nidovirales, family Coronaviridae, and the subfam- they found that the affinity between neocoronavirus and
ily Orthocoronaviridae, there are four genera of coronavirus— ACE2 was 10~20 times than that of SARS-CoV-1 [13]. On
Alphacoronavirus, Betacoronavirus, Deltacorona virus, and the same day, Zhou Qiang’s team from West Lake University
Gammacoronavirus [6–8]. The envelope of coronavirus is published the results online on the preprint platform BioRxiv,
composed of bilayer lipid and transmembrane protein, and successfully analyzing the full-length structure of ACE2, the
the spinous processes outside the membrane are crown-like cell receptor of SARS-CoV-2 [14], and Zhou’s team found
under the electron microscope. Its nucleocapsid consists of a that ACE2 exists as a dimer, with both open and closed con-
positive-strand RNA and a capsid protein, with a helically formations that contain a mutual recognition interface with
symmetric structure. The genome size of coronavirus is 26– SARS-CoV-2. On February 21, three biological research
32 kb, and its structure is highly conserved, as follows: 5 ′ teams published online the three-dimensional crystal structure
leading sequence-replicase-spike (S) protein-envelope (E) of the S protein receptor-binding region (RBD) of SARS-
protein-membrane (M) protein-nucleocapsid (N)-3′ poly (a). CoV-2 and the ACE2 receptor [15]. After the S protein binds
About 67% of its genome is used to code for replication en- to ACE2 receptor, it is cleaved in S1 region by cell protease
zymes, and the rest is used to code for structural proteins and TMPRSSs to expose the fusion region located in S2 region,
helper proteins, as shown in Fig. 1 [9, 10]. There are seven thus facilitating the fusion of virus envelope and cell mem-
coronaviruses currently infecting humans, of which the brane system, helping the viral nucleocapsid enter the cyto-
SARS-CoV-2 is the third coronavirus to cause a major epi- plasm. In terms of nucleotide order, SARS-CoV-2 inserts four
demic, after severe acute respiratory syndrome (SARS) and amino acids at protease cleaving sites between S1 and S2,
Middle East respiratory syndrome (MERS). At present, there which can make cleaving more efficient. After entering the
Eur J Clin Microbiol Infect Dis

cell, the virus uses the cell’s own protein synthesis system to mucosa mediated by progesterone during pregnancy may lead
produce replicase, other structural proteins, and helper to the adhesion of the virus in the upper respiratory tract and
proteins. make it difficult to be cleared [21, 22].
Physiological changes in pregnant women not only in-
crease their susceptibility to the virus, but also increase the
Reasons for pregnant women’s susceptibility severity of the disease. According to epidemiological statisti-
to the virus cal studies, the indicators used to assess the severity of the
disease themselves are directly affected by pregnancy [23].
Pregnant women are more susceptible to the virus and show a The cardiovascular changes, the increase in metabolic rate
worse prognosis than non-pregnant women. Epidemiological and oxygen consumption, the decrease in functional residual
data show that the susceptibility, morbidity, and mortality of capacity, and the mismatch between basic ventilation and per-
pregnant women to influenza virus are significantly increased fusion, all of these factors caused by pregnancy are easy to
compared with non-pregnant women. In the outbreak of the lead to the occurrence of hypoxic respiratory failure in women
influenza during 1957–1958, the mortality of pregnant wom- after infection with SARS-CoV-2 [24]. On the other hand, if
en was 10%, which was twice as high as that of non-pregnant virus infection occurs, pulmonary vascular resistance will in-
women [16]. Furthermore, statistics show that of the 484 peo- crease, which may lead to pulmonary hypertension and heart
ple in USA who died from the 2009 H1N1 influenza, 28 (5. failure [25]. According to current statistics, a significant pro-
8%) were pregnant women, who accounted for only 1% of the portion of deaths with COVID-19 are due to dyspnea. While
US population [17]. During the outbreak of SARS in 2003, the incidence of physical dyspnea in the third trimester of
several small clinical reports reported that pregnant women pregnancy is 50–70%. Without doubt, SARS-CoV-2 infection
infected with SARS had worse outcomes than non-pregnant will undoubtedly worsen the degree of breathing difficulties.
women. For example, a hospital in Hong Kong reported the
infection in 10 pregnant women and 40 non-pregnant women, Changes in the immune system
of which 3 (30% maternal mortality) of the pregnant women
died of SARS, and no deaths occurred in the non-pregnant A successful pregnancy is the mother’s tolerance to the allo-
group (P = 0. 006) [17]. Through these statistics, we can clear- geneic fetus. Because nearly half of the embryo’s genome
ly find that pregnant women are at high risk of viral infectious comes from the father, which are then expressed as paternal
diseases, which have been proved to be closely related to antigens that can be recognized by the maternal immune sys-
physiological changes in the respiratory, circulatory, secretory, tem as foreign antigens. Therefore, the mother will undergo a
and immune systems during pregnancy. series of complicated processes to ensure the acceptance of
fetus [26], and these immune changes may increase the
Changes in respiratory system mother’s susceptibility to certain infectious diseases [27].
Many scholars believe that during pregnancy, Th2/Th1 is de-
A series of physiological changes occur in the maternal respi- viated to Th2, while in abortion, it is reversed [28, 29]. The
ratory system during pregnancy. Anatomically, the effects of transfer of immunity to Th2 is the cause of changes in the
progesterone and relaxants in the first trimester of pregnancy peripheral response to respiratory virus infection [30] and
can lead to the relaxation of ligaments in the ribs [18]. And the autoantigen [31]. Danza et al. found that the total number of
diaphragm will move up as the uterus grows. Besides, the CD3 + T cells in the blood decreased [32]. Moreover, the
subcostal angle and transverse diameter of the thoracic cavity surge in estrogen and progesterone in the first trimester of
will increase further in the third trimester. The above anatom- pregnancy leads to reversible degeneration in thymus, which
ical factors, together with the decreased compliance of chest may account for the decrease in CD4 + and CD8 + T cells
wall, eventually lead to a 20 to 30% reduction in functional [33]. Besides, in order to study the relationship between preg-
residual capacity (FRC) [19], which makes the mother prone nancy and virus immune, Thomas et al. [34] assessed longi-
to hypoxia, subsequently compensated by increased tidal vol- tudinal changes among more than 50 participants at three time
ume and hyperventilation. In addition, elevated progesterone points during pregnancy and two time points during postpar-
can be transmitted through estrogen-dependent progesterone tum, such indicators are observed as white blood cell count,
receptors in the hypothalamus, thus stimulating the respiratory analysis of the function of NK cells and CD4+ T cell response,
center and increasing tidal volume by 50% compared with determination of cytokines in maternal blood, level of
non-pregnancy [20]. Hyperventilation causes pregnant wom- defensins, steroid hormones, and so on. The results showed
en to inhale more air within the same period of time. If SARS- that compared with postpartum, the late gestation was charac-
CoV-2 is in the air, pregnant women are more likely to get the terized by a decreased number and activity in NK cells and T
disease than ordinary people and are infected by droplets, cells, which may affect the viral clearance rate and lays a
aerosols, and other means. In addition, the changes of nasal foundation for the onset and deterioration of infectious
 Eur J Clin Microbiol Infect Dis

diseases [35, 36]. Thus, in addition to a decrease in the number Effects of viral infection on the fetus
of T cells in the blood during pregnancy, the activity of these
cells was significantly reduced even in the absence of a sig- There has been considerable concern about the effects of
nificant preference for the Th2 phenotype [37–39], all of SARS-CoV-2 infection during pregnancy on the fetus or new-
which contributes to the susceptibility of pregnant women to born. No evidence has been found that the development of
the virus. COVID-19 in the third trimester of pregnancy can lead to
severe adverse outcomes in fetus and the newborn arose from
The expression of ACE2 is increased during pregnancy infections that may be caused by vertical intrauterine trans-
mission. Chen et al. [49] retrospectively analyzed the clinical
ACE is the core of the renin-angiotensin system (RAS) and data of 9 labor-confirmed COVID-19 pregnant women and
has long been considered a key regulator of blood pressure in explored the potential of vertical transmission of the virus.
mammals. The presence of its homolog ACE2 in humans was The results showed that the clinical characteristics of these
not confirmed until 50 years after ACE was discovered [40]. patients with SARS-CoV-2 infection during pregnancy were
Different from ACE, ACE2 functions as a carboxyl similar to those of non-pregnant adult that previously suffered
monopeptidase to lyse the single residues of ANG I to gener- from COVID-19, and that the SARS-CoV-2 test of amniotic
ate the single residues of ANG 1–9 and ANG II which is then fluid, umbilical cord blood, neonatal throat swabs, and breast
decomposed as ANG 1–7 [41]. ANG 1–7 is a bioactive pep- milk samples of 6 patients were negative. Recently, Dr.
tide with vasodilatory activity that can counteract the contrac- Stephen Morse, an epidemiologist at the Columbia
tile effects of ANG II, so ACE2 is thought to modulate the University’s mailman school of public health, says: “Based
effect of the RAS on vascular tension [42, 43]. on previous observations of pregnant women with MERS
With the development of medical science and technol- and SARS, although limited in number, intrauterine coronavi-
ogy, ACE2 is not only considered as an angiotensin- rus transmission from mother to fetus has never been con-
related peptide. In recent studies, scholars believe ACE2 firmed,” when he is asked about babies recently diagnosed
is the “doorknob” for SARS-CoV-2 entering the door of with 2019- nCoV infection [49].
the host cells [44], and the upregulation of ACE2 is likely However, even if we do not find proofs of vertical trans-
to increase the susceptibility of COVID-19. Studies have mission, it is not enough to make us relax. Because the present
shown that smoking is also a susceptibility factor for study shows that even if the virus infection is absent in the
SARS-CoV-2, and analysis of gene chips in smoking pa- placenta, the mother’s response to infection tends to promote
tients has found that ACE2 expression is upregulated the fetus inflammatory response, which is defined as the fetal
when comparing with non-smoking patients [45], which inflammatory response syndrome (FIRS), characterized by
is consistent with clinical evidence. In the same way, a high levels of inflammatory cytokines in placenta, such as
high expression of ACE2 in pregnant women also in- IL-1, IL-6, IL-8, and TNF-α but a lack of culturable microor-
creases the susceptibility of pregnant women to SARS- ganisms. These cytokines have been shown to affect the cen-
CoV-2. Brosnihan et al. [46] proposed an increased level tral nervous system and circulatory system and tend to cause
of ACE2 in pregnant women’s kidneys. And Joyner et al. fetal abnormal morphology in animal models, including ven-
[47] also reported an increase in immunocytochemical tricular expansion and bleeding [50–52]. In addition to the
staining of ANG 1–7 and ACE2 in the kidney of pregnant morphological effects on the fetal brain, the presence of
rats, indicating that this increase was gradual in both cor- FIRS has been associated with an increased risk of diagnosis
tex and medulla during pregnancy. Besides, Levy et al. of autism, schizophrenia, neurosensory deficits, and late-stage
found that the amount of ACE2 mRNA in the kidney, psychosis [53, 54]. To better understand the mechanisms by
placenta, and uterus increased significantly during preg- which maternal infections cause neurodevelopmental and psy-
nancy, resulting in a twofold increase in total compared to chological abnormalities in offspring, several groups have
non-pregnant women [48]. It is speculated that increased conducted extensive studies. Animal models, including ro-
level of ACE2 is able to regulate blood pressure during dents, rabbits, and sheep, were injected with TLR ligands to
pregnancy, and this adaptation may be a favorable condi- determine whether inflammation downstream of the TLR sig-
tion for SARS-CoV-2 infection. In addition, ACE2 is not nal pathway affected development and offspring behavior.
only a receptor, but also involved in post-infection regu- Both LPS (TLR4 ligand) and poly (I:C) (TLR3 ligand) treat-
lation, including immune response, cytokine secretion, ments during pregnancy lead to deficits in pre-pulse inhibition
and viral genome replication. Therefore, the relationship (PPI), social interaction, and progeny learning [55]. It is not
between upregulation of ACE2 and SARS-CoV-2 in preg- difficult to find pregnant women in the state of infection,
nancy needs to be further studied, and new targets for whether or not there is vertical transmission, will bring serious
drug development are expected to be found from these effects on the fetus. Therefore, active treatment should be
aspects. given when pregnant women are infected with SARS-CoV-2
Eur J Clin Microbiol Infect Dis

so as to prevent more serious effects on the future develop- ethyl in chloroquine is replaced by one hydroxyethyl in
ment of the mother and fetus. hydroxychloroquine. Though the two drugs share similar ther-
apeutic effects, the side effects of hydroxychloroquine are
significantly less than that of chloroquine [60]. At present,
Treatment the main clinical applications are chloroquine phosphate and
hydroxychloroquine.
The lack of cellular structure of the virus contributes to its Previous studies have clearly suggested that chloroquine
great variability, which also makes people still weak in anti- has shown immunomodulatory and broad-spectrum antiviral
viral treatment. Due to the lack of cell structure and the strong effects, and such mechanisms ensure its therapeutic effects in
variability of virus, people still have difficulty in antiviral a variety of infectious diseases, and has begun to show new
treatment. Since 2013, the FDA has approved only 12 drugs applications of this old drug, and COVID-19 may also in its
to treat viral infections, 10 for hepatitis C virus (HCV) and therapeutic range. Evidence and clinical trials have confirmed
HIV, one for cytomegalovirus (CMV), and one for influenza the inhibitory effect of chloroquine on HIV/AIDS, MERS-
virus (IFV). Currently, there is no specific drug for sarsSARS- CoV, SARS-CoV, and other viruses. Moreover, the dose of
cCovV-2. At present, people only have to choose existing antiviral is lower than the blood concentration of the treatment
drugs based on the past experience of antiviral and strive to of malaria, and no toxicity was found to host cells [61]. Martin
develop vaccines or direct-acting antiviral drugs or host- et al. [62] showed that the inhibitory effect of chloroquine on
directed therapies at the same time [56]. However, due to the cells of SARS-CoV infection can be demonstrated before or
presence of the fetus, many antiviral drugs are prohibited dur- after the cells are exposed to the virus, which means that
ing pregnancy because of their proven teratogenicity. For ex- chloroquine shows an effect both on prevention and on treat-
ample: ribavirin is listed as an X-grade drug in the Federal ment of SARS-CoV. Firstly, chloroquine is an alkaline com-
Drug Administration (FDA), indicating that it is prohibited pound whose non-protonated parts enter cells and are proton-
during pregnancy. Ribavirin’s FDA (Federal Drug ated and concentrated in acidic organelles with low PH (such
Administration) (www.fda.gov) pregnancy drug safety rating as endosomes, golgi vesicles, and lysosomes), thereby in-
is X, indicating that its use is contraindicated for pregnant creasing the PH in the nucleus and blocking ph-dependent
women. Susan S. Roberts et al. [57] conducted a 5-year study replication of coronavirus retroviruses [63]. In addition, the
with the goal of observing the live births of 131 mothers who drug can interfere with the terminal glycosylation of the cell
were directly (mother) exposed to ribavirin. After 5 years, 49 receptor ACE2, which has been identified as a functional cel-
babies were born alive, and congenital malformations are as lular receptor of SARS-CoV [64]. And this virus-receptor
follows: torticollis (2), hypospadias (1), polydactyly and a binding can be inhibited and make the infection invalidated.
neonatal tooth (1), glucose 6 phosphate dehydrogenase defi- Last but not least, chloroquine has also been found to have an
ciency (1), ventricular septal defect, and cyst of 4th ventricle immunomodulatory effect. It can inhibit the production and
of the brain (1). Clearly, ribavirin should be banned during release of TNF-α and IL-6 and has been used in the treatment
pregnancy. In addition, many prescription drugs lack reliable of autoimmune diseases such as rheumatoid arthritis and lupus
data to support their safety in treating pregnancy-related con- erythematosus [65]. In the middle and late stage of SARS-
ditions [58]. In fact, far fewer clinical drug trials are conducted CoV infection, TNF-α and IL-6 concentrations are correlated
during pregnancy than in any other major health field [59]. In with the severity of the disease, so the anti-inflammatory ef-
order to treat pregnancy combined with COVID-19 as quick- fect of chloroquine can also reduce immune lesions. It has
ly, effectively, and safely as possible, we have proposed some been reported that the use of hydroxychloroquine in systemic
drugs that might be used to treat COVID-19 based on the lupus erythematosus leads to defective differentiation in Th17
existing evidence, so as to provide convenient evidence for cells, and the expression of cytokine IL-17 was also limited to
clinicians to choose drugs. some extent, which is a potential evidence of chloroquine in
reducing cytokine storm [66]. These trials were sufficient to
Chloroquine, chloroquine phosphate, support the therapeutic effect of chloroquine on COVID-19.
and hydroxychloroquine Wang et al. [67] demonstrated that chloroquine functioned at
both entry and at post-entry stages of the 2019-nCoV infection
Chloroquine was first synthesized in 1934 by Hans Andersag in Vero E6 cells by time-of-addition assay. Besides its antiviral
in Bayer, Germany, through structural modification of the activity, chloroquine has an immune-modulating activity,
oldest antimalarial drug, quinine. Chloroquine phosphate, a which may synergistically enhance its antiviral effect in vivo.
FDA-approved antimalarial drug, has been used clinically We collected some evidences for the use of chloroquine in
for more than 70 years. Hydroxychloroquine is a new antima- pregnancy combined with COVID-19. Although chloroquine
larial drug developed by scientists on the basis of chloroquine is classified as class C in the FDA for pregnancy, the effect of
in 1944. The difference between the two drugs is that one chloroquine on pregnancy is proved to be mild. Klumpp et al.
 Eur J Clin Microbiol Infect Dis

[68] believed that in the 20 years since the advent of chloro- included, of which 40 were diagnosed with ET, while 71 pa-
quine, an estimated 1 billion people have used chloroquine, tients with ET not receiving any medication during pregnancy
including pregnant women. They have never found reports of were taken as controls. The results showed that none of the 63
fetal damage, and the agencies responsible for malaria control patients who received IFN-α during pregnancy had major
in malaria-endemic areas have not banned the use of antima- malformations or stillbirths, and that IFN-α did not signifi-
larials by pregnant women. And records in WHO do not show cantly increase the risk of malformations, miscarriages, still-
any adverse effects of chloroquine on pregnancy, childbirth, or births, or premature births. Thus, in the case of COVID-19
newborns. In addition, regarding the pregnancy safety of during pregnancy, IFN is expected to be effective and safe.
hydroxychloroquine, Yusuf Cem Kaplan et al. [69] conducted
a meta-analysis that included seven cohort studies and one Lopinavir/litonavir
randomized controlled trial, involving 1820 infants. The
meta-analysis reported no significant increases in rates of ma- At present, lopinavir/ritonavir is recommended for antiviral
jor congenital (OR 1.13, 95% confidence interval (CI) 0.59, therapy of COVID-19 in many treatment schemes in China.
2.17), craniofacial (OR 0.62, 95% CI 0.13, 3.03), cardiovas- Lopinavir/ritonavir used to combat HIV [76]. Lopinavir can
cular (OR 1.06, 95% CI 0.29, 3.86), genitourinary (OR 1. 8, prevent the division of HIV Gag-Pol, and litonavir can inhibit
95% CI 0.42, 4.53), nervous system malformations (OR 1.81, the activity of HIV protease by acting on aspartyl proteases of
95% CI 0.31, 10.52), stillbirth (OR 0.69, 95% CI 0.35, 1.34), virus, making it unable to shear the precursor protein of Gag-
low birth weight (OR 0. 69, 95% CI 0.21, 2.27), or prematu- Pol polymerase. The combination of lopinavir and litonavir
rity (OR 1.75, 95% CI 0.95, 3.24). Based on this evidence, we can inhibit the proliferation of HIV virus by producing non-
speculate that hydroxychloroquine has the potential to be an reproducible particles in immature forms during the virus rep-
effective drug in pregnancy with COVID-19. lication process [77]. Because lopinavir/ritonavir has a clear
binding site with SARS-CoV, and the SARS-CoV-2 sequence
Interferon shows a high homology with SARS-CoV-1, lopinavir/
ritonavir is strongly recommended for the treatment of
Type I interferon (I-IFN) mainly includes IFN-α, β, κ, and λ, COVID-2019. Shen Lin et al. [78] established the structural
of which IFN-α and IFN-β are currently the main clinical model of protease C30 of SARS-CoV-2 and papain-like virus
interferons for anti-CoVs. Studies have shown that I-IFN has protease through homologous modeling, and then docked ri-
antiviral effects on various cell models, such as embryonic tonavir and lopinavir with the protease model respectively.
kidney cells (fRhK-4) of rhesus monkey and monkey kidney Through docking, 100 poses were found when docking rito-
cells (Vero-E6), etc. [70]. In the study of infected macaques, navir to CEP_C30, with the libdock score of the optimal pose
preventive treatment of IFN-α significantly reduced replica- 192.346. Eighty-eight poses were found when docking
tion of SARS virus, expression of viral antigen in type I alve- lopinavir to CEP_C30, with the libdock score of the optimal
olar epithelium, and lung injury [71]. The antiviral effect of I- pose. The results suggest that the therapeutic effect of ritonavir
IFN was clearly demonstrated not only in animal experiments on COVID-19 may be mainly due to its inhibition of corona-
but also in human trials. In an open-label, non-randomized virus endopeptidase C30. In addition, during the outbreak of
clinical trial of 22 SARS patients, nine were subcutaneous SARS, scholars [77] in Hong Kong, China, used lopinavir/
injected with I-IFN, and the results showed that all nine pa- ritonavir and ribavirin to treat 41 patients. The results showed
tients survived with fewer side effects [72]. IFN-β1a shows that compared to the 111 patients treated only with ribavirin,
stronger antiviral activity than IFN-α, and there was evidence patients treated with combination therapy had a lower risk of
that when IFN-α begins to show anti-SARS-CoV effects at adverse events such as ARDS or death (2.4% vs 28.8%).
1000 IU/mL, recombinant human IFN-β1a is able to inhibit Thus, we can find that the addition of lopinavir/ritonavir
SARS-CoV activity strongly [73]. Besides, a retrospective shows promise to benefit the treatment of COVID-19.
study [74] showed that there was no significant difference in So, can lopinavir/ritonavir be used in pregnant women? An
case fatality rate between IFN-β1a and IFN-α2a in patients open-label, randomized controlled trial by Koss CA et al. [79]
infected with MERS (P = 0. 24). When taking these proofs involved 356 pregnant women infected with HIV. Lopinavir/
into consideration, we speculated that I-IFN may play a role ritonavir or efavirenz was randomly administered at 12 to
in clinical treatment of COVID-19, and IFN-β1a may be more 28 weeks of pregnancy. Univariate and multivariate logistic
preferable. regressions were used to analyze the potential risk factors for
Is I-IFN safe enough for women during pregnancy? preterm labor (less than 37 weeks). The results showed that
Yazdani BP et al. [75] conducted a meta-analysis to observe lopinavir/ritonavir was not associated with an increased risk of
whether I-IFN has adverse effects on patients with primary preterm compared with efavirenz, except for nutritional fac-
thrombocytopenia (ET) during pregnancy. A total of 63 case tors (OR = 1.12, 95% CI 0.63 2.00, p = 0.69). Besides,
reports of IFN-α direct exposure during pregnancy were Martinez et al. [80] analyzed 955 women exposure to
Eur J Clin Microbiol Infect Dis

lopinavir/litonavir during pregnancy. Result showed that the showed that metformin could significantly reduce adverse ma-
prevalence of birth defects in infants with prenatal exposure to ternal and neonatal outcomes such as gestational hyperten-
lopinavir/litonavir was not significantly different from that in sion, hypoglycemia, neonatal intensive care, and so on. As a
internal or external controls. These data provide patients and result, it is a safe and effective alternative or complementary
clinicians with reliable information on the safety of lopinavir/ therapy for insulin in women with gestational diabetes. And
ritonavir in treating pregnant women with COVID-19. Thus, such safety is also promising for pregnant women with
lopinavir/ritonavir is safer than other direct antiviral drugs. In COVID-19.
addition, lopinavir/ritonavir is the preferred antiviral therapy Statins, another drug in the HDT regimen, are able to in-
for pregnancy with COVID-19, according to the second edi- duce autophagy and phagocytic maturation by activating re-
tion of the strategy recommendations for management of ceptor of peroxisome proliferator-activated receptor γ and
COVID-19 in pregnancy (published at Huazhong University transforming growth factors β [88] and play an anti-
of Science and Technology Union Hospital). So this drug inflammatory role in influenza and other lung injury diseases
deserves our full consideration in the treatment of COVID- [89]. A trial involving 477 cases exposed to simvastatin or
19 during pregnancy. lovastatin during pregnancy showed the incidence of congen-
ital abnormalities in neonates was 3.8%, similar to the average
Host-directed therapy rate of 3% [90]. Although the number of reports is relatively
small, there is no evidence of an increase in congenital defor-
HDT (host-directed therapy) refers to a variety of therapeutic mities in children exposed to simvastatin or lovastatin before
approaches that work without direct anti-infection in the fight birth, compared with the general population. Therefore, such
against infectious diseases [81]. Its goal is to “intervene the drugs as metformin and statins are much friendlier for preg-
mechanism of pathogen infection, activate the body’s protec- nancy. Alimuddin Zumla [91] pointed that metformin, statins,
tive immune response, suppress the overactive inflammatory can be used as adjuvant with cyclosporine, lobinavir/ritonavir,
response, and balance the immune response of diseased interferon-1b, ribavirin, monoclonal antibodies, and antiviral
parts.” Clinical data indicate that COVID-19 patients of severe peptides targeting SARS-CoV-2, thereby reducing the use of
type present with cytokine storms, which are characterized by antiviral drugs and reducing side effects. Therefore, the appli-
elevated levels of IL-2, IL-7, IL-10, granulocyte colony- cation of HDT is very suitable for pregnant women with
stimulating factor, and TNF-α, resulting in pathological dam- COVID-19.
age to multiple organs of the body [82]. In acute infections,
HDT is expected to inhibit overactive inflammatory re- Glycyrrhizin
sponses, the same as in COVID-19. Alimuddin Zumla [83]
pointed out that HDT has been proved to be safe and effective, A 2016 international study showed that up to 60% of pregnant
of which metformin, glitazone, and atorvastatin are commonly women use herbal-based alternative medicines [92]. Licorice
used drugs [84]. The application of HDT may reduce immu- is one of the most frequently used drugs in China.
nopathology and enhance immune response, which is hopeful Glycyrrhizin is considered to be the main bioactive ingredient
in reducing mortality in patients with COVID-19. Studies in licorice, which is then metabolized to glycyrrhetinic acid. It
have shown that metformin increases the production of mito- shows anti-inflammatory, antiviral, antiallergic, and immune-
chondrial ROS and enhances autophagy in macrophages [85]. regulating effects in various studies [93]. In recent years,
Zmijewski JW et al. [86] treated mice exposed to LPS with glycyrrhizin has made progress in the treatment of hepatitis
metformin and found that metformin inhibited the level of B, AIDS, SARS, and other viral infectious diseases. Chen
mitochondrial complex I in the lungs and reduced the severity et al. [94] found that glycyrrhiza had anti-SARS-CoV activity
of lung damage. And mitochondrial complex I plays a vital by means of neutralization and plaque determination. And
role in regulating toll-like receptor 4-mediated activation of scientists from the clinical center of Frankfurt University in
neutrophils. Thus, we concluded that one of the mechanisms Germany compared the antiviral effects of ribavirin, 6-
that metformin takes effect in acute inflammation is to inhibit azaguanosine, pyrazofuran, mycophenolate acetate, and
mitochondrial complex I. So, can metformin be considered glycyrrhizin on two SARS patients [95]. Results showed that
when pregnant women choose an HDT drug? Gilbert et al. glycyrrhizin had the strongest inhibitory effect on SARS-CoV
[87] gave the answer. They included eight studies involving replication. The half maximal effective concentration (EC50)
200 women exposed to metformin in the first trimester of was 300–600 μg/ml and the half maximal cytotoxic concen-
pregnancy. The results showed that exposure to metformin tration (CC50) > 20,000 μg/ml. Furthermore, glycyrrhizin can
in the first trimester of pregnancy was not associated with an not only inhibit virus replication but also impair virus adsorp-
increased incidence of major malformations [OR = 0.50 tion and membrane penetration in the early stage of virus
(95%CI: 0.15, 1.60)]. Li et al. [88] included 11 studies involv- replication, which is expected to make it a specific drug for
ing 2712 women with gestational diabetes. The results the treatment of COVID-19.
 Eur J Clin Microbiol Infect Dis

Maternal and fetal safety of glycyrrhizin is a major concern NMDD can be considered for use in pregnant women with
in pregnant women with COVID-19. One study showed that COVID-19. In addition, nanomaterials can be used as vaccine
no reproductive or phylogenetic toxicity was found in rats adjuvants because of their superior biocompatibility, high bio-
exposed to licorice water extract of 500–2000 mg/kg from availability, and favorable biocompatibility. Yoon et al. have
2 weeks before mating to the 19th day of pregnancy. In human disclosed a nano-delivery system for SARS vaccine; they
experiments, Strandberg et al. [96] divided 107 pregnant combined the SARS-CoV DNA vaccine (psi-S) that encodes
women who had exposed to glycyrrhizin into three groups S protein with the polymer polyvinylamine (PEI), which ef-
according to the exposure dose: low (< 250 mg/ week), medi- fectively delivered psi-S into cells and induced antigen-
um (250–499 mg/week), and high (500 mg/week), and com- specific humoral and cellular immune responses [102].
pared them with 95 women of normal gestational age. The Therefore, the characteristics of nanomaterials effectively
results showed that the risk of preterm delivery (< 37 weeks) targeting specific sites can improve the immunogenicity of
more than doubled at high doses compared to low doses, con- new vaccines, avoid primary clearance in the liver, and reduce
sistent with the results of the Raikkonen et al. [97]. On the its toxic side effects. It has broad prospects in the prevention
contrary, some scholars disagree with this result. Choi et al. and treatment of pregnant women with COVID-19.
[98] prospectively studied the pregnancy outcomes of 185 Similarly, for pregnant women with COVID-19, the use of
singleton pregnancies treated with over-the-counter prepara- NMDD is an effective way to ensure that drugs can selectively
tions or naturopathic preparations containing glycyrrhiza dur- target maternal disease without fear of teratogenic or other
ing pregnancy, while 370 age-matched singleton pregnancies adverse effects on the fetus [103]. The ideal nanocarrier for
not exposed to any potential teratogen were taken as controls. the treatment of maternal disease should be one that is poorly
The results showed that there was no difference between the bound to the placenta and can be rapidly absorbed by the
main malformations and the control group [OR = 3. 9, 95%CI maternal target organ, which can be achieved by constructing
0.44–3.5, P = 0. 27), and 91% of the exposed women used a a NMDD with a large amount of cryptography and an optimal
higher dose of licorice, without an increased risk of preterm charge to ensure that placental attachment is avoided [103].
labor (< 37 weeks). Therefore, they believe that licorice is not Most studies have shown that nanoparticles administered by
a major teratogen or a risk factor for preterm birth. Differences the mother produce little or no fetal toxicity at drug concen-
in these results may be related to different types of exposure trations. Wick et al. [104] reported that there was no negative
(diet and pharmaceutical formulations) or the amount of use or effect on human placental viability (hCG, glucose consump-
co-exposure factors. Therefore, glycyrrhizin was proposed as tion, and lactate production) and morphology when pregnant
an antiviral drug, while dosage, form, and measurement women are exposed to or ingested polystyrene (50, 80, 240,
should be considered in clinic. In addition, studies [99] have 500 nm) nanoparticles during in vitro perfusion. Menjoge
shown that glycyrrhizin can inhibit the activity of P450 en- et al. [105] also failed to observe a negative effect on placental
zyme and thus increase the serum drug concentration metab- function by measuring biochemical and physiological indica-
olized by the liver; therefore, the drug dose should be reduced tors such as blood oxygen transfer rate and fetal venous flow
appropriately when it combined with glycyrrhizin. in the same model. However, there are exceptions which seem
to relate to the specific chemical composition of the material
Nanoparticle-mediated drug delivery [106]. Therefore, we should also focus on the development of
nanomaterials; make reasonable selection based on the com-
Nanomaterials are defined as having at least one dimension position of the preparation, potential biological distribution,
between 1 and 100 nm, although the definition is often relaxed toxicity, etc.; and give patients proper guidance. Taken togeth-
in the pharmaceutical literature to encompass larger er, NMDD will open the door to drug development programs
(submicron) structures several hundred nanometers across that specialize in treating maternal diseases.
[100]. They show a variety of medical applications, in which
the role of drug delivery has attracted the attention of scholars,
especially in the field of antiviral therapy. Caster [101] turned Conclusions
the first-line drug for HIV into a nanomaterial-
NANOefavirenz and NANOlopinavir. Preclinical studies In recent years, the coronavirus has realized the jump from
have shown that it is effective in inhibiting HIV-1 replication animals to human through the gene mutation, leading to the
in terms of bioequivalence and can slow down the body’s outbreak of epidemic many times, causing huge loss of peo-
resistance to HIV-IIIB and type A viruses. Moreover, ple’s lives and property. It is foreseeable that similar outbreaks
nanoparticle-mediated drug delivery (NMDD) can reduce and epidemics are inevitable in the future. Therefore, large-
the total dose while maintaining clinical efficacy, thus improv- scale investment in research and development of coronavirus
ing patient tolerance and reducing treatment cost. With the vaccines and therapeutic drugs is needed. However, pregnant
advantage of precise targeting and fewer side effects, women are a group that cannot be ignored in drug
Eur J Clin Microbiol Infect Dis

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Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu
the aspects of effectiveness and safety that can be used in the
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also provide some direction for today’s drug research and
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Acknowledgments The authors thank all patients for their participation. spike receptor-binding domain bound with the ACE2 receptor.
Special thanks are also extended to colleagues at the Zhejiang Chinese bioRxiv:2020–2022
Medical University and Zhejiang University. 16. EICKHOFF TC, SHERMAN IL, SERFLING RE (1961)
Observations on excess mortality associated with epidemic influ-
enza. JAMA 176:776–782
Funding information National Natural Fund Project
17. Creanga AA, Johnson TF, Graitcer SB, Hartman LK, Al-Samarrai
This work was supported by grants from the National Natural Science
T, Schwarz AG, Chu SY, Sackoff JE, Jamieson DJ, Fine AD,
Foundation of China (No. 81973894).
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