Journal Pre-proof

Prior and Novel Coronaviruses, COVID-19, and Human Reproduction: What Is

Known?

James Segars, MD, Quinton Katler, MD, MS, Dana B. McQueen, MD, Alexander
Kotlyar, MD, Tanya Glenn, MD, Zac Knight, PhD, Eve C. Feinberg, Hugh S.
Taylor, MD, James P. Toner, MD, PhD, Jennifer F. Kawwass, MD, for the ASRM
Coronavirus/COVID-19 Task Force

PII: S0015-0282(20)30385-X
DOI: https://doi.org/10.1016/j.fertnstert.2020.04.025
Reference: FNS 32441

To appear in: Fertility and Sterility

Received Date: 10 April 2020

Revised Date: 13 April 2020
Accepted Date: 13 April 2020

Please cite this article as: Segars J, Katler Q, McQueen DB, Kotlyar A, Glenn T, Knight Z, Feinberg EC,
Taylor HS, Toner JP, Kawwass JF, for the ASRM Coronavirus/COVID-19 Task Force, Prior and Novel
Coronaviruses, COVID-19, and Human Reproduction: What Is Known?, Fertility and Sterility (2020), doi:
https://doi.org/10.1016/j.fertnstert.2020.04.025.

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Copyright ©2020 Published by Elsevier Inc. on behalf of the American Society for Reproductive
Medicine
 F & S ___ style revision

Title: Prior and Novel Coronaviruses, COVID-19, and Human Reproduction: What Is Known?

Running Title: (40 characters or less)

Coronaviruses and Human Reproduction

Author names and affiliations:

James Segars, MD1, Quinton Katler, MD, MS2, Dana B. McQueen, MD3, Alexander Kotlyar,
MD4, Tanya Glenn, MD4, Zac Knight, PhD5, Eve C. Feinberg3, Hugh S. Taylor, MD4, James P.
Toner, MD, PhD2, Jennifer F. Kawwass, MD2 for the ASRM Coronavirus/COVID-19 Task
Force

1. Division of Reproductive Sciences, Department of Gynecology and Obstetrics, Johns

Hopkins University School of Medicine, Baltimore, MD, USA

2. Division of Reproductive Endocrinology and Infertility, Department of Gynecology and

Obstetrics, Emory University School of Medicine, Atlanta, Georgia.

3. Division of Reproductive Endocrinology &, Infertility, Department of Obstetrics &

Gynecology, Northwestern University, Chicago, Illinois

4. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of

Medicine, New Haven, Connecticut

5. American Society of Reproductive Medicine, Birmingham, Alabama

Corresponding Author:
Jennifer F. Kawwass, MD
Division of Reproductive Endocrinology and Infertility
Emory University School of Medicine
550 W Peachtree, Atlanta, Georgia 30308
Email: [email protected]

Capsule (30 words or less):

A review of prior and the novel coronaviruses and their impact on human reproduction,
specifically male and female gametes, pregnancy, and postpartum suggests that much remains
unknown.

Keywords:
Novel coronavirus, COVID-19, reproduction, pregnancy, review

1
Structured Abstract (241 words)

Objective: To summarize current understanding of the effects of novel and prior coronaviruses
on human reproduction, specifically male and female gametes, and in pregnancy.

Design: Review of English publications in PubMed and Embase to April 6, 2020.

Methods: Manuscripts were screened for reports including coronavirus, reproduction, including
pathophysiology and pregnancy.

Intervention(s): None.

Main Outcome Measure(s): Reproductive outcomes; effects on gametes; pregnancy outcomes;

neonatal complications.

Results: Seventy-nine reports formed the basis of the review. Coronavirus binding to cells
involves the S1 domain of the spike protein to receptors present in reproductive tissues,
including angiotensin converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins. SARS-CoV-
1 may cause severe orchitis leading to germ cell destruction in males. Reports indicate decreased
sperm concentration and motility for 72-90 days following COVID-19 infection. Gonadotropin-
dependent expression of ACE2 was found in human ovaries, but it is unclear whether SARS-
CoV-2 adversely affects female gametogenesis. Evidence suggests that COVID-19 infection has
a lower maternal case fatality rate than SARS or MERS, but anecdotal reports suggest that
infected, asymptomatic women may develop respiratory symptoms postpartum. COVID-19
infections in pregnancy are associated with preterm delivery. Postpartum neonatal transmission
from mother to child has been reported.

Conclusion: COVID-19 infection may adversely affect some pregnant women and their
offspring. Additional studies are needed to assess effects of SARS-CoV-2 infection on male and
female fertility.

2
INTRODUCTION

The rapid spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has

led to a pandemic of Coronavirus Disease 2019 (COVID-19) across the globe. As of April 8,

2020, there are over 1.4 million cases and 86,000 deaths attributed to the virus worldwide. As a

result, nations have implemented suppression and mitigation strategies to control community

spread, including mandated social distancing, restrictions to non-urgent medical care, and closure

of non-essential businesses. Despite these efforts, the spread of SARS-CoV-2 is ongoing,

creating a public health crisis and impacting the population world-wide.

Coronaviruses are a group of viruses that can cross species barriers and become human

pathogens. All seven identified human coronaviruses originated from animal reservoirs including

domestic animals, bats, or mice. While most human coronaviruses cause mild illness, severe

acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome

coronavirus (MERS-CoV) and the novel SARS-CoV-2 have been associated with severe lower

respiratory tract infections, acute respiratory distress syndrome, and death (1).

The novel SARS-CoV-2 virus spreads rapidly, with 2-3 people infected from every index case, a

reproduction number (R0) or transmission rate of 2.24 - 3.58 (2). In contrast, the 2009 H1N1

seasonal influenza had an R0 of 1.46-1.48. The incubation period for SARS-CoV-2 ranges from

2-14 days, and asymptomatic spread occurs prior to onset of symptoms (3, 4). Transmission is

thought to be mainly through respiratory droplets and fomites (5). In one experiment, viable

virus was detected in aerosols for up to three hours, with an estimated half-life of 1.1 hours. In

addition, virus was detected on surfaces for days after application, with viable SARS-CoV-2

3
identified on plastic and stainless steel up to 72 hours (6). SARS-CoV-2 RNA has also been

detected in blood and stool and it is not yet known whether the infection can be acquired through

exposure to non-respiratory bodily fluids (7).

Symptoms of SARS-CoV-2 infection include fever, cough, fatigue, shortness of breath, sputum

production, headache and myalgias. In addition, patients may report gastrointestinal symptoms

(8) or anosmia. The severity of infection ranges from asymptomatic carriers, to mild flu-like

disease, to critical illness and death. Critically-ill patients may experience respiratory failure,

shock or multiorgan dysfunction. Approximately 80% of infections are mild with flu-like

symptoms, 15-20% are severe, requiring hospitalization and supplemental oxygen, and 5% are

critical and require mechanical ventilation (9). Risk factors for severe illness include age and

underlying medical comorbidities such as cardiovascular disease, diabetes, chronic respiratory

disease, hypertension and cancer (10). Death may occur in up to 3% of infections. Death from

SARS-CoV-2 is more common in individuals over age 60 or with underlying medical issues but

can occur in younger persons, perhaps related to the inoculum. Associated cardiac arrhythmias

may be fatal.

While persons of advanced age are most likely to experience severe symptoms, women of

reproductive age are also at risk for development of severe disease and death. Furthermore,

reproductive age women can act as asymptomatic carriers and increase viral transmission.

OBJECTIVE

4
The aim of this review is to summarize what is currently known about the impact of prior

coronaviruses and the novel SARS-CoV-2 infection on reproduction and pregnancy.

METHODS

A systematic search in the literature published in the PubMed and Embase databases was

conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic

Reviews and Meta-Analyses (PRISMA). Literature review of available literature in English, both

published and peer-reviewed on-line publications from 1996-April 6, 2020. Additional sources

were identified from citations of retrieved literature. Search strategy for the PubMed and Embase

searches is shown below. There was no limitation on sample size. Published reports of

experiences with the SARS-CoV-2 virus have increased greatly in the past months, but no

randomized trials to date regarding possible treatments were identified. Most reports pertaining

to reproduction or pregnancy involved small cohorts, case reports, guidelines, and editorials.

Similarly, prior publications of other coronaviruses were limited in number.

We reviewed all titles for eligibility. All reports including pregnancy or reproductive tissues

were included. We excluded editorials and publications of guidelines. We excluded papers that

were duplicates or did not contain information related to pregnancy or reproduction, the presence

of virus in reproductive tissues, effects on gametes, pregnancy outcomes, or neonatal

complications. Case reports were included. Because of the limited nature of the reports and the

absence of randomized trials we did not use the Cochrane RoB 2.0 tool. Similarly, because of the

5
limited scope of the cohort studies, we did not use the Newcastle-Ottawa Scale to rate the

studies.

Full text articles were then reviewed and evaluated for inclusion by authorship teams. Two

independent reviewers (J.S. and Z.K.) Any disagreements were resolved through discussion with

third reviewer (J.K.). The authors acknowledge the number of publications about the novel

SARS-CoV-2 virus is increasing at an exponential rate and there may be bias toward reporting of

positive findings.

SEARCH STRATEGY

We used a broad inclusive search strategy so as not to miss a seminal contribution. The

comprehensive search was conducted by an experienced information specialist. Search phrases

for PubMed included: (("severe acute respiratory syndrome coronavirus 2"[Supplementary

Concept] OR "severe acute respiratory syndrome coronavirus 2"[All Fields] OR "2019 ncov"[All

Fields]) OR ("severe acute respiratory syndrome coronavirus 2"[Supplementary Concept] OR

"severe acute respiratory syndrome coronavirus 2"[All Fields] OR "sars cov 2"[All Fields]) OR

(corona[All Fields] AND ("viruses"[MeSH Terms] OR "viruses"[All Fields] OR "virus"[All

Fields])) OR ("coronavirus"[MeSH Terms] OR "coronavirus"[All Fields]) OR ("COVID-19"[All

Fields] OR "COVID-2019"[All Fields] OR "severe acute respiratory syndrome coronavirus

2"[Supplementary Concept] OR "severe acute respiratory syndrome coronavirus 2"[All Fields]

OR "2019-nCoV"[All Fields] OR "SARS-CoV-2"[All Fields] OR "2019nCoV"[All Fields] OR

(("Wuhan"[All Fields] AND ("coronavirus"[MeSH Terms] OR "coronavirus"[All Fields])) AND

(2019/12[PDAT] OR 2020[PDAT]))) OR ("COVID-19"[Supplementary Concept] OR "COVID-

6
19"[All Fields] OR "covid19"[All Fields])) AND (("gravidity"[MeSH Terms] OR

"gravidity"[All Fields] OR "pregnant"[All Fields]) OR ("pregnancy"[MeSH Terms] OR

"pregnancy"[All Fields]) OR ("live birth"[MeSH Terms] OR ("live"[All Fields] AND "birth"[All

Fields]) OR "live birth"[All Fields]) OR ("abortion, spontaneous"[MeSH Terms] OR

("abortion"[All Fields] AND "spontaneous"[All Fields]) OR "spontaneous abortion"[All Fields]

OR "miscarriage"[All Fields]) OR ("abortion, induced"[MeSH Terms] OR ("abortion"[All

Fields] AND "induced"[All Fields]) OR "induced abortion"[All Fields] OR "abortion"[All

Fields]) OR ("parturition"[MeSH Terms] OR "parturition"[All Fields] OR "birth"[All Fields])

OR ("J In Vitro Fert Embryo Transf"[Journal] OR "ivf"[All Fields]) OR ("IUI"[Journal] OR

"iui"[All Fields]) OR ("sex"[MeSH Terms] OR "sex"[All Fields]) OR ("fertility"[MeSH Terms]

OR "fertility"[All Fields]) OR ("infertility"[MeSH Terms] OR "infertility"[All Fields]) OR

("germ cells"[MeSH Terms] OR ("germ"[All Fields] AND "cells"[All Fields]) OR "germ

cells"[All Fields] OR "gamete"[All Fields]) OR ("oocytes"[MeSH Terms] OR "oocytes"[All

Fields] OR "oocyte"[All Fields]) OR ("embryonic structures"[MeSH Terms] OR

("embryonic"[All Fields] AND "structures"[All Fields]) OR "embryonic structures"[All Fields]

OR "embryo"[All Fields])).

The Embase strategy of phrases included: ('2019 ncov' OR 'sars cov 2' OR 'corona virus'/exp OR

'corona virus' OR (corona AND ('virus'/exp OR virus)) OR 'coronavirus'/exp OR coronavirus OR

'covid 19' OR covid19) AND (pregnant OR 'pregnancy'/exp OR pregnancy OR 'live birth'/exp

OR 'live birth' OR (live AND ('birth'/exp OR birth)) OR 'miscarriage'/exp OR miscarriage OR

'abortion'/exp OR abortion OR 'birth'/exp OR birth OR 'ivf'/exp OR ivf OR iui OR 'sex'/exp OR

7
sex OR 'fertility'/exp OR fertility OR 'infertility'/exp OR infertility OR 'gamete'/exp OR gamete

OR 'oocyte'/exp OR oocyte OR 'embryo'/exp OR embryo).

RESULTS

The search revealed 663 manuscripts after removal of duplicates. Ninety-seven manuscripts

related to pregnancy and coronavirus and only 7 were related to embryos or early reproduction.

Small cohorts, case reports, comments on guidelines, guidelines, editorials were retrieved. After

exclusion, 79 manuscripts were included in the review based on relevance and new data.

PATHOPHYSIOLOGY OF CORONA VIRUSES

Molecular features of the viral coronavirus family, which includes severe Acute Respiratory

Syndrome Coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-

CoV), and the recently identified novel Coronavirus (SARS-CoV-2), have been well-elucidated.

A review of the coronavirus structure and function help to inform us on the pathophysiology of

coronavirus infectivity. Coronaviruses are large, single-stranded, enveloped RNA viruses

approximately 32KB (11). The viral RNA genome is housed inside a nucleocapsid, which itself

is contained within a viral envelope (12). This envelope comprises three distinct proteins: a

“membrane protein” and “envelope protein,” which are both directly responsible for viral

assembly, as well as a “spike protein,” which mediates viral entry into host cells (12). When

viewed with electron microscopy, these spike proteins are surface-exposed markers that produce

8
a recognizable “crown-like” appearance to the virus. The spike proteins serve a critical step in

initiating human infection, as well as determining host tissue specificity and inducing host

immune response (13-15). The coronavirus spike protein is composed of two unique subunits

that facilitate viral-host binding (16-19). The S1 domain of the spike protein functions in viral

binding and attachment to the host cell membrane. Numerous receptors on the human cell

membrane that are involved in S1 subunit binding have been identified to date, including

angiotensin converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins (20, 21). The S2

domain of the spike protein is responsible for fusion of the viral and host cell membranes,

allowing the SARS-CoV-2 viral genome to enter the host cell. This process involves a complex

interaction between viral and host machinery, which culminates in rapid viral replication within

target cells. International research efforts are currently underway aimed at using the S1 domain

of the spike protein as a target for therapeutic anti-viral therapy, as well as vaccine development.

The involvement of SARS-CoV-2 infection within human male and female reproductive systems

has yet to be fully elucidated. However, results from other coronavirus subtypes, specifically

SARS-CoV, help inform knowledge of tissue-specific viral pathophysiology. Current data

suggest that the female reproductive system may be spared from viral infection.

Immunohistochemical and in situ hybridization studies on tissues from a small cohort of

deceased patients that were infected with SARS-CoV failed to identify SARS-CoV viral RNA

within the female reproductive tract, including both ovarian and uterine tissue (22), though

ACE2 receptors can be found there. Importantly, there is evidence to suggest that coronavirus

infection may impact the male reproductive tract. The ACE2 protein, a main receptor for

coronavirus viral entry, is selectively expressed by Leydig cells of the adult testes (23). There are

9
numerous reports of male reproductive injury after SARS-CoV infection. Leading theories

postulate that this is an immune-mediated response to infection since direct inoculation of the

coronavirus RNA within testicular tissue has not been described. In a 2005 study of eight

postmortem SARS-CoV patients, testicular tissue contained focal atrophy despite lacking

identifiable SARS viral RNA (24). Accordingly, there have been reported cases of SARS-CoV

causing severe orchitis, as evidenced by extensive IgG precipitation in testicular interstitial tissue

causing germ cell destruction and widespread testicular leukocyte infiltration (25). Further

studies on the reproductive involvement of coronavirus infections are warranted, particularly

within recovered patients.

CORONAVIRUS EFFECTS ON MALE AND FEMALE GAMETES

There are limited data regarding the impact of SARS-CoV-2 on human reproduction as the virus

is novel and has only recently infected humans. To date, there have been no reports of the virus

in the female reproductive tract, in vaginal secretions, in amniotic fluid or in peritoneal fluid.

Although there is nothing to suggest that female or male gametes would be impacted directly by

infection with SARS-CoV-2 or other coronaviruses, there is evidence that fever can impact

spermatogenesis. Therefore, male fertility may be diminished for 72-90 days following COVID-

19 due to decreased sperm concentration and motility (26, 27).

The SARS-CoV-2 virus utilizes ACE2 receptors to gain entry into the human cells. The male

reproductive system expresses ACE2 within adult Leydig cells in the testis and there are data to

10
suggest that ACE2 plays a role in spermatogenesis. The presence of ACE2 receptors is much

more prominent in the male reproductive system than the female reproductive system, but

gonadotropin-dependent expression of ACE2 has been reported in human ovaries (28, 29). At

this time, it is unknown if the SARS-CoV-2 virus utilizes ACE2 receptors in the reproductive

system and what, if any, impact this would have on oocyte quality, embryo development, or

ensuing pregnancy.

Gametes obtained from patients with other viral illnesses, such as HIV and hepatitis, must be

treated with special precautions aimed at reducing exposure of the non-infected partner and cross

contamination of reproductive tissue within the laboratory (30). These precautions are not

currently recommended for SARS-CoV-2, given the lack of evidence for transmission through

blood or sexual contact (31). Similarly, there is no current recommendation for screening oocyte

or sperm donors for SARS-CoV-2. These are areas in which further investigation is necessary in

order to assure the safety of stored gametes and the safety of patients undergoing assisted

reproduction.

CORONAVIRUS EFFECTS ON PREGNANCY OUTCOMES

Coronavirus epidemics have occurred three times in the past twenty years: in 2003, severe acute

respiratory syndrome (SARS); in 2012, Middle East respiratory syndrome (MERS-CoV); and

now in 2020, coronavirus disease 2019 (COVID-19). While perhaps more lethal than COVID-

11
19, both SARS and MERS had more limited spread. And while they all cause respiratory disease,

their effects on pregnancy differ.

SARS

The case fatality rate for all reported cases of SARS in pregnancy (n=17) was 15% (32-37), and

was higher among pregnant women. Mechanical ventilation was required three times more often

in pregnant versus non-pregnant women. A case control study comparing ten pregnant to forty

non-pregnant women affected by SARS reported a 60% ICU admission rate and a 40% case

fatality rate (CFR) in the pregnant group compared to only an 18% and 0% rate in the non-

pregnant group (32).

Four of seven pregnant patients with SARS miscarried in the first trimester (37). Four of five

women infected after 24 weeks gestation were delivered prematurely, largely due to their

deteriorating maternal condition from SARS, at 26, 28 and 32 weeks gestation (38). The infants

born at 26 and 28 weeks developed RDS requiring surfactant, but were normal weight for

gestational age. However, among infants born weeks (5 to 7) after initial infection, fetal growth

restriction and fibrin deposition on placental interface was seen in two of three pregnancies,

suggesting compromise. There was no evidence of vertical transmission. Overall, SARS was a

very serious disease for pregnant women and their fetuses.

MERS

12
Among pregnant patients with MERS (n=12), 63% were admitted to the ICU (7/11) and three

died (CFR of 23%) (39-43). The only woman known to contract MERS in the first trimester

went on to deliver a healthy infant at term (44). Of those contracting the disease after the first

trimester (n=9), one had a spontaneous loss at 20 week gestation (45), one presented at 34 weeks

gestation with pre-eclampsia and had an intrauterine fetal demise (40), and a third with

preexisting respiratory issues developed MERS at 24 weeks gestation and then ARDS. Despite

ventilation and cesarean delivery, both the neonate and mother subsequently died (40). Three of

nine other patients were delivered preterm due to maternal hypoxia. MERS also had a high

fatality rate and premature delivery rate.

COVID-19

Through April 5, 2020, there have been 19 case reports or series and 2 case-control reports of

pregnant COVID-19 patients and/or their neonates (43, 46-62). All but four are based on the

Chinese experience. The US, Israel, Korea and Honduras have published one experience each

(43, 46, 54, 63). These reports taken together report the experience of 162 COVID-19 positive

pregnant patients and their 184 infants (Table 1). The majority of these patients presented in

labor or near term; only twelve cases before 36 weeks gestation are reported. There is only one

reported case of miscarriage. No studies have yet directly examined pregnant COVID-19 patients

at earlier stages of pregnancy.

The evidence from the two case-control studies (involving 46 patients and 287 controls) so far

shows that COVID-19 during early pregnancy is not more severe than among non-pregnant

women (53, 63); similar patterns of symptomatology, disease severity and outcome were seen.

13
Nonetheless, some infected pregnant patients do develop very serious disease requiring

mechanical ventilation, and most very ill COVID-19 patients are delivered soon after the disease

becomes severe, whether premature or full term. At least 5 pregnant patients have required

mechanical ventilation, and 2 patients have died.

Full term infants born when their mothers have active COVID-19 infections have done well

overall. Most are normal weight and have normal Apgar scores. While most have been electively

delivered by cesarean section to reduce the risk of maternal transmission and reduce disease

acuity, eighteen cases of fetal distress are reported. Among the 184 fetuses reported, 1 had

intrauterine growth restriction (IUGR), 13 were delivered prematurely, 12 were small for

gestational age (SGA) and 1 was large for gestational age (LGA). One stillbirth and one neonatal

death were reported.

Table 2 summarizes the pregnancy-related experience of the three coronavirus epidemics. Peer-

reviewed case reports to date suggest the following:

• COVID-19 has a lower maternal case fatality rate than either SARS or MERS.

• Pregnant patients display similar signs and symptoms of COVID-19 as non-pregnant

patients.

• Pregnant patients are not more susceptible to coronavirus infection, nor at higher risk for

severe illness.

• Severe illness may precipitate premature labor or lead to early delivery.

• Adverse infant outcomes have been reported, but it is unclear whether these outcomes are

directly related to COVID-19 infection.

14
Coronaviruses and vertical transmission

Given the teratogenicity concerns associated with viruses such as Zika, there remains the

question of whether vertical transmission is possible with SARS-CoV-2. While no known cases

of vertical transmission have been noted with similar respiratory viruses such as SARS and

MERS, this cannot be assumed for SARS-CoV-2 (64, 65). Numerous cases reports have

described pregnant women who were infected by SARS-CoV-2. In one study of 38 women from

China, COVID-19 infection did not lead to maternal deaths and there were no confirmed cases of

vertical transmission (66). A case series of nine COVID-19 positive women that delivered via

cesarean section showed no viral RNA in the amniotic fluid, cord blood, or breastmilk (47).

However, a recent case report in JAMA (50) suggests that vertical transmission may be possible.

In this case report, an otherwise healthy infant was born by cesarean section to a 29-year-old

with RT-PCR confirmed SARS-CoV-2 infection. This infant was immediately placed into

isolation and a blood sample at two hours of age was noted to show an elevated SARS-CoV-2

IgG. While the IgG can be secondary to transplacental transfer, the infant was also positive for

SARS-CoV-2 IgM which cannot be explained by maternal-fetal transfer (50). Furthermore, IgM

antibodies only appear three-to-seven days after infection. All five RT-PCR tests on the infant

were negative for SARS-CoV-2 (50). The antibody profile of this infant is suggestive of

exposure to SARS-CoV-2 in-utero. A follow-up study done on six infants born to COVID-19-

positive mothers showed positive IgM antibodies in two of them. Yet, all throat swabs and blood

samples from the neonates tested negative for the virus. Overall, evidence of vertical

transmission in the setting of COVID-19 infection is currently inconclusive. Continued

observation is necessary as more data is gathered during the course of this pandemic.

15
Prohibitions on the use of potential therapies in Pregnancy

As of March 31, 2020, there were no identified vaccines or targeted therapies for the treatment of

COVID-19. Currently, treatment is aimed at supportive methods such as oxygenation/mechanical

ventilation and treating complications. As no effective treatment has been identified, a barrage of

potential therapies are being trialed both within and outside of research protocols. Although this

list is ever-changing, the majority of these medications target the ability of the virus to replicate

or are designed to suppress or modulate the immune system, thereby limiting inflammatory

damage (67, 68). During pregnancy these potential remedies fall into three different departments:

those established to be safe in pregnancy, those with unknown status, and those which have clear

or relative contraindications during pregnancy. It is imperative to consider that although some of

these interventions are safe in pregnancy, none so far have been identified as definitive treatment

and all have potential risks. These concerns need to be considered as an additional risk assumed

by pregnant women; some potential therapies may carry risk to the fetus or be unavailable to

pregnant women.

Several investigated medical treatments for COVID-19 are known either to be safe or non-

teratogenic in pregnancy. These include various immune modulators such as

hydroxychloroquine/chloroquine, methylprednisolone/glucocorticoids, and the anti-viral

medications lopinavir-ritonavir (69-73). It is important to note that although non-teratogenic, the

use of glucocorticoids in pregnancy has been associated with diabetes, weight gain, preterm

premature rupture of membranes, hypertension, and intrauterine growth restriction. Interferon

therapy, often used in Hepatitis C treatment, has been well established to be safe in pregnancy

16
(74). The use of convalescent plasma, or plasma derived from individuals who previously

contracted COVID-19, has been shown to reduce disease sequela in those with severe disease

(75). Given that its risk profile should be similar to a blood transfusion, there are no overt

contraindications in pregnancy.

Remdesivir is an anti-viral that was seen to both prevent and treat infection caused by Middle

East respiratory syndrome coronavirus in monkeys (76). Although current clinical studies

exclude pregnant women, Remdesivir may be administered in critically-ill pregnant patients

(NCT0428070500) (77). To date, no information is available concerning the effects of

Remdesivir in pregnancy. Due to the increased release of cytokines and subsequent

inflammatory damage during COVID-19, Tocilizumab, a monoclonal antibody that binds the

receptor IL-6, has been used in China, with at least one clinical trial that is ongoing

(NCT04310228) (78, 79). A major concern for pregnant patients is that IgG isotype antibodies

cross the placenta at an increasing rate in accordance with gestational age (79). However, the

effect of each medication on fetal development is unknown. Furthermore, in the rheumatology

literature it is recommended that Tocilizumab be avoided during pregnancy given the lack of

data on adverse fetal effects (80). Other anti-viral medications which have been utilized that have

clear evidence of teratogenicity, either in humans or animal models, include Favipiravir and

Ribavirin (68, 81, 82). Notably, the aforementioned medications are experimental, thus it is

imperative to have a risk-benefit discussion with patients given the medication side-effect

profiles, potential effects in pregnancy, and unknown benefits. Until randomized trials with

adequate controls are completed, it is difficult to draw definitive conclusions concerning the

efficacy of any of these treatments (71).

17
Neonatal morbidity and mortality

Thus far, there has been no indication that infants born to COVID-19 positive mothers

experience any significant morbidity or mortality. In the aforementioned case series of nine

COVID-19-positive patients who underwent cesarean section, all of their infants had negative

COVID-19 testing and had 1-min Apgar scores of 8-9 and 5-min Apgar scores of 9-10. In

addition, none of the infants in this series experienced asphyxia or neonatal death (47). Three

newborns have been confirmed with COVID-19 and their infection was likely secondary to

exposure to infected caregivers. All three neonates experienced either fever, cough, or vomiting,

then subsequently recovered with no severe sequelae (67). Given the disease course seen in older

children, the disease severity can be expected to be worse for neonates with pre-existing cardiac

or pulmonary conditions such as congenital heart disease (67).

Coronaviruses and Maternal Infectivity

There are a significant number of unknowns concerning COVID-19 and pregnancy, especially

regarding the infectivity of a pregnant woman. Therefore, the majority of data are extrapolated

from previous experience with other coronaviruses, SARS-CoV and MERS-CoV, as well as

influenza pandemics such as the 1918 flu and the Asian flu in the late 1950s (35, 83). However,

pregnant women are not more likely than non-pregnant woman to become infected with SARS-

CoV-2, based on data from regions with the first COVID-19 exposures and from previous

pandemics (84). Nor do pregnant women appear to suffer a more severe disease course or higher

mortality rate compared to non-pregnant women of a similar age.

18
It has been established that SARS-CoV-2 is spread by respiratory droplets, yet the potential for

other routes of transmission, particularly during labor, is unknown (84). Limited data are

available for COVID-19, but it is possible to extrapolate from limited information available on

SARS-CoV-2 and other coronaviruses. In the SARS-CoV outbreak, small case reports showed

no viral RNA in placental, umbilical cord blood, amniotic fluid, or breastmilk (35, 37, 84). It is

important to note that fecal matter that was aerosolized via the flushing of toilets was noted to

spread disease (35). One could hypothesize that amniotic fluid could become aerosolized and

infect others if viral RNA was present through mixing with fecal matter. MERS-CoV had an

extremely high death toll, however only twelve cases were documented in pregnancy, and no

information is available on viral RNA in pregnancy-specific tissue (35).

To date, there is limited information concerning which fluids in labor could potentially transmit

SARS-CoV-2 directly or by aerosolization. While a single maternal vaginal swab in the only

suspected case of vertical transmission was negative, it is too early to conclude whether

transmission can occur via vaginal secretions (50). Rectal swabs have not been obtained in

pregnant patients; however, a series of ten pediatric patients did confirm SARS-CoV-2 RNA in

rectal specimens (85). Thus, information regarding vaginal deliveries, while limited, remains

concerning. As previously noted, case reports have shown no viral RNA in amniotic fluid, cord

blood, or breast milk (47). Until more information is gathered, it is prudent for personnel present

during delivery to treat all fluids as potentially contagious and wear appropriate personal

protective equipment.

CONCLUSIONS & DISCUSSION

19
On January 7, 2020 thanks to the initial efforts of the late Dr. Jixian Zhang, the SARS-CoV-2

virus was identified as a cause of severe cases of pneumonia that began on December 8 in

Wuhan, China. In the first three months of 2020, the novel virus has infected over 1.4 million

people and caused more than 87,000 deaths. Declared a pandemic by the WHO on March 11,

2020, the sickness has overwhelmed healthcare resources as it spread. Containment of SARS-

CoV-2 has proven exceptionally difficult due to asymptomatic and pre-symptomatic spread of

disease, as well as the relatively high person-to-person transmission. As the virus moved from

host to host, as is typical of the single-stranded RNA viruses, SARS-CoV-2 has mutated.

Notably, there is an enormous phenotypic difference in disease severity from asymptomatic

infection to death, but the reasons for this striking variability remains obscure. Despite the

overwhelming magnitude of the disease and its worldwide prevalence, information regarding the

effects of the novel coronavirus on human reproduction are currently limited. This lack of

evidence should not be considered reassuring, since only three months have elapsed since the

novel coronavirus jumped species and infected humans.

There is reason to be concerned based on data from other coronaviruses. As is typical of this

family of viruses, the SARS-CoV-2 spike protein binds the ACE2 receptor, a protein found in

many reproductive tissues, including the testis. Of concern, evidence exists that related

coronaviruses have caused severe orchitis. While sperm counts can be reduced by high fever

alone, the question of other possible long-term effects on male and female gametes is pressing.

Specifically, whether there might be shedding of virus in some individuals that might affect the

safety and storage of gametes. As noted, evidence continues to emerge regarding effects of the

20
novel coronavirus in pregnancy and some initial reports suggest that complications, particularly

after delivery, may be increased. Additional studies are urgently needed.

Because of the risk of viral transmission between patients, staff, physicians and providers, and to

comply with local restrictions for non-emergency surgeries, many programs of assisted

reproduction have suspended procedures throughout the globe during the height of the pandemic.

As the assisted reproductive technology (ART) programs resume operations it will be important

to gather information regarding the status of individuals infected with the novel coronavirus, and

to assess gametes and reproductive outcomes for those who had COVID-19. These studies will

be enabled by the availability of serologic testing and more widespread RNA testing for the

novel coronavirus. Likewise, researchers should collect data regarding outcomes of pregnancies

in women who became infected during pregnancy. While a vaccine may prevent disease, until

one is available, information is needed on the safety of medical treatments and outcomes in

pregnancy.

One limitation of this review is that because of the rapidly increasing number of publications, it

is possible that new information may be published contradicting the findings. Because of concern

about possible adverse effects, there may be a risk of bias toward reporting positive outcomes.

Additionally, since reports have focused on the acuity of treatment, the reproductive effects may

be present, but not yet reported. The strength of the report is that our search was comprehensive

and conducted, as much as possible, in accordance with PRISMA guidelines.

21
The immense impact of the COVID-19 pandemic in lives lost, healthcare expenses, and

economic consequences of countries and individuals is inestimable because the epidemic is still

rampant throughout the globe. While data are limited, and incomplete at this time, there is

justifiable concern that reproductive consequences of the novel coronavirus may have lasting

effects for male reproduction and for some pregnant women and children.

Acknowledgements:

The authors thank Drs. Catherine Racowsky and Dr. Ricardo Azziz.

22
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27
 Table 1. COVID-19 Pregnant Patients, Summary of Publications through April 5, 2020.
CHINA CHINA CHINA CHINA CHINA CHINA CHINA CHINA CHINA CHINA CHINA CHINA US ISRAEL CHINA CHINA CHINA HONDURAS KOREA CHINA UK CHINA CHINA
Zhongnam Hosp Mat/Child Hosp in Tongji Hosp in Mat/Child Hosp Tongji Hosp in Tongji Hosp in Wuhan Zhongnam Hosp Tongji Hosp in Tongji, Mat/Child, Renmin Renmin H Renmin H 5 hospitals in Three Gorges Daegu Fatimal China CDC
Site outside Wuhan Columbia U ? Hubei Hosp Escuela
in Wuhan Hubai Wuhan in Wuhan Wuhan Wuhan Children's Hosp in Wuhan Wuhan (Wuhan), Tienmen, Jingzhou Wuhan Wuhan Hubei Central Hosp Hosp (multicenter)
Type Case series Case series case series Case control case series case control Case case series Case series Case series case series case series case series Case series case case control case series case case case Lit Search Lit search Lit search Case series
When 1/20--1/31/2020 1/20--2/10/2020 by 2/22/2020 1/24--2/29/20 1/20--2/10/2020 12/8-2/25/20 2/1/20 non stated 2/16-3/8/2020 1/1-2/8/2020 1/20--2/5/2020 1/17--1/23/2020 1/30-2/23/2020 not stated not stated 1/1--2/20/2020 2/9/20 3/9/20 2/14/20 2/25/20 3/25/20 1/16--2/8/2020
First author Chen H Chen S Chen Y Li Y Liu D Liu Y Wang S Zeng L Zeng H Yu Zhu Fan Chen R Breslin ? Zhang Nie Liao Zambrano Lee D Schwartz Mullins Khan Dong
Arch Path Lab
Journal Lancet J Med Virol Front Peds preprint Am J Roent J Infection Clin ID JAMA Peds JAMA Lancet ID Transl Peds Clin ID Can J Anesth AJOG ? Zhoungua Fu… preprint Balkan Med J Trav Med ID preprint RCOG ? Lancet
Med
# cases (/controls) 9 5 4 30 / 242 ctl 15 13 1 neonate 33 neonates 6 neonates 7 10 neonates 2 (MDs) 17 7 1 16 vs 45 ctl 33 1 1 1 16 + 45 32 100 103
Age (years) 25-31 23-34 23-40 22-36 34 29-34 31-39 34, 29 29 mean 27-39 25 41 28 25-40 27-38
GA at infection 3rd trimester 38-41 37-39 3rd trimester 14 in 3rd, 4 in 2nd 2 <28wk 40 37-41 37, 36 3 tri 26-37 36-41 35 31 38 31-39
Respiratory comorbidities 0 1 of 7
Symptoms
Fever 7 of 9 5 of 5 after delivery 3 of 4 5 of 30 13 of 15 10 of 13 yes 6 of 7 6 of 10 4 of 17 2 of 7 4 of 33 1 1 1 65%
Cough 4 of 9 2 of 5 2 of 4 1 of 30 9 of 15 3 of 13 no 1 of 7 4 of 17 4 of 7 0.01 13 of 33 1 1 1 38%
Dyspnea 1 of 4 1 of 30 1 of 15 no 1 of 7 1 of 17 4 of 7 7 of 33 14%
Malaise / fatigue 2 of 9 2 of 4 0 4 of 15 no 1 of 17 5 of 7 7 of 33 1 15%
Myalgia 3 of 9 2 of 4 0 0% no 0 5 of 7 5 of 33 1
Severe pneumonia 0 of 9 0% 1 of 13 no 0 2 of 7
Deaths 0 of 9 no 0 0 of 7
Severity
Asymptomatic 4 of 5 1 of 13 22%
Mild 1 of 5 yes 13 of 33 41%**
Common 15 of 16 47%
Moderate 19 of 33 12%
Severe 1 of 16 1 of 33 6% 2%
Investigations
CXR/CT evidence of pneumonia 5 of 5 18 of 30 15 of 15 mom and infant 86% 32 of 33 1 1 1 100%
Maternal complications
Mortality 0% none 0 0% 2 of 103
Mechanical ventilation 0 of 34 ECMO x 1 6% yes none 0 1 of 7 1 of 33
Cesarean delivery 9 of 9 2 of 5 75% 32 of 34 10 of 11 10 of 10 3 of 3 3 of 3 17 of 17 5 of 27 1 1 all 90% 85
Fetal complications
Miscarriage 0
IUGR 1 of 3 0
Preterm delivery 5*** of 36 6 had PTL 7 of 10 3 of 17 1 of 27 1 47% 29%
LBW 5*** of 36 2 SGA, 1 LGA 0 5 of 27 16%
Fetal distress 2 of 9 0 of 5 3 of 36 3 of 10 6 of 10 0 4 of 27 1
Neonatal complications
Low apgar score 0 of 9 0 of 5 0 1 of 3
Stillbirth 0 0 0 of 11 1 of 13 0 3%
Neonatal deaths 0 of 9 0 of 5 0% 0% 0 of 11 0 none 0% 3%
ARDS 0% 0% 0 of 11 no but pos CXR 1 of 3 none mild pneum x 1 1 of 27 3 "bacterial"

NP swab pos at 1 of 7 pos. had

SOB in 6, abnl CXR in 4, RDS ?. Neonate pos
none, though 2 36h. Breast milk, 3 of 33 pos PCR. SOB, abnl CXR,
Vertical transmission? 0 of 6* 0 of 5 none none 2 of 6 IgM pos in 2, NND in 1, rash in 1. neg none? none 0 of 7 immed after no diff 1 of 28 none none none none 0%
develped rashes cord blood, ? Source resolved quickly
PCR birth
placenta neg after neg PCR x 2

28
Table 2: Pregnancy and Coronaviruses: A summary of published, peer-reviewed reports
Characteristic COVID-19 SARS MERS
# cases 162 17 12
Age (years) 23-40 27-44 31-39
GA at infection 150 at 36+ wks; 12 4-32 4-38
earlier
Symptoms at presentation
Fever 50% 100% 58%
Cough 34% 76% 67%
Dyspnea 16% 35% 58%
Investigations
CXR/CT evidence of 85% 100% 100%
pneumonia
Maternal complications
Mortality 2% 18% 25%
Mechanical ventilation 4% 35% 41%
Fetal complications
Miscarriage 2% 25% 18%
IUGR 9% 13% 9%
Preterm birth 38% 25% 27%
Neonatal complications
Neonatal deaths 2% 0% 9%
Vertical transmission Low vs none 0% 0%
Updated with more recent reports of COVID-19 cases. Otherwise, from Dashraath P, Jing Lin Jeslyn W, Mei Xian Karen L, Li Min L,
Sarah L, Biswas A, Arjandas Choolani M, Mattar C, Lin SL, Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy,
American Journal of Obstetrics and Gynecology (2020), doi: https://doi.org/10.1016/ j.ajog.2020.03.021.

29
Table 2: Pregnancy and Coronaviruses: A summary of published, peer-reviewed reports
Characteristic COVID-19 SARS MERS
# cases 162 17 12
Age (years) 23-40 27-44 31-39
GA at infection 150 at 36+ wks; 12 4-32 4-38
earlier
Symptoms at presentation
Fever 50% 100% 58%
Cough 34% 76% 67%
Dyspnea 16% 35% 58%
Investigations
CXR/CT evidence of 85% 100% 100%
pneumonia
Maternal complications
Mortality 2% 18% 25%
Mechanical ventilation 4% 35% 41%
Fetal complications
Miscarriage 2% 25% 18%
IUGR 9% 13% 9%
Preterm birth 38% 25% 27%
Neonatal complications
Neonatal deaths 2% 0% 9%
Vertical transmission Low vs none 0% 0%
Updated with more recent reports of COVID-19 cases. Otherwise, from Dashraath P, Jing Lin Jeslyn W, Mei Xian Karen L, Li Min L,
Sarah L, Biswas A, Arjandas Choolani M, Mattar C, Lin SL, Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy,
American Journal of Obstetrics and Gynecology (2020), doi: https://doi.org/10.1016/ j.ajog.2020.03.021.