Keywords
COVID-19 - severe acute respiratory syndrome coronavirus 2 - ovary - testis - conception
- pregnancy
Palavras-chave
Covid-19 - síndrome respiratória aguda grave pelo coronavírus 2 - ovário - testículo
- concepção - gravidez
Introduction
In the last 8 months, the world has been experiencing a pandemic caused by the new
coronavirus (SARS-CoV-2). Starting with the first reported cases of pneumonia in the
city of Wuhan, Hubei province, China,[1] by August 16, 2020, 21,294,845 COVID-19 cases had already been confirmed, with a
total of 761,779 deaths.[2] On that date, the Brazilian Ministry of Health had registered 3,340,197 cases of
the disease, and 107,852 deaths.[3]
It is a fact that scientific information on the impact of SARS-CoV-2 on the health
of pregnant women, fetuses and newborns is considered of limited confidence, lacking
good-quality evidence, and drawing biased conclusions. As a matter of fact, the initial
impressions that the evolution of COVID-19 was no different between pregnant and non-pregnant
women,[4]
[5]
[6] and that SARS-CoV-2 was not vertically transmitted,[4]
[7]
[8] are confronted by the documentation of worsening of the disease during pregnancy,
poor obstetric outcomes,[9]
[10]
[11]
[12]
[13]
[14] and the possibility of vertical transmission.[15]
[16]
[17]
[18]
[19]
[20]
Of note, uncertainty is the rule at the moment. Some state that, then, there are no
convincing reasons to recommend people to avoid pregnancy.[21] In contrast, it seems that there are at least 5 uncertainties/reasons to advise
against pregnancy at this time, if it is possible, namely: 1) there is confounding
evidence on the evolution of COVID-19 in pregnant and non-pregnant women; 2) despite
the fact that the bulk of the literature suggests the effectiveness of the placental
barrier in preventing fetal infection by SARS-CoV-2, fewreports[15]
[20] indicating vertical transmission sustain medical concerns; 3) it is not clearly
known whether infection by SARS-CoV-2 in the first trimester can cause birth defects
or pregnancy loss; 4) it is not known whether the newborns of women infected by SARS-CoV-2
will have the same clinical evolution as those born to healthy mothers; and 5) the
possibility of SARS-CoV-2 transmission through the sexual route, and the role of its
theoretical effect on the gonads and gametes, in vivo and in vitro.
The present review article aims to compile available data on each of the aforementioned
uncertainties, providing theoretical background for counseling and caring for women
who are planning a pregnancy, those who are pregnant, or those who have given birth
during the COVID-19 pandemic.
SARS-CoV-2 in Reproductive Tissues and Gametes
SARS-CoV-2 in Reproductive Tissues and Gametes
The expression of angiotensin-converting enzyme 2 (ACE2) and other viral entry facilitators
in male and female gonads and gametes, as well as the endometrium,[22]
[23]
[24]
[25] raises concerns on the interference of SARS-CoV-2 on reproductive health and conception.[26] To date, it is not known if the new coronavirus affects reproductive function via
the ACE2 receptors, and which consequences, if any, the infection by the virus would
have on the quality of the gametes, embryo development and implantation, or pregnancy
in its very beginning.[27]
Indeed, there are reports of human orchitis related to other coronaviruses.[28] Then, the possibility of immediate or long-term SARS-CoV-2-related impairment in
the male reproductive functions is a genuine concern. Theoretically, inflammation
in the seminiferous epithelium, Leydig and Sertoli cells, and the epididymis could
lead to oxidative stress and sperm DNA fragmentation, as well as diminished testosterone
secretion and disrupted spermatogenesis.[29]
Regarding conception, the possibility of sexual transmission is another matter of
concern. SARS-CoV-2 has already been detected in the small intestine, liver, pancreas,
kidney and sweat glands, so, at least theoretically, there are other potential routes
of transmission than the respiratory one.[30] The data available on the sexual route of transmission are controversial. In a Chinese
cohort study,[31] SARS-CoV-2 was detected in semen samples from infected patients, both in the acute
and in the recovery phases. In contrast, other reports did not find the virus in semen
collected 8 days after COVID-19 diagnosis,[32] or 30 days.[33] Divergent findings about SARS-CoV-2 in the semen support the need for larger studies,
which should not just confirm the presence of the virus in the semen, but provide
information about its length of stay and the possibility of transmission by sexual
contact.
COVID-19 during Pregnancy
COVID-19 during Pregnancy
Maternal and fetal complications were documented in previous epidemics caused by other
coronaviruses, namely the severe acute respiratory syndrome (SARS)[34] and the Middle East respiratory syndrome (MERS).[35] In addition to historical aspects, physiological adaptations during pregnancy are
usually considered to be potential factors of vulnerability to any type of infection.
Moreover, some authors suggest that pregnant women are more vulnerable to infective
respiratory agents than the general population, and they may respond to COVID-19 with
a “cytokine storm,” which may lead to severe morbidity.[36] Beyond this, the signs or symptoms related to pregnancy may overlap with other symptoms
of COVID-19, thereby making the diagnosis challenging. So, as a precaution, pregnancy
and the puerperium are now considered high-risk situations for severe illness from
COVID-19.[37]
[38]
In June 2020, a systematic review[39] of 755 pregnant women presenting with COVID-19 provided only poor-quality evidence,
and the authors could not rule out potential worsening of the clinical conditions
of pregnant women infected with SARS-CoV-2, or whether the infection is associated
with comorbidities or not. Actually, the absence of studies with reliable methodology
still greatly limits data interpretation. Thus, it cannot yet be said that the disease
evolves in the same way in pregnant and non-pregnant women, nor can pregnancy be excluded
from the list of potential risk conditions.
In the United States, the Centers for Disease Control and Prevention (CDC) has recently
published a series[12] of 8,207 pregnant women in the United States, associating pregnancy to an increased
risk of hospitalization (31.5% in pregnant women versus 5.8% in non-pregnant women; adjusted relative risk [aRR] = 5.4; 95% confidence interval
[95%CI] = 5.1 to 5.6), admission to the Intensive Care Unit (aRR = 1.5; 95%CI = 1.2
to 1.8), and the need for mechanical ventilation (aRR = 1.7; 95%CI = 1.2 to 2.4) due
to COVID-19. Nevertheless, the increase in morbidity was not reflected in increased
mortality, which was similar between pregnant and non-pregnant women (0.2% in both
groups; aRR = 0.9; 95%CI = 0.5 to 1.5).
Recent data show that most of the women (∼ 85%) contracting SARS-CoV-2 will exhibit
mild characteristics of the disease. The rates of severe disease vary between 9.3%
and 11.1%, and the rates of critical disease vary between 2% and 6.9%, which are just
as similar to the rates for the general population.[40] However, local scenarios of care for pregnant women should also be taken into account
to better advise the women about the possibility of becoming pregnant. In Brazil,
for example, a country with high rates of maternal mortality when compared with developed
countries, 124 pregnant or postpartum women have died due to COVID-19 until June 18,
2020–representing a mortality rate of 12.7% –, a figure that currently surpasses the
total number of COVID-19-related maternal deaths reported throughout the rest of the
world. These data suggest an aggravation of the bad preexisting conditions of prenatal
care due to COVID-19 infection.[10]
In the context of the COVID-19 pandemic, the high rates of preterm birth, cesarean
section,[41]
[42] and preeclampsia,[43] and the increased risk of admissions to the intensive care unit[12] persist as the most common reasons for concern. Outstandingly, the most frequent
COVID-19 adverse obstetric outcome seems to be preterm birth, occurring in 41.1% (95%CI:
25.6 to 57.6) of cases.[42] In view of this little-known disease, it is recommended to consider pregnancy a
potential aggravating factor for COVID-19, as is customary for other diseases, and,
conversely, to consider this infection a cause of negative obstetric and perinatal
outcomes. As a precautionary action, it is reasonable to institute unrestricted monitoring
measures for pregnant women infected with SARS-CoV-2, and even to suggest that they
should be rigorously tested before delivery or before the first contact with the newborns.[39]
Evidence of Vertical Transmission of SARS-CoV-2
Evidence of Vertical Transmission of SARS-CoV-2
Vertical transmission of previous coronaviruses was hypothesized in preliminary studies,[44]
[45] but such an occurrence was not reported with either SARS or MERS; therefore, it
seems that the likelihood of intrauterine maternal-fetal transmission of coronaviruses
is low.[46]
[47]
To date, it cannot be said that the placental barrier is capable of preventing the
vertical transmission of SARS-CoV-2. Often times, tests of the amniotic fluid, cord
blood, and neonatal throat swab samples were not able to evidence the vertical transmission
of SARS-CoV-2, at least in mid-[8] and late pregnancy.[42]
[47] However, third trimester placentas from COVID-19 patients have been proven to be
more likely to present maternal/fetal vascular malperfusion,[48] and the existence of vertical transmission of SARS-CoV-2 has already been demonstrated
in some case reports[49]
[50] and small case series.[51]
[52] Moreover, the detection of anti-SARS-CoV-2 immunoglobulin M (IgM) in cord and/or
early-life neonatal blood supports the suspicion of intrauterine infection, since
IgM is not transplacentally transferred from the mother to the fetus.[17]
Recently, in early July 2020, during one of the virtual sessions of the Annual Meeting
of the European Society of Human Reproduction and Embryology (ESHRE), researcher Wafaa
Essahib presented evidence of the expression of ACE2 and other viral-entry facilitators
in human oocytes and blastocysts, supporting a new hypothesis of transmission of the
virus from the mother to the embryo, which would be cause for apprehension for initial
pregnancies under COVID-19.[53] Moreover, the expression of the ACE2 receptor has been reported in the placenta,
which may increase the risk of vertical transmission of the virus.[54]
It is worth saying that, if maternal-fetal transmission happens, little is known about
its impact over embryogenesis, morphogenesis, fetal development, and health.
The Health of the Fetus and the Newborn
The Health of the Fetus and the Newborn
Initial data suggested that maternal SARS-CoV-2 infection does not seem to be more
harmful in the first trimester than it is throughout the whole pregnancy. Infection
was not associated with increased thickness of the nuchal translucency or risk of
pregnancy loss.[55] However, other viruses, depending on the gestational age at the moment of infection,
have been associated with congenital anomalies and developmental delay later on, like
Zika.[56] Thus, the little time since the first studies on the behavior of SARS-CoV-2 is insufficient
to evaluate its real impact on neonates.
The RNA of SARS-CoV-2 has already been found in placental and amniotic membrane samples,
indicating the possibility of fetal viral exposure during labor and delivery.[57] Placental infection has also been demonstrated as one of the negative outcomes of
pregnancy, not just by identification of viral RNA, but by histological findings of
subchorial inflammatory infiltrates, increased intervillous fibrin deposition, and
funisitis (suggesting inflammatory response from the fetus).[14]
According to the systematic review of 598 newborns, strong evidence of SARS-CoV-2
infection was not available until June 2020, especially considering the lack of reliable
information on the care provided during and after delivery, as well as the lack of
adequate collection of biological samples from newborns for the SARS-CoV-2 test.[39] Indeed, the data available to date suggest that COVID-19 infection is uncommon among
newborns, which are frequently asymptomatic. Furthermore, it was not possible to associate
a higher risk of infection to vaginal birth, breastfeeding or close contact with the
infected mother.[58]
It is worth highlighting the fact that there has been a decrease in extremely premature
births during the COVID-19 pandemic.[59]
[60] There are still no definite explanations for this unprecedent reduction, but there
are two hypotheses: the disease leads to a greater number of early pregnancy losses;
or the measures of social distancing and confinement lead to lower exposure of pregnant
women to the behavioral and socio-environmental factors linked to prematurity.
Postponing Pregnancy versus Age-related Fertility Loss
Postponing Pregnancy versus Age-related Fertility Loss
Since the deleterious effect of postponing pregnancy by a few months may not be significant,[61]
[62]
[63]
[64]
[65] even for women of advanced reproductive age or with diminished ovarian reserve,[64] such a decision has been encouraged by some authors.[65]
[66]
In a very recent retrospective cohort study on in vitro fertilization treatment for
women with diminished ovarian reserves, Romanski et al.[65] observed that a delay of up to 180 days did not seem to negatively affect live birth
rates, even for women with anti-Mullerian hormone levels < 0.5 ng/mL, or those older
than 40 years of age. The authors recognized a potential selection bias in their study,
but considered the results sufficient to reassure that short-term delay in the treatment
will not affect its outcomes, in situations that such a delay is deemed necessary
or prudent, like the current COVID-19 pandemic.
For cases of infertility that require assisted reproduction, the dilemmas can be even
greater. Advice on whether or not to postpone treatment includes information on the
lack of knowledge of the effects of COVID-19 on pregnancy, as well as the possible
risks of vertical transmissibility and transmission via the gametes, as well as risks
of the virus being stored in the gametes and the embryo.[26]
[66] It should be emphasized that the treatment per se lasts several days, and requires
several return visits, and, depending on the region's epidemiological situation, it
may be inadvisable for patients to move and expose themselves to medical environments.
Besides that, the infection can occur during the treatment period, causing suspension
at any stage, which can generate significant emotional distress. Finally, the lack
of consensus on screening methods contributes to the uncertainty, since the diagnostic
tests contain highly-variable sensitivities and specificities, and unfortunately there
is no consensus on which one is the best and safest to detect the disease in real
time.[67]
Perspectives for the Future
Perspectives for the Future
Pregnancy and Delivery
At this moment, the best knowledge on COVID-19 in pregnancy is based on observational
studies, case series and reports, as well as estimates from the surveillance of sanitary
authorities in each country. These provide insufficient information to consider changes
in the management and definition of the appropriate interventions. Wise strategies
minimizing the risk for the pregnancy and poor obstetric outcomes, mainly those associated
to preterm birth, preeclampsia, and cesarean section, will probably be defined once
there is wide knowledge of the disease, which will come with time and experience.
There is no doubt that many aspects remain unclear to date, and randomized clinical
trials are expected to provide knowledge from preconception counseling and preventive
measures during prenatal care to clinical presentation and management of the infection
during pregnancy and the puerperium. Oxford-Horrey et al.[68] opportunely highlight that supportive care must focus on recovery rather than delivery
as the main treatment endpoint. Unfortunately, the inclusion of pregnant women in
registered trials still seems to be small: among all 3,009 studies registered for
COVID-19 in the ClinicalTrials.gov database (https://clinicaltrials.gov) on August 16, 2020, only 66 (∼ 2.2%) included pregnant women, of which only 6 had
been completed, 1 had been withdrawn, and 20 were not yet recruiting.
Specifically in Brazil, the high rates of maternal deaths related to COVID-19 might
be associated with poor quality in prenatal and obstetric care. Indeed, SARS-CoV-2
may be an aggravating agent of a previous inflammatory status present in hypertensive
disease and/or obesity, which are very prevalent in the country. However, social risks
and limited access to health care are probably associated to late proper care, potentially
contributing to maternal deaths.[69]
Finally, childbirth care under COVID-19 is still one of the main concerning aspects.
However, it is worth observing that, to date, there is no evidence of the intrapartum
transmission of SARS-CoV-2 to the newborn, and vaginal birth with appropriate precaution
measures remains the mode of delivery in mild maternal disease. Moreover, it is essential
to reinforce that interventions to shorten the lenght of the second stage of labor
and/or to avoid delayed umbilical cord clamping and/or skin-to-skin contact are not
supported by good evidence, as well as COVID-19 alone is not an indication for cesarean
section. Instead, high rates of cesarean deliveries under COVID-19 are concerning,
since they have the potential to promote clinical maternal deterioration.[70]
Fetal and/or Newborn Health
The effects of viremia on the embryo and/or the fetus in the first and second trimesters
of pregnancy are poorly known. Actually, women who became pregnant just before or
just after the beginning of the pandemic have not yet delivered their babies; therefore,
information from the main pregnancy outcomes is still lacking. With regard to neonates,
perhaps the great prospect for the future is the clarification of the causes of prematurity.
To date, no one can determine if the higher rates of preterm birth under COVID-19
are spontaneous or elective due to maternal clinical complications or fetal compromise.
As a matter of fact, it is not known whether children born to mothers infected by
the SARS-CoV-2 will have the same clinical evolution as those born to healthy mothers.
And such an answer is totally dependent on time.
Availability and Reliability of Diagnostic Tests
COVID-19 screening in early pregnancy has been proposed as strategy to better plan
maternal-fetal health surveillance programs in epidemic areas, combining serological
tests and nucleic acid testing,[71] mainly for those women presenting for delivery. Those who defend universal screening
for parturient women do so based on the benefits of determining hospital isolation
practices and bed assignments, informing the neonatal care team, and guiding the use
of personal protective equipment.[72] In contrast, the observation of 3,963 women admitted to labor and delivery in California,
United States, resulted in a very low prevalence of positive SARS-CoV-2 testing,[73] raising doubts about the benefit of mass testing, especially in countries like Brazil,
in which the testing of large populations still does not seem to be a reality.
Vaccination
There is no doubt that scientific community is watching a race to launch a vaccine
against SRAS-CoV-2. There is also no doubt that, with the first vaccine approved in
a phase-III study, we will see one of the fastest, if not the fastest, launches of
a vaccine in the entire history of active immunization. But there are questions that
will be answered only over time: how effective will the vaccine be? Will there be
enough distribution to interrupt or, at least, slow the spread of the virus? How safe
will vaccinated women be to decide to become pregnant with the virus still spreading?
And, finally, since the immune responses to vaccination in pregnant women may not
be the same as those observed in non-pregnant women,[74] how will the safety of vaccination in pregnancy will be assessed?
Conclusion
Health professionals and society as a whole have doubts about the impact of COVID-19
on reproductive outcomes, from the impact of SARS-CoV-2 in the gonads and/or gametes
to its consequences to the newborn. Data regarding COVID-19 during pregnancy, as it
happens with any other pathological condition, are uncertain, possibly due to missingness
of pregnancy status, underreporting of cases and disease outcomes, inadequate collection
of biological samples for testing, insufficient accuracy of the tests available, and
inaccuracy of the mathematical models in predicting the number of asymptomatic individuals.
Good quality data are urgently needed to support an adequate counseling to women attempting
pregnancy and to those who are already pregnant. With limited evidence available to
date, concerning uncertainties from conception to birth inevitably raise the possibility
of postponing pregnancy, if possible, to a post-Covid-19 scenario or the one with
an effective and broadly-distributed vaccine.
