Keywords
COVID-19 - pregnancy - prenatal care - delivery
Descritores
COVID-19 - gravidez - pré-natal - parto
Introduction
The coronavirus infection (COVID-19) is caused by the new virus labeled SARS-CoV-2.
The first case was reported in Wuhan, China, in December 2019, and the illness rapidly
spread throughout China and other countries. The infection typically presents as a
fever and cough. Pneumonia is frequently observed in the diagnostic imaging tests
of infected patients.[1] The World Health Organization (WHO) estimates an overall mortality rate ranging
from 3 to 4%, with a high rate of patients requiring admission to intensive care units
(ICUs).[2]
[3]
Pregnancy is a time of changes, both physical and psychological. Information about
the impact of this infection on these changes is anxiously awaited by the medical
community. There has been an unprecedently large number of medical publications. In
the present article, we provide a brief analysis of COVID-19, pregnancy in the COVID-19
era, and the effects of COVID-19 on pregnancy, in addition to a critical analysis
of COVID-19 in Italy.
The Virus: History, Characteristics and Pathogenicity
The Virus: History, Characteristics and Pathogenicity
SARS-CoV-2 belongs to the family Coronaviridae, order Nidovirales. Coronaviruses are
enveloped, nonsegmented, positive-sense ribonucleic acid (RNA) viruses.[4] The family Coronaviridae was first discovered in 1965 after growing in an embryonic
tracheal culture obtained from an adult presenting with a common cold.[5] After years of cataloging different viruses related to human and animal diseases
such as gastroenteritis, hepatitis, and bronchitis, these viruses were called coronaviruses
because of the crown-like appearance of their surface projections.[6]
During the 20th century, studies inoculating the virus in voluntaries and epidemiological studies
have reported an association between coronaviruses and respiratory diseases, but the
virus was considered to have a low pathogenicity.[7]
[8] It is usually presented as a mild to moderate illness that was self-limited and
lasted short periods of time.[9]
Four types of coronaviruses have been identified (α, β, gamma, and delta).[10] They are classified according to their tropism and pathogenicity. The β viruses
display great pathogenicity; they cause pneumonia and SARS and were responsible for
the SARS-CoV and MERS-CoV outbreaks. Conversely, the α viruses usually present as
mild to moderate upper respiratory tract infections.[11] The recently identified SARS-CoV-2 presents a similarity between 20 and 60% to MERS-CoV
and a similarity between 45 and 90% to SARS-CoV. However, it also presents great similarity
with the genome of coronaviruses found in bats (96%).[12]
[13]
The alveolar damage provoked by SARS-CoV and SARS-CoV-2 is likely caused by its reaction
with the angiotensin-converting enzyme 2 (ACE 2), which is present mainly in type
II pneumocytes.[14] SARS-CoV-2 is hypothesized to have twice the affinity of SARS-CoV. The binding of
ACE 2 to SARS-CoV or SARS-CoV-2 leads to its expression and subsequent alveolar damage.
Angiotensin-converting enzyme 2 expression varies in different races and is more concentrated
in men.[15]
[16] During inoculation, the virus crosses the mucosal membranes, mainly the nasopharynx
and larynx, and reaches the pulmonary mucosa. In the lungs, the virus induces local
inflammation and overtakes the systemic circulation, arriving to other organs that
express ACE 2, such as the heart, lungs, and intestine.[17] There is evidence of possible orofecal transmission.[18] The virus presents a long life and stability in aerosols and on various surfaces.[19]
Pregnancy and Respiratory Viruses
Pregnancy and Respiratory Viruses
Pregnancy presents characteristics that make pregnant women more susceptible to respiratory
pathogens and severe pneumonia. These changes include increased oxygen consumption,
elevated diaphragm, and edema of the respiratory tract mucosa, which cause pregnant
women to have an intolerance to hypoxia. This was noted during the H1N1 outbreak in
2009, in which pregnant women were four times more likely to be admitted to a hospital
than the general population.[20] Pneumonia is one of the more prevalent nonobstetric infections of pregnant women.
It is the third most common indirect cause of maternal death and requires ventilatory
support in 25% of cases.[21] Despite the therapeutic options available for pulmonary infection, during pregnancy,
the morbidity and mortality of viral infections are more severe than those from bacterial
pneumonia.[22] During the 1918–1919 outbreak, the maternal mortality rate reached 27%, and the
risk increased proportionally with gestational age. When pneumonia was associated,
the mortality rate reached 50%.[23] Premature rupture of membranes, stillbirth, intrauterine growth restriction, and
preterm birth are frequent complications of pulmonary infections.[24]
Pregnancy and Covid-19
To determine the main symptoms and outcomes, a systematic review of the prenatal and
perinatal effects of CoV infections on pregnancy was performed. A total of 538 articles
were analyzed, and 27 were selected. When analyzing these data, it is important to
note that the clinical manifestations were reported from women affected by severe
forms of the disease, of whom 91.8% presented with pneumonia. Of these cases, 51.9%
were COVID-19, 32.9% were SARS-CoV, and 15.2% were MERS-CoV. Of the pregnant women
with CoV infection that evolved to pneumonia, 82.6% presented with fever, 57.1% presented
with cough, and 27% presented with dyspnea. Lymphopenia was found in 79% of these
women and elevated liver enzymes in 36.6%. In total, 34.1% were admitted to the ICU.
Mechanical ventilation was required in 26.3% of the cases. When the most severe forms
of CoV infections requiring ICU care were compared, COVID-19 presented better outcomes
than SARS-CoV and MERS-CoV. A total of 9.3% of COVID-19 admissions were sent to the
ICU, 5.4% required mechanical ventilation, and no maternal deaths were reported. For
SARS-CoV and MERS-CoV, 44.6% and 53.3% of admissions were sent to the ICU, 40.9% and
40% required mechanical ventilation, and mortality rates of 28.6% and 25.8% were reported,
respectively.[25] These outcomes may be related to the vulnerability to respiratory pathogens and
susceptibility to severe pneumonia that occur due to physiological adaptive changes
during pregnancy (increased oxygen consumption, edema of respiratory tract mucosa,
diaphragm elevation), leading the patient to have an increased intolerance to hypoxia.
These modifications may be responsible for the increased vulnerability during the
H1N1 influenza outbreak, in which pregnant women were four times more likely to be
admitted to the hospital than the general population.[20] Chest imaging may be required for the clinical evaluation and diagnosis of pregnant
women with suspected COVID-19 infection. Chest X-ray examinations have little radiation
exposure and can be helpful for diagnosis. Chest computed tomography (CT) has a high
sensitivity for the diagnosis of COVID-19 and may be considered for diagnosis in epidemic
areas.[26] One study performed chest CT scans in 15 pregnant women infected with COVID-19.
All presented with mild symptoms of the disease, and the gestational age ranged from
12 to 38 weeks. Ground-glass opacity was the most common early finding, and the lower
pulmonary lobes were more affected.[27] However, the effects of CoV infection on pregnancy have important prenatal and perinatal
outcomes: miscarriage occurrence in 39.1% of infected pregnant women, premature rupture
of membranes in 20.7%, preterm birth in 24.3% between 37 and 34 weeks, and preterm
birth in 21.8% before 34 weeks. The effects of COVID-19 on fetal growth restriction
and pre-eclampsia remain unknown. However, in SARS-CoV and MERS-CoV, fetal growth
restriction occurred in 11.7% of pregnant women and pre-eclampsia in 16.2%. There
were also high rates of cesarean section (83.9%). Moreover, perinatal deaths occurred
in 11.1% of infected women, 34.6% of fetal distress, and 57.2% of admissions in neonatal
ICU, and no neonatal asphyxia was reported. There was no evidence of vertical transmission
in this series. When analyzed separately, the effects of the CoV infections presented
very different results. There are no data about miscarriage in COVID-19 patients.
MERS-CoV did not present miscarriages; however, SARS-CoV had a high miscarriage rate
of 39%. MERS also did not increase premature rupture of the membranes and intrauterine
growth restriction ratios, but premature rupture of the membranes occurred in 50%
and 18.8% of pregnant women with SARS-CoV and COVID-19, respectively. Pre-eclampsia
was absent in patients with SARS-CoV, but it occurred in 13.6% and 19% of pregnant
women with COVID-19 and MERS, respectively. The preterm birth results deserve attention:
in pregnant women with COVID-19, 41% of deliveries occurred before 37 weeks and 15%
before 34 weeks. Preterm birth before 34 weeks occurred in 32.1% of pregnant women
with MERS-CoV, before 34 weeks in 21.9%, and before 37 weeks in 15% of pregnant women
with SARS-CoV.[25] The prenatal care of women infected by COVID-19 or suspected/probable cases must
be assessed every 2 to 4 weeks via ultrasound assessments of amniotic fluid volume
and fetal growth evaluation, including umbilical artery Doppler when necessary.[28] No evidence of vertical transmission was reported in a study involving nine patients.
In this series, infection in a neonate was diagnosed; however, no evidence of vertical
transmission was confirmed.[29] This finding was also enforced in a study with 3 neonates and 230 children.[30] Chinese guidelines recommend the isolation of COVID-19 positive neonates for 2 weeks
if the mother is negative for COVID-19.[31] Breastfeeding is not recommended for newborns from COVID-19 positive mothers according
to Chinese Guidelines. The newborn must be isolated from the mother, based on two
cases of newborn infections described.[32]
Pregnancy in the Era of Covid-19
Pregnancy in the Era of Covid-19
With the onset of the pandemic, investigations must be performed regarding the effects
of the viremia during the first and second trimesters and the prediction of possible
adverse outcomes. The higher rates of asymptomatic COVID-19 infections associated
with the absence of recommendations for the routine detection or screening of COVID-19
during the first and second trimesters of the pregnancy may represent a challenge.
Additionally, the effects of the stress and panic started by the onset of the global
pandemic, in addition to the prolonged confinement, must be considered when assisting
both noninfected and infected pregnant women. Therefore, all citizens, physicians,
and particularly mothers-to-be are called to strictly follow designated guidelines.
Thus far, it is clinically and socially useful to classify those who need a diagnostic
test into probable, suspected, or confirmed SARS-CoV-2 (COVID-19) positive cases.[33]
A probable infected person is defined as one with a doubtful or inconclusive test
to SARS-CoV-2 using RT-PCR to test for SARS-CoV-2. A suspected case is an individual
with an acute respiratory infection with at least one of these symptoms (fever with
a temperature >37.5°C, cough, and respiratory distress) of unexplained origin, or
coming from a country where there is local transmission of the virus in the 14 days
before the onset of symptoms, or a person with any type of acute respiratory infection
that has been in contact with a probable or confirmed SARS-CoV-2 case in the 14 days
before the onset of symptoms, or a person with a severe acute respiratory infection
requiring hospitalization without another explanation for the clinical presentation.
Last, a confirmed case is a positive result to a SARS-CoV-2 test performed by a registered
laboratory independent of any clinical sign of the disease.[34]
Given that the current COVID-19 pandemic differs from the previous SARS-CoV outbreak
of 2002 and the MERS-CoV outbreak of 2012 but has a higher human-to-human transmission
rate, it is advisable to reduce access to hospitals or medical offices as much as
possible unless respiratory symptoms arise: in these cases, nasopharyngeal swabs must
be performed. If a mother-to-be accesses first aid facilities or requires admission
to a hospital with symptoms of an acute respiratory infection, it must be considered
a suspected case.[35]
A telephone triage is recommended if the mother is symptomatic or in self-isolation,
and a clinical examination (where possible, and according to the degree of symptoms
and fever) should be planned after several days. Mothers should be contacted by telephone
for clinical follow-up with advice to alert the general practitioner if symptoms worsen.
If the mother has a positive SARS-CoV-2 test, she will undergo a general clinical
follow-up with ultrasound assessment of fetal growth every 4 to 6 weeks.[36] Unless they are positive, the mothers should plan to attend appointments at an antenatal
clinic at 36–37 weeks and at the hospital at 40 weeks.
Covid-19 Effects in Pregnancy
Covid-19 Effects in Pregnancy
Few case series on COVID-19 in pregnancy have been reported. The clinical series usually
included less than 13 cases each, and all have reported on pregnancies primarily in
the third trimester, demonstrating a lack of knowledge of the infection during the
first and second trimesters. When these studies were analyzed together, the clinical
manifestations were shown to usually develop after the 32nd week. Given the few cases assessed during early gestational ages, clinical manifestations
are usually observed close to late preterm and at delivery. Cesarean section was the
preferred delivery mode for undescribed reasons, potentially because the patients
were receiving oxygen therapy in most cases. However, the birthweight was usually
normal in these studies.[37]
[38]
[39]
Fever is the main clinical manifestation and was present in > 78% of cases in the
third trimester. Cough is the second manifestation to present in the infection. Sore
throat was present in < 22% of cases, and dyspnea and diarrhea occurred in < 14%.
It is important to note that a postpartum low-grade fever may indicate the need to
test for COVID-19, as observed in a small series of five cases. All patients presented
signs of pulmonary infection on CT and no other clinical manifestations.[40]
One case series of 13 pregnancies reported that 100% of cases were delivered via cesarean
section. This report cites that 50% were emergency cesarean sections, mainly because
of fetal distress, and there was one stillbirth. A total of 46% of 13 pregnancies
had preterm birth. One woman developed severe pneumonia with multiple organ failure.
Fetal distress was also reported in 22% of cases.[29]
The different types of reporting, in addition to different types of registering the
findings and outcomes, as observed in the present analysis, leads to the necessity
of a central, transparent, and accessible data center for COVID-19 cases. The majority
of clinical manifestations were reported during the late third trimester; however,
these conclusions may be biased because of the traditional conclusion of the cases
in obstetrics, the maternal and newborn discharge. More studies are required to evaluate
the effects of the infection during the early trimesters because no screening tests
were suggested for the pregnant population to evaluate the effects in asymptomatic
patients.[41]
Antiviral Therapies in Pregnancy
Antiviral Therapies in Pregnancy
In Wuhan, China, studies are currently being conducted for the medical treatment of
the viral infection using two antiviral drugs, remdesivir and hydroxychloroquine (HCQ).
Remdesivir has demonstrated antiviral activity in animal models of SARS-CoV and MERS-CoV
and in certain tests.[42] Hydroxychloroquine is an antirheumatic drug that has demonstrated an immunomodulatory
capacity; it has been shown to prevent inflammation and organ damage and to reduce
the proinflammatory signaling activation and cytokine production of IL-1, TNF, and
type I interferons. In pregnant patients with autoimmune diseases, HCQ is strongly
recommended for disease control and should be considered a potential therapeutic agent
in cases of SARS-CoV-2 infections in pregnancy.[43] Other medical treatment options are available even for pregnant patients. The association
of lopinavir/ritonavir is not contraindicated in pregnancy, except for Kaletra oral
solution, which is forbidden in pregnancy and in children < 14 years old. Darunavir/ritonavir
should be evaluated case by case, and the use of darunavir/cobicistat is not recommended
because there is evidence that pregnancy might reduce the pharmacological actions
of active darunavir. Currently, there is a lack of data about possible teratogenic
effects, effects on milk passage, or effects of remdesivir on neonates.[44]
[45]
Pregnancy and Health Care
Pregnancy and Health Care
A hydroalcoholic solution should be available for mothers coming to the waiting room,
interpersonal distance of more than one meter must be maintained, and no accompanying
persons are allowed unless the mother is not self-sufficient. In addition, the room
should be ventilated every 10 minutes, and all surfaces and items should be disinfected.
If a symptomatic mother is present in the waiting room, she must wear a surgical mask
and be assessed as soon as possible. Moreover, ventilating and disinfecting the waiting
room is mandatory. If the mother is asymptomatic, the use of a surgical mask is considered
unnecessary unless respiratory symptoms are present in the health caregivers; however,
proper hand hygiene must be observed before and after each individual examination.
If the mother is symptomatic (see definition above), she will be invited to wear a
surgical mask while the health caregivers are called to wear a mask, glasses, gloves,
and disposable gowns. The surface must be cleaned with disinfectant (alcohol solution
at least 75%), and the room should be ventilated. In addition, nasopharyngeal swabs
must be taken together with complete isolation in a dedicated room, and the Office
of Public Hygiene should be informed. If the general condition of the mother is stable,
she will be advised to observe a period of isolation of 14 days, and in those testing
SARS-CoV-2 positive, a clinical and ultrasound follow-up will be planned every 4 to
6 weeks onwards. If her general condition is unstable or poor, the mother will be
admitted to a referral tertiary care center.
Different management strategies should be arranged to assist mothers in the delivery
room. For asymptomatic mothers, the general rules described above should be followed,
and depending upon availability, health caregivers should wear surgical masks. As
noted above, only one accompanying person is allowed in the delivery room unless he/she
has tested positive for SARS-CoV-2.
If the mother is symptomatic with a general stable condition, the use of all individual
protection devices is mandatory for both mothers and doctors/midwifes/nurses, and
maternal and neonatal swabs must be taken. Both the mother and baby must be kept in
an isolated room, and secondary to the swab results, they must be followed up for
3 days before hospital discharge. If the mother is symptomatic but in an unstable
condition, referral to a tertiary care unit with a resuscitation facility should be
arranged. Acute infection with COVID-19 does not represent per se an indication for
cesarean section during intrapartum or a contraindication for breastfeeding given
that the mother observes proper hand washing and hygiene every time before and after
breastfeeding and will continue to wear a surgical mask.[46] Only one accompanying person is allowed: if respiratory symptoms are present, all
the aforementioned individual protection methods will be strictly followed. The admittance
of a suspected or known SARS-CoV-2 positive individual is forbidden. All recommendations
for protection will be strictly undertaken. Separating mothers and their newborns
should be avoided, and breastfeeding should be encouraged according to the will and
right of the mother.[47] There is supporting evidence of a lack of vertical transmission,[48] the virus has not been found in the amniotic fluid, cord blood, or maternal milk,[49]
[50] and there are no registered cases of maternal death.[51] A possible explanation might be the absence of the ACE receptor at the fetal-maternal
interface, which was the opposition of that for the human AXL protein in the Zika
virus infection.[52]
[53]
[54]
[Figs. 1] and [2] show the flowcharts of the antenatal prenatal care and delivery room, respectively,
which were in part developed by the Instituto Superiore Sanità (ISS, www.iss.it) and Emilia-Romagna Region (www.salute.regione.emilia-romagna.it) ([Tables 1] and [2]).
Fig. 1 Flowchart of the antenatal prenatal care.
Fig. 2 Flowchart of the delivery room.
Table 1
Maternal and perinatal outcomes of pregnant women with Covid-19
|
Cases
|
Maternal Age (years old)
|
Gestational age at clinical manifestation (weeks)
|
Gestational age at delivery
|
Methods of Diagnosis
|
Delivery Mode
|
Birthweight (grams)
|
|
Chen et al[29]
|
9
|
28 (26–40)
|
37+2 (36–39+4)
|
37+2
|
qRT-PCR
|
9 CS
|
2970 (1880–3820)
|
|
Zhu et al[53]
|
7
|
30 (25–34)
|
34+5 (30+4-38+4)
|
34+6
|
CT
|
6 CS 1 VD
|
2300 (1520–3800)
|
|
Liu et al[27]
[*]
|
11
|
32 (23–40)
|
2–19 days before admission at 32w (12–38)
|
NA
|
CT
|
10 CS 1 VD
|
NA
|
|
Yu et al[37]
|
7
|
32 (29–34)
|
5 days (2–9) before admission at 39w (37–41)
|
39+2(37–41+5)
|
qRT-PCR and CT
|
7 CS
|
3250 (3000–3500)
|
|
Chen et al[40]
|
5
|
29 (25–31)
|
39+1 (38+6-40+3)
|
39+1 (38+6-40+4)
|
qRT-PCR
|
2 CS 3 VD
|
3700 (3235–4050)
|
|
Lee et al[38]
|
1
|
28
|
36+2
|
37+6
|
qRT-PCR
|
CD
|
3130
|
|
Liu et al[54]
|
13
|
22–36
|
2 days before 28 weeks and 11 days on third trimester
|
NA
|
qRT-PCR
|
10 CD (100%)
|
NA
|
Abbreviations: CS, cesarean section; CT, computed tomography; NA, not available; VD,
vaginal delivery; w, weeks.
* data including three puerperal patients.
Table 2
Main clinical manifestation of pregnant women with Covid-19
|
Cases
|
Fever
|
Cough
|
Sore throat
|
Diarrhea
|
Dyspnea
|
|
Chen et al[29]
|
9
|
78%
|
44%
|
22%
|
11%
|
11%
|
|
Zhu et al[53]
|
7
|
100%
|
42%
|
14%
|
14%
|
NA
|
|
Liu et al[27]
[*]
|
11
|
86%
|
59%
|
6%
|
6%
|
6%
|
|
Yu et al[37]
|
7
|
85%
|
14%
|
NA
|
14%
|
14%
|
|
Chen et al[40]
|
5
|
0%
|
0%
|
NA
|
NA
|
0%
|
|
Lee et al[38]
|
1
|
Present
|
Present
|
Present
|
NA
|
NA
|
|
Liu et al[54]
|
13
|
77%
|
NA
|
NA
|
NA
|
23%
|
Abbreviations: NA, Not available.
* data including three puerperal patients.
Now is a time of new perspectives regarding dealing with infections of pandemic proportions.
Much will be learned from this stress test on the health care systems and how they
cope, and the successes and failures of recommendations and guidelines from health
organizations and their timing will be analyzed. However, much can and has already
been done to create solutions for clear communication between medical scientists.[55] The cases reported mainly focused on patients with evident clinical manifestations,
in whom the disease can progress quickly and become severe in a few hours. However,
there is evidence showing that pulmonary imaging findings may be evident in very early
stages of COVID-19 infection. These data can change the course of the traditional
care of respiratory infections, when imaging is reserved for worsening clinical conditions.[56] Additionally, the consequences of a period of intense stress and anxiety during
pregnancy, as spontaneous preterm labor and psychiatric disease on the siblings are
already known, and special attention must be reserved for those pregnant, noninfected
women, in this time of an overloaded health care system and exhausted health care
workers.[57]
