How might COVID-19 affect pregnant
women and their
babies?
On March 16th, 2020, the UK government issued advice
on self-isolation for members of the population who were deemed to be
‘vulnerable’ to COVID-19 infection. This included women who were
pregnant, regardless of gestational age 22. The
evidence in favour of isolation in pregnancy has since been questioned,
particularly with regards to pregnant healthcare workers. The latest
guidance from the Royal College of Obstetricians and Gynaecologists on
COVID-19 sought to address this by recommending a removal from
patient-facing roles in those healthcare workers who were beyond 28
weeks gestation. Those who remain within the first or second trimester
could continue to work with reasonable precautions to avoid infectious
contact 23.
What is the theoretical risk of
COVID-19 infection in
pregnancy?
The theoretical risk of COVID infection in pregnancy should ideally be
considered in two categories:
- What is the risk to the mother, including the risk of progression to
severe disease?
- What are the risks to the fetus, including transmission, in-utero
infection and post-natal disease?
Why is a pregnant woman ‘at
risk’?
There is no doubt that pregnancy results in modulation to the maternal
immune system. It was initially proposed that pregnancy itself as an
immunosuppressive state, in order to prevent rejection of a
semi-allogenic fetus 24. However, it seems far more
likely that the maternal immune system adapts during pregnancy in order
to strike a balance between fetal tolerance and maternal susceptibility
to infection, effects which may be mediated by oestrogen and
progesterone 25. Indeed, epidemiological data does not
suggest an increased susceptibility to infections in pregnancy, however
the course and prognosis of a disease may be altered.
Modulation to the immune system during pregnancy may result in an
environment favouring TH2 (humoral/antibody) rather than TH1 (cytotoxic)
immune responses 26. Pregnant women remain able to
mount appropriate antibody responses to vaccines and appear to
demonstrate a reduction in pro-inflammatory cytokines but an increase in
pro-phagocytotic factors. Innate immunity, driven by macrophages and
neutrophils, appears maintained or enhanced 27. While
the concept of immune suppression may be over-simplified, this shift to
favour humoral immunity may result in an altered response to viral
respiratory pathogens, while an overall functioning of innate immunity
would otherwise prevent increased pathogen susceptibility. These changes
are thought to be more prominent in the third trimester of pregnancy.
It is important to also consider the cardiovascular and respiratory
changes that the body undergoes to adapt to the needs of the developing
fetus. There is a modest increase in heart rate and stroke volume during
pregnancy, with an overall increase in cardiac output and corresponding
left ventricular hypertrophy. To increase oxygen provision and carbon
dioxide excretion there is also a reduction in the functional residual
capacity and inspiratory reserve volume of the lungs to allow for an
increase in tidal volume. The gravid uterus pushes upwards, elevating
the diaphragm and altering chest compliance, resulting in difficulties
in ventilation. In other words, the pregnant mother operates at the
limits of her physiological capacity, which means further deficits to
lung function caused by a respiratory infection could result rapidly
decompensated disease.
Taken together, we should consider women of advancing gestation to be
equally likely to contract SARS-COV-2 as the general population but more
at risk of having severe or decompensated disease if present. This is
corroborated by evidence from the 2009 influenza pandemic, where
pregnant women had an increased risk of hospitalisation, severe disease
and pre-term delivery due to fetal distress or deteriorating maternal
disease 28.
What is the risk of severe maternal
disease with
COVID-19?
At the moment, it appears too early to say. There is evidence that
pregnant women with SARS suffered from more severe disease than
non-pregnant women, with adverse maternal outcomes 29.
The absolute number of pregnant women infected with SARS was small,
however it is hypothesised that COVID-19 would have a similar effect in
pregnancy 30.
A retrospective analysis of 9 pregnant women in the third trimester of
pregnancy confirmed to have COVID-19 on throat swab did not show an
increase in severe disease 31. Larger analysis of
pooled patient data has observed no increased risk of developing severe
or critical COVID-19 in pregnancy and, as yet, no maternal deaths32, 33. Pregnant women appear to have a similar
symptom presentation to the general population and a comparable disease
course. Sadly, there is one case of a severe maternal infection at 34
weeks, reported as part of a case series of 13 patients34. In this case, premature delivery of a stillborn
infant was required, and the patient subsequently developed multi-organ
failure due to sepsis, requiring extra-corporeal membrane oxygenation.
To date, it appears encouraging that COVID-19 infection does not follow
a similar pattern to SARS and H1N1 influenza in pregnancy, although the
absolute numbers of infected women remain low.
What is the risk of SARS-COV-2
infection developing in the
fetus?
The risk to the developing fetus remains difficult to quantity. Previous
data from SARS did not show any specific cases of fetal infection but
did demonstrate an increased risk of adverse pregnancy outcomes when
maternal disease was present 35, 36.
To date, there is no evidence of vertical transmission of COVID-19 to
the fetus, with negative swabs from the neonatal throat, amniotic fluid
and placenta 31, 33, 34, 37, 38. Breast milk samples
from early lactation do not show any viral RNA 31, 37.
Placental histology of three confirmed cases of third trimester COVID-19
did not show any evidence of villitis, chorioamnionitis or SARS-COV-2 on
qRT-PCR, but diffuse fibrin deposition was present around the villi39, which could indicate altered placental blood flow.
This begs the question – is it possible for SARS-COV-2 to infect the
fetus? Most cases of vertical transmission of infection diseases in
pregnancy are via haematogenous spread across the placenta. This seems
an unlikely route for SARS-COV-2. Single cell analysis of early
pregnancy specimens using RNA-sequencing has revealed that while the
syncitiotrophoblast of the placenta does express ACE2, the fetal blood
does not 40. This, presumably, does not preclude the
direct passage of viral particles present in high levels during maternal
viraemia, or through breaches in the placental barrier. Ascending
infection from the maternal genital tract cannot be ruled out, as
SARS-COV-2 is yet to be isolated from genital fluids41. However, it could it be possible for SARS-COV-2 to
enter the amniotic fluid in cases of premature rupture of membranes
(PROM). In these circumstances there would be a theoretical risk of
viral entry to the fetal lung or gastrointestinal epithelium.
In the absence of first trimester studies of maternal COVID-19
infection, or any cases of proven fetal infection, we cannot conclude
whether maternal COVID-19 would result in fetal anomalies. However, it
is reassuring that SARS-19 did not result in fetal teratogenicity,
despite an overall increase in poor obstetric outcomes. At this point,
should we reassure our patients that the risk of anomalies is unlikely,
but not proven? Certainly, this is an area worthy of urgent study.
Erring on the side of caution and acknowledging the lack of reassuring
evidence regarding the effect of COVID-19 on the early human embryo, the
European Society of Human Reproduction and Embryology (ESHRE) in a
statement from the 19th of March 2020 advised all
patients defer getting pregnant until the epidemic ends42. This statement was echoed by other national and
international societies and resulted in almost complete cessation of
fertility treatments of any sort 43.
The risk of transmission of infection to the neonate at the time of
birth remains unquantified. In the reported case studies above, all
babies were born by caesarean section. There are five cases of infection
early in the neonatal period to SARS-COV-2 positive mothers, however in
each case it was deemed possible for neonatal COVID-19 infection to have
been acquired by transmission in the neonatal period, with placental,
uterine and amniotic fluid swabs either negative or not performed44, 45. The risks of vaginal delivery are unknown, but
presumably small.
What would be the indirect effects
of maternal COVID-19 on the
fetus?
There is a theoretic risk of indirect fetal injury during maternal
COVID-19 infection as a result of 1) severe maternal sepsis, 2) maternal
cytokine storm resulting in placental injury or 3) direct placental
infection resulting in placental disease. The effect on the fetus would
likely be secondary to the gestation at which the insult was received
and the severity of the initial maternal infection.
Disease in the first trimester could result in miscarriage due to
placental or maternal infection, with a potential need for uterine
evacuation in severe cases. In later gestations, placental injury from
infection or cytokine damage might result in fetal hypoxia, manifesting
as intra-uterine growth restriction or fetal distress, or placental
abruption. SARS pregnancies appeared to demonstrate an increase in
miscarriage when disease was acquired in the first trimester and
intra-uterine growth restriction at latter gestations, however the
patient numbers are too small to conclude a significant effect35, 36.
As yet, there is little data to suggest whether this may be true – all
but 2 of the 55 reported cases of infection in Chinese patients occurred
in the third trimester with a short interval between maternal infection
and delivery. To date, there are 3 reported cases of PROM and 5 of fetal
distress necessitating delivery 31, 34, 46, which may
indicate an increased risk of fetal distress during labour. Multiple
cases of delivery between 32-36 weeks gestation have been reported, but
it is not clear whether these were iatrogenic or due to spontaneous
onset of premature labour. There is one documented case of stillbirth in
a woman suffering with COVID-19 whose neonate tested negative at
delivery 34, but no reports of miscarriage.
Intra-uterine growth restriction cannot be inferred from the present
data due to a lack of maternal demographics allowing for personalised
growth calculations.
How are we managing pregnant women
in the UK with known or suspected COVID-19
infection?
The Royal College of Obstetricians and Gynaecologists have released new
guidance for the management of COVID-19 in pregnancy, which is
constantly evolving as our information on the pandemic is growing23. This document outlines how individual units should
treat confirmed or suspected cases of COVID-19, including how to
minimise the risk of spread to others within the department.
Some key points to highlight are:
- As initial data may represent an increased risk of fetal distress in
labour, secondary to maternal sepsis or fetal hypoxia, all women with
COVID-19 should be managed on a maternity unit with continuous fetal
monitoring in labour.
- Due to the theoretical risk of growth restriction to the developing
fetus after maternal COVID-19 infection the RCOG have advised for all
women who have suffered COVID-19 symptoms to attend for a growth scan
2 weeks following the resolution of symptoms.
- If maternal investigations for suspected severe COVID-19 are required,
specifically a CT chest, this should not be delayed due to concerns
regarding fetal x-ray exposure, as it is valuable to facilitate
maternal treatment.
- In women who have suspected or confirmed COVID-19 infection in the
third trimester, elective delivery should be delayed, if it is safe to
do so, until after maternal recovery.
- Breast-feeding should still be encouraged, as no evidence suggests
SARS-COV-2 can be transmitted in the breast milk, however symptomatic
mothers should attempt to avoid aerosol transmission to the neonate
with good hand hygiene, and the provision of face masks where
necessary. Delayed cord clamping is not contra-indicated.
How should we explain the risks of
COVID-19 infection in pregnancy to our patients, when we don’t fully
understand them
ourselves?
The emergence of this new disease poses a significant challenge for the
healthcare systems across the globe. Pregnant women, being a
particularly vulnerable group, have been faced with additional
uncertainties related to the effect of the virus on the pregnancy as
well as their health and wellbeing. It is therefore important for any
obstetrician and gynaecologist to be very frank with women attempting to
start a pregnancy, as well as those that are already pregnant, that the
evidence for significant harm or lack thereof is very limited. We must
inform women that due to the pressures on the emergency services, there
may be a delay in seeing them if they present with early pregnancy
complications, such as pain or bleeding and that confirmation of a
miscarriage or ectopic pregnancy may be delayed. Similarly, treatment
options may be reduced due to availability of theatre or anaesthetic
staff, or lack of personal protective equipment in cases of confirmed
COVID-19 positive patients.
Recent concerns regarding the risk of spread COVID-19 during
laparoscopic surgery has put in question the routine application of this
well-established procedure as the mainstay of treatment of ectopic
pregnancies 47. Laparoscopies will still be carried
out with additional precautions; however, some units may choose to forgo
this approach completely and offer open surgery as the only surgical
option. First trimester combined screening for aneuploidies may also be
delayed or stopped completely for the time being. This may result in an
increased rate of aneuploid pregnancies detected later with additional
physical and psychological comorbidities as a result of late diagnosis
and mid trimester terminations. Current evidence seems to indicate an
increased risk of caesarean deliveries in women affected by COVID-19 and
these are also not without immediate and long-term comorbidities. As the
situation is dynamic, it is our responsibility as healthcare
professionals to keep up with the developments and relay any relevant
information to our patients in order to alleviate the high parental
anxieties and more importantly, do no harm.
Further areas of
research
The COVID-19 pandemic remains an international public health concern of
previously unparalleled proportions. Clearly, this is a constantly
evolving situation. Any recommendations that are made can only be based
on current evidence and are likely to change as our knowledge is
updated.
It is a relief that there is no current suggestion of vertical
transmission to the unborn fetus, though larger case studies will be
required to determine this for definite and ensure there is no direct
teratogenic effect of fetal infection. Case-control studies following
infected women through the first trimester onwards will provide
important information to elucidate this and will allow for correlation
of maternal and fetal outcomes with infection. In response to this, the
UK Obstetric Surveillance System (UKOSS) have created a system for
mandatory reporting of all confirmed cases of COVID-19 in pregnancy to
assess the incidence within the population and monitor outcomes.
Monitoring of COVID-19 in pregnancy will remain a challenge. At present,
Public Health England will only permit testing of those patients whose
symptoms are severe enough to require admission to hospital. A large
cohort of asymptomatic or mildly affected SARS-COV-2 positive women will
not be included within the UKOSS study as a result of this. Any data
obtained as a result of this, or other, studies may be skewed towards
the more severe end the spectrum of maternal and fetal disease. It will
be many years before the longer-term effects of COVID-19 on pregnancy
are understood.
Contributions to
authorship
AR conceived the article and researched the original manuscript. DG, MB
and LP provided specialist input, intellectual guidance and assistance
with writing. All authors contributed to edits and approved the final
draft.
Sponsorship
AR’s research fellowship is funded by the Addenbrookes Charitable Trust
and National Institute of Health Research.
Conflicts of
Interest
No authors have conflicts of interest to declare
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