Specific therapies in pregnant women are discussed
The health crisis caused by the novel SARS-cov-2 (2019-nCoV) related
pandemic requires urgent and necessary therapeutic response. Pregnant
women are just as exposed as the general population and should not be
excluded, because of their status, from discussions on effective and
well tolerated candidate treatments. While in countries that have opted
for national containment, daily non-emergency medical and surgical
activities are suspended, obstetric services continue to operate
relentlessly and are experiencing a surge in so-called ”at-risk”
pregnancies. Some countries have now recommended routine screening of
all pregnant women 1 but the low availability and
performance of the current tests limits their use. Management of an
infected pregnant women is essentially conditioned by maternal
symptomatology. Women with little or no symptoms do not require routine
treatment or in-patient care and simply need to be monitored for up to
15 days for evidence of respiratory deterioration. In the absence of
validated specific treatment, the primary approach to therapy is mainly
symptomatic and delivery is considered in the event of critical
respiratory distress in order to maximize oxygenation and lung capacity2–4 . However, it has been reported that women with
respiratory signs may be given antiviral treatment to improve their
clinical condition 2,4
To date, there is no proven effective strategy, although many teams are
working tirelessly to identify an effective treatment. Four molecules
are leading in this race:
1) Remdesivir is a novel nucleotide analogue prodrug which incorporates
into nascent viral RNA chains and results in pre-mature termination. Its
effectiveness has been already demonstrated against others coronaviruses
such as SARS-Cov and MERS-Cov5, and it has proven to
be highly effective on in vitro 2019-nCoV infection6.
Compassionate use in human were also reported 7 and
phase 3 studies are currently underway.
2) (Hydroxy)chloroquine has been known for years because of its
effectiveness in the treatment of inflammatory diseases and against
malaria. Recent studies have shown antiviral effects of chloroquine and
in vitro studies concluded that it was highly effective in the control
of 2019-nCoV 6,8. Elevation of endosomal pH and
interference with terminal glycosylation of the cellular receptor,
angiotensin-converting enzyme 2 conduct to block virus infection.
(Hydroxy)chloroquine has been used in 2019-nCoV infected humans with
highly controversial restuls9,10 and well-designed
randomized studies should be available soon.
3) Lopinavir, a viral protease inhibitor, with its pharmacological
booster Ritonavir (LPV/R) are commonly used in HIV positive patients. It
has already been used for SARS-Cov. Some countries such as China and
India approved its use in symptomatic infected patients although a first
randomized, controlled, open-label trial showed no benefit of LPV/R over
standard care in patients with severe 2019-nCoV
disease11.
4) Ribavirin, is a guanosine analog that interferes with the replication
of RNA and DNA viruses. It has been used for years in the treatment of
chronic hepatitis C. Based on its direct anti‐viral activity against
2019‐nCoV in vitro and some evidence for its potential efficacity during
the prior SARS-Cov and MERS-Cov outbreaks, it has been suggested as a
potential candidate for the treatment of 2019-nCoV
diease12. 2019-nCoV infected patients treated with
Ribavirin have been reported by Chinese studies4,13but its exact benefit remains to be demonstrated in well designed
randomized studies as well.
To date, all four drugs are being independently tested in Phase 3
studies, mostly national, to investigate their efficacy and safety in
the management of 2019-nCoV disease. Several European countries have
also set up, as a result of joint efforts since mid-March, a randomized,
multicentre, open-label trial to evaluate and compare the efficacy and
toxicity of the first three treatments mentioned
above.14
With regard to the possibility of treating pregnant patients with these
molecules, few data are available for Remdesivir. Only one study reports
its use in six pregnant women in a randomized trial during Ebola
epidemics. The authors reported no adverse effect15.
Many more pharmacological studies on maternal-fetal tolerance of
Hydroxy(chloroquine), Lopinavir and Ribavirin are available. The
historical use of (hydroxy)chloroquine in antimalarial treatment, but
also in connective tissue diseases, has resulted in a well-documented
safety and tolerance profile in pregnant women16.
Animal studies, undertaken during the Zika virus epidemic, have also
suggested that chloroquine may also reduce the risk of viral
transplacental transmission to the fetus17. The
optimal dosage to be used in pregnant women will have to be specified,
but it appears that there is no pharmacokinetic difference between
chloroquine and its major metabolite between pregnant and non-pregnant
women18. With respect to the use of protease
inhibitors during pregnancy, such as Lopinavir, some teams have reported
an increased risk of preterm delivery. However, a specific analysis of
more than 4,000 pregnant women found a similar incidence and rate of
adverse pregnancy outcomes than in controls at all three trimesters of
pregnancy, including preterm birth, low birth weight and birth defects19. Significant teratogenic effects have been
demonstrated in all animal species exposed to Ribavirin, it is therefore
currently contraindicated in pregnant women and in their male sexual
partners, although the ribavirin pregnancy registry did not bring
evidence of teratogenicity in humans20.
The use of antiviral therapy in infected pregnant patients should follow
the same indication as in the general population, but some obstetric
specificities should be emphasized.
1) The main goal should be to slow down and at best stop the clinical
progression of the disease, i.e to remain asymptomatic and to avoid
progression to acute respiratory distress syndrome in symptomatic cases.
In the latter, the obstetrician is often called on to perform an
emergency delivery and thus to induce extreme prematurity. Expert
consensus provided obstetric guidance, but the management of cases at
between 25 and 32 weeks’ remains challenging in the absence of effective
antiviral treatment1.
2) The second objective would be to rapidly decrease viral load and
duration of contagiousness in infected pregnant women. The majority of
them are doing well, but the infection can disrupt their obstetrical
calendar. Some procedures need to be performed at a specific age, such
as first trimester serum markers, ultrasound examinations, chorionic
villi sampling (CVS). The same applies to access to termination of
pregnancy. All such procedures may indeed be delayed, either to limit
contagion, to limit the burden on the health care team (due to
reinforced barrier measures…) or in the particular case of
CVS/amniocentesis, to limit the theoretical risk of fetal transmission.
3) Finally, the third advantage could be to introduce preventive
treatment in case of maternal contact with an infected person, similar
to what is done for seasonal influenza and oseltamivir21.
The use of immunotherapy such as Tocilizumab, plasma of recovered
coronavirus patient, Interferons, were not discussed here as they are
currently understudy only for critically ill COVID-19 patients. No place
for these treatments in a patient who is still pregnant should be
considered for the time being, since if the pregnant woman presents a
very severe form, the birth will be considered as a priority.
The results of the Phase 3 therapeutic studies should be available soon.
However, it is unfortunate that infected pregnant women are not included
in any appropriate research protocols. Consequently, in this period of
pandemic, mutual exchanges of experience between all countries’
maternity hospitals must be carried out in order to ensure the best
possible management of infected pregnant women.