Download Viral respiratory disease in pregnancy

Viral respiratory disease in pregnancy
Ryan E. Longman and Timothy R.B. Johnson
Purpose of review
Recently there has been an increased concern over viral
respiratory infections and their potential for a pandemic.
This concern makes it important to review the most current
guidelines for the management of viral respiratory diseases
in pregnancy.
Recent findings
The topics covered are influenza, avian influenza, and severe
acute respiratory syndrome.
Summary
Pregnant women have an increased susceptibility to viral
respiratory diseases. The most common respiratory virus to
infect pregnant women is influenza. All women who intend
to become pregnant or are pregnant should receive the
influenza vaccine. If a pregnant woman develops influenza
she should be treated with supportive care. Antiviral
medications should be reserved for cases where the
benefits outweigh the risks. Avian influenza (H5N1) is a new
emerging virus usually contracted from direct contact with
diseased birds. There is no commercially available vaccine
at this time to prevent infection. Pregnant women should be
treated aggressively with supportive care and antiviral
medications, as the significant risk of maternal mortality
outweighs the potential fetal risks. Pregnant women
diagnosed clinically with severe acute respiratory syndrome
should be treated empirically, as a serologic diagnosis can
take weeks to confirm. The treatment of pregnant women
with severe acute respiratory syndrome should be without
ribavirin.
Keywords
avian influenza, influenza, severe acute respiratory
syndrome
Curr Opin Obstet Gynecol 19:120–125. ß 2007 Lippincott Williams & Wilkins.
Obstetrics and Gynecology, University of Michigan, Women’s Hospital, Ann Arbor,
Michigan, USA
Correspondence to Dr Timothy R.B. Johnson, MD, Bates Professor and Chair,
Obstetrics and Gynecology, University of Michigan, Women’s Hospital, 1500
East Medical Center Drive, Room L4000, Ann Arbor, MI 48109-0276, USA
Tel: +1 734 763 0983; fax: +1 734 763 5992; e-mail: [email protected]
Current Opinion in Obstetrics and Gynecology 2007, 18:120–125
Abbreviations
ACOG
CDC
PCR
SARS
American College of Obstetricians and Gynecologists
Center for Disease Control
polymerase chain reaction
severe acute respiratory syndrome
ß 2007 Lippincott Williams & Wilkins
1040-872X
Introduction
Pregnancy significantly alters maternal respiratory physiology. The rise in progesterone levels stimulates the
brain’s respiratory center, creating a functional state of
hyperventilation, while the enlarging gravid uterus alters
lung volumes and creates the maternal perception of
dyspnea. In addition, pregnancy has also been noted to
affect the immune system by decreasing the cytotoxic
lymphocytic activity. All of these physiologic changes
that take place are intended to help the pregnant patient
successfully adapt to gestation, but they can also be
detrimental to maternal well-being.
One of the deleterious effects caused by these adaptations in pregnant patients is the diminished ability to
compensate for and resist viral respiratory infections. The
most common respiratory virus that takes advantage of
this susceptibility is influenza. In addition, there has
recently been increased concern over new antigenic
strains of influenza and other classes of viruses that result
in aggressive virulent respiratory disease. The purpose of
the present article is to review these viral respiratory
diseases in the gravid patient and to address recent
updates in management.
Influenza
Influenza is an acute respiratory disease that affects an
estimated four million people per year. The three isotypes of the influenza virus that cause disease are influenza A, influenza B, and influenza C. Influenza A is the
most common and the most virulent [1,2]. The virus is
spread through aerosolized respiratory droplets followed
by disease onset 1–4 days after exposure. The symptoms
with which patients present are fever, cough, headache,
malaise, nausea, vomiting, rhinorrhea, and myalgia. The
viral illness usually resolves after 5 days [1,3].
Influenza prevention consists of a yearly vaccine. There
are two types of vaccines commercially available: an
inactivated vaccine that is delivered intramuscularly,
and a live attenuated vaccine that is delivered intranasal. Vaccines developed for use in the United States
aim to immunize against three antigenic strains of influenza per year – two subtypes of influenza A, and influenza
B. The annual selection of viruses included in the
vaccine depends upon the occurrence of new subtypes
of influenza causing outbreaks in other parts of the
world. Current vaccines provide protection against the
virus with an efficacy of 70–100% in healthy adults.
Severe adverse reactions are rare [4].
120
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Viral respiratory disease in pregnancy Longman and Johnson 121
If the patient did not receive the vaccine and symptoms
of influenza have already appeared, then treatment consists of supportive care with or without antiviral medications. There are two groups of antiviral medications
used in the treatment of influenza: ion channel blockers
and neuraminidase inhibitors. Amantadine and rimantadine are both ion channel blockers. These blockers act by
blocking the influx of hydrogen ions into endocytosed
vesicles that contain virus particles. By inhibiting the
influx of hydrogen ions they prevent a drop in vesicle pH.
Without this decrease in pH, the virus is not able to
activate its replication pathway. Both amantadine and
rimantadine are 50% effective in preventing infection
and 70–90% effective in preventing illness in exposed
individuals. When given to patients with acute influenza
illness, within the first 48 h of symptoms, they have been
shown to decrease the time to recovery by 1 day [4]. The
two neuraminidase inhibitors used in the treatment of
influenza are zanamivir and oseltamivir. They act to
decrease the activity of neuraminidase, which prevents
the influenza virus from entering and being released from
cells. Zanamivir and oseltamivir should be started within
the first 2 days of the influenza illness and have been
shown effective in reducing the duration of symptoms by
24–36 h [4]. Amantadine and rimantadine are approved
for the prophylaxis and treatment of influenza A, while
zanamivir and oseltamivir are approved for treatment
only of influenza A and influenza B. Treatment with
these medications should last for 5 days and for no longer
than 2 weeks to prevent drug resistance [4].
Pregnant women have an increased rate of morbidity and
mortality from influenza infection. The increased risk of
influenza for the pregnant patient was first reported after
the epidemic of 1918 when mortality was noted to be as
high as 49% [5,6], and was further noted during the
epidemic of 1957 when 50% of reproductive age women
that died were pregnant [7–9]. Later studies better
qualified the risk of influenza for the pregnant patient
to the third trimester when the risk of hospitalization for
an acute cardiopulmonary illness is three to four times
more likely than for a nonpregnant or postpartum woman
[10–12].
The influenza virus can cross the placenta [13] but does
not increase the risk of a preterm delivery or a low-birthweight infant [11,14]. The effect of fetal viremia
on congenital anomalies and psychiatric disorders is
contested [3,15,16].
Management of influenza in pregnant patients consists of
prevention and supportive care. Prevention consists of
providing pregnant women with the yearly influenza
vaccine. The American College of Obstetricians and
Gynecologists (ACOG), along with the Center for
Disease Control (CDC), recommend that all women that
are or intend to become pregnant during the influenza
season should be vaccinated. A new recommendation in
the ACOG committee opinion from 2004 [17] is that
pregnant patients can be vaccinated in all three trimesters. ACOG also reminds practitioners that it is the
inactivated intramuscular vaccine that should be used
during pregnancy and not the attenuated intranasal
vaccine [17].
Even though significant evidence continues to show the
efficacy [18,19] and safety [20,21] of the influenza
vaccine, only a small percentage of pregnant patients
actually receive it [22–24]. To better identify reasons for
the low vaccination rate in pregnant women, the ACOG
and the CDC surveyed a national sample of obstetricians.
They found that while 95% would recommend the
vaccine in the second and third trimesters, only 52%
would suggest it during the first trimester. Of
those physicians that would recommend the vaccine,
36–38% did not provide the vaccine at their practice.
Based on these findings the ACOG and the CDC
made two recommendations: first, educate providers
to recommend the vaccine in the first trimester; and,
second, increase the availability and access of the vaccine
to patients [25].
The use of antipyretics should be stressed for the
treatment of fever as not only does it reduce fetal
tachycardia, but it has also been associated as a protective
agent against congenital abnormalities [3]. Some authors
have suggested elective delivery in pregnant women if
their respiratory status becomes compromised, but there
is no definitive evidence to support this form of management [26]. Delivery should be reserved for obstetrical
indications.
The use of antiviral medications in pregnancy is
controversial. There are only very limited animal studies
and human cases were these medications have been
administered to pregnant women [27–33]. The most
studied of all the antiviral medications in pregnancy is
amantadine. Animal studies of the drug have yielded
conflicting results. Vernier et al. [28] treated both rabbits
and rats with amantadine at doses as high as 32 mg/kg and
found no evidence of teritogenic events. Lamar et al. [29]
also treated rabbits and rats with amantadine but at doses
of up to 100 mg/kg. The rabbits treated with amantadine
showed no evidence of teratogenic malformations or fetal
resorptions, while the rats were noted to have increased
rates of teritogenic malformations and fetal resorptions at
doses of 50 mg/kg, 12 times the human dose [29]. The
human studies in which amantadine was administered to
pregnant patients consist of two case reports and two
small case series. One of the case reports found pregnant
women exposed to amantadine in the first trimester of
pregnancy produced fetuses with cardiac anomalies,
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122 Maternal-fetal medicine
while the second case report and the two case series failed
to identify any increased risk of teratogenisis [30–33].
There are no animal or human reports in the English
literature on the effects of rimantadine, zanamivir, or
oseltamivir on gestation [27]. Even though no conclusive
data have shown antiviral medication to be harmful or
teratogenic, the ACOG recommends that use of the
medication be limited only to cases where the potential
benefits outweigh the potential risks [17].
The best way to prevent infection with avian influenza is
to avoid travel to infected regions. If travel to an infected
area is necessary, then direct contact with poultry
and their feces should be avoided. When consuming eggs
or other poultry products, they must be thoroughly
cooked [40]. Unfortunately, there are no commercially
available vaccines for the H5N1 virus and the seasonal
influenza vaccine does not provide protection against
avian influenza strains [41,42,43,44,45].
Avian influenza
Treatment for avian influenza consists of supportive care
and an antiviral medication, oseltamivir. There is limited
evidence that oseltamivir can reduce viral replication and
improve survival. To be effective, oseltamivir should be
administered within 48 h of the onset of symptoms, but
since the illness has such a high mortality rate it is
suggested that the medication be started even if the
patient is outside the 48 h time period [34,35].
Recently there has been increasing concern over the
emergence of new antigenic influenza strains. The strain
that appears to raise most concern is a type A avian
influenza, H5N1.
Wild birds are known to harbor the avian influenza virus
in their intestines and act as the natural reservoir for the
disease. While the wild birds remain asymptomatic they
can infect other bird species, such as poultry, which
can develop a symptomatic illness. There are several
subtypes of avian influenza and they usually produce
an illness that manifests itself as a mild effect on the
respiratory system or reduction in egg production.
Occasionally, infection can occur with a more pathogenic
strain that can cause severe disease with a mortality rate
of almost 100%. The viral strains that cause the severe
form of the disease are the H5 and H7 subtypes
[34,35].
The risk of human infection with avian influenza is low
because the strains only rarely cross species from birds to
people. Of the several subtypes of avian influenza, only
four strains are known to have infected humans: H5N1,
H7N3, H7N7, and H9N2. With the exception of the
H5N1 strain, which is extremely pathogenic, these viral
strains only produce mild disease [34,35].
The first set of confirmed human cases of H5N1 influenza
was in 1997 in Hong Kong, where 18 individuals were
diagnosed with the virus [34,36,37]. Two additional
outbreaks have occurred since then. Transmission
appears to occur from direct contact with infected poultry
or their feces [34,35]. Only very rare occurrences of
person-to-person transmission have been reported [38].
The clinical course of H5N1 in humans can be aggressive with rapid deterioration. After an incubation period
of 2–8 days, patients present with a high fever and
typical influenza-like symptoms. Patients tend to
rapidly deteriorate over the next 1–2 weeks, developing
pneumonia, respiratory distress, and multiorgan failure.
Approximately 50% of the cases are fatal [34,35].
The clinical diagnosis of H5N1 influenza can be
confirmed with the detection of H5-specific RNA or
by viral isolation [39].
There is only one reported case in the literature of a
pregnant woman with avian influenza. The case occurred
in a 4-month pregnant woman in the Anhui Province of
China. The patient became ill approximately 7 days after
participating in the slaughtering and defeathering of sick
poultry that was being prepared for consumption by her
family. Five days after becoming acutely ill she presented
to the hospital with increasing fever, dyspnea, tachycardia, and tachypnea. The patient’s chest radiograph
showed diffuse bilateral infiltrates. The woman was
admitted to hospital and started on antibiotics. That
night her respiratory status deteriorated and she required
intubation with mechanical ventilation. The next day
the patient’s chest radiograph showed increased diffuse
infiltration. The patient developed disseminated intravascular coagulation along with multiorgan failure and
died 3 days after hospital admission. A definitive diagnosis of avian influenza was made by identifying H5N1
genes from tracheal aspirates using polymerase chain
reaction (PCR) and was confirmed with complete
sequencing of the viral genome [46].
Even though this is only one case, it demonstrates the
potential rapid and aggressive course of avian influenza in
pregnant patients. Pregnant women with suspected avian
influenza should be treated early and aggressively with
supportive care and oseltamivir. The possible benefits
of oseltamivir, an antiviral medication, would certainly
outweigh the fetal risks, given the high potential for
maternal mortality.
Severe acute respiratory syndrome
Severe acute respiratory syndrome (SARS) is a novel
coronavirus that first appeared as a worldwide cause of
respiratory disease in 2003 [47,48]. The virus was felt to
originate in the Guangdong Province in Southern China.
It is suspected that the novel coronavirus originated when
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Viral respiratory disease in pregnancy Longman and Johnson 123
it jumped species from the civet cat to humans. The
index case that led to the worldwide spread of the virus is
that of a 64-year-old physician from southern China
that traveled to Hong Kong and infected multiple
other individuals in his hotel, which resulted in a subsequent spread of the outbreak to Hong Kong, Vietnam,
Singapore, and Canada [49–54,55].
The clinical course of patients with SARS follows a
triphasic pattern. The first phase is characterized by
viral replication that presents with fever, myalgia, and
constitutional symptoms. These symptoms are usually
transient and resolve after a few days. Phase two, which is
characterized as the immune pathologic stage, presents
with recurrence of fever, oxygen desaturation, and radiological progression of pneumonia while the viral load falls.
Most patients usually respond to treatment by the end of
the second stage, but approximately 20% will proceed to
phase three, which is characterized by acute respiratory
distress syndrome requiring ventilator support [50,55,
56,57].
The diagnosis of SARS is initially based on clinical
presentation. Patients that are given a clinical diagnosis
of SARS are then further categorized into two groups.
The first group is made up of patients with suspected
SARS, which consists of people that present with fever,
cough, and a history of close contact with a SARS patient,
people that travel to a SARS-infected region, or people
that live in a SARS-infected region. A recently deceased
patient who died with an unexplained respiratory illness
without an autopsy and who had a history of recent
contact with a SARS patient, lived in a SARS endemic
region, or recently traveled to a SARS-infected region
should also be categorized as a suspected SARS case. The
second group of patients is categorized as probable SARS
cases. A probable case of SARS is a suspected case that
also has chest radiographic evidence of infiltrates consistent with pneumonia or respiratory distress syndrome,
positive laboratory testing, or autopsy findings consistent
with respiratory distress syndrome and no identifiable
cause [58,59]. Patients with either a suspected case or a
probable case of SARS are both treated empirically. The
distinction of suspected versus probable is only for the
use of reporting cases. The CDC [58] requires suspected
and probable cases to be reported, while the World
Health Organization [59] only requires the reporting of
probable cases.
A definitive diagnosis of SARS is made through laboratory
testing. There are three types of tests used to confirm the
diagnosis. The first is serologic testing for SARS virus
antibodies by means of enzyme-linked immunosorbent
assay or indirect fluorescent antibody testing. For the
serologic test to be positive there must be a four-fold or
greater rise in the antibody titer between the acute and
convalescent stages, or the documentation of a negative
antibody test in the acute stage followed by conversion to
a positive test in the convalescent stage. The difficulty
with serologic testing is that SARS patients can take up to
21 days to seroconvert, making it a difficult tool to use to
obtain a negative diagnosis. The second method of
testing is reverse transcriptase-PCR to identify RNA
from the SARS coronavirus. RNA must be isolated
from at least two different specimens or from the same
specimen collected on two different days of the illness.
The third method is isolation of the virus by cell culture
with reverse transcriptase-PCR confirmation [58,60].
Once a clinical diagnosis of SARS is made, patients are
treated empirically while waiting for laboratory test results
to make the definitive diagnosis. Treatment consists of
methylprednisone, ribavirin, levofloxacin, and ventilation
if the oxygen saturation drops to below 96% while on
6 l/min oxygen [61].
Only 15 cases of SARS have been reported in pregnant
patients since 2002 [51,52,62,63,64]. Even though the
case numbers of pregnant women with SARS is limited,
there appears to be a 25% mortality associated with SARS
in pregnancy [62], which is significantly higher than the
general population mortality of 9.6% [49].
Wong et al. [62] performed a multicenter observational
study of 12 pregnant women with a diagnosis of probable
SARS. All 12 patients were treated with broad-spectrum
antibiotics, ribavirin, and hydrocortisone while their
diagnosis was confirmed with antibody testing or reverse
transcriptase-PCR. Wong et al. found an overall rate of
intensive care unit admission of 50%, a rate for mechanical ventilation of 33%, and a rate for maternal death of
25%. Of the seven patients with a first-trimester pregnancy, 57% had spontaneous abortions. Of the five
women diagnosed with SARS in the second and third
trimesters, 80% had preterm deliveries and 40% had
intrauterine growth restriction. None of the newborns
showed evidence of seroconversion [62]. In another
study by Lam et al. [63] that looked at the same 12
pregnant women but in a comparison with 40 matched
nonpregnant SARS patients, the authors found that the
pregnant women had longer hospital stays along with
increased risks of renal failure, sepsis, disseminated
intravascular coagulation, intensive care unit admissions,
and death.
Not all reports in the literature show such a poor prognosis for pregnant patients with SARS. There are three
case reports of pregnant women with SARS that were
treated in North America (two in the United States and
one in Canada). The two cases in the United States were
of pregnant patients in their first and second trimesters,
while the Canadian patient was in her third trimester.
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124 Maternal-fetal medicine
The three patients were treated with broad-spectrum
antibiotics and steroids, without ribavirin. All three
women recovered and delivered healthy newborns
[51,52,64]. One of the main differences between these
cases and the series from Hong Kong was the use
of ribavirin.
The suggested treatment of pregnant women with SARS
is similar to that of their nonpregnant counterparts with
two exceptions – pregnant women should receive
clarithromycin and amoxicillin/clavulanic acid instead
of levofloxacin [61], and ribavirin should be avoided,
especially in the first trimester. Ribavirin is a known
teratogen in animals and has not been tested in humans
[65,66]. In addition, there is no proof that ribavirin
hastens the recovery from SARS [58,64].
Pregnant women with mild or controlled disease do not
require elective delivery. The suggested criteria for
early delivery are rapid maternal deterioration, failure
to maintain adequate oxygenation, multiorgan failure,
fetal compromise, and difficulty with ventilation
secondary to a gravid uterus [67].
Newborns delivered by women with either acute or
convalescent SARS do not appear to be at risk of vertical
transmission, but since antibodies to SARS have been
found in the breast milk, patients are advised against
breast feeding until more is known about transmission
[51,52,62,63,64,67,68].
Conclusion
Viral infection plays an important role in respiratory
diseases of pregnant women. The most common viral
respiratory infection in pregnant women is influenza.
All women that are pregnant or intend to become
pregnant should receive the influenza vaccine. Women
that did not receive the vaccine and develop an acute
case of influenza should be treated symptomatically,
including the use of antipyretics. Pregnant women
should only be treated with antiviral medications when
the benefits outweigh the risks. A new emerging
antigenic strain of influenza is H5N1. The virus is
usually contracted through direct contact with infected
birds. There is no commercially available vaccine at this
time to prevent H5N1 infection. Pregnant women
should be treated aggressively with supportive care
and antiviral medication, as the significant risk of
maternal mortality outweighs the potential fetal risks.
SARS is a novel coronavirus that can cause severe
respiratory disease with a significant level of mortality
in pregnant women. Pregnant women diagnosed clinically with SARS should be treated empirically, as a
serologic diagnosis can take weeks to confirm. The
treatment of pregnant women with SARS should be
without the use of ribavirin.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current World
Literature section in this issue (p. 198).
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