Abstract
Infections of the respiratory tract are a common cause of maternal morbidity. Physiological and immunological changes that occur in pregnancy may contribute to a higher incidence, morbidity and mortality than that observed in the general population. Diagnostic and management strategies for pulmonary infections are broadly similar in pregnant women as in non-pregnant women. Concerns regarding the safety of antimicrobial agents during pregnancy may modify treatment considerations.
Introduction
Infections of the respiratory tract are a common cause of maternal morbidity. Physiological and immunological changes that occur in pregnancy may contribute to a higher incidence, morbidity and mortality than that observed in the general population. Diagnostic and management strategies for pulmonary infections are broadly similar in pregnant women as in non-pregnant women. Concerns regarding the safety of antimicrobial agents during pregnancy may modify treatment considerations.
Maternal Adaptions in Pregnancy
Immune Changes in Pregnancy
The maternal immune system has to adapt to the semi-allogenic developing fetus, and maintain an appropriate immune response to pathogens whilst tolerating fetal antigens. Modulation of the maternal immune system is thought to occur by promoting the dominance of humoral immunity and suppression of cell-mediated immunity during pregnancy. Macrophages at the maternal–fetal interface release cytokines which preferentially stimulate T-helper cell type 2 (Th2) responses (thus augmenting the humoral immune response and antibody production), whilst simultaneously suppressing cytotoxic T-cells (with effects on cell mediated immunity). As the role of cell-mediated immunity and cytotoxic T-cells are particularly important in the control of intracellular pathogens, pregnancy may increase the risk of infection from intracellular pathogens, such as viruses, certain bacteria and fungi.
Physiological Changes in Pregnancy
Detailed physiological changes that occur in pregnancy are described in Chapter 4. Some of these changes contribute to an increased risk of complications in the event of respiratory infection. Specifically, increased progesterone levels increase the sensitivity of the respiratory centre to carbon dioxide and, as a consequence, there is an increase in minute ventilation which is driven by an isolated increase in tidal volumes (i.e. respiratory rate remains unchanged). This alveolar hyperventilation leads to increased renal bicarbonate excretion to preserve a physiological pH. Anaemia occurs due to an increase in blood volume unmatched by increases in the haemoglobin levels and blood oxygen concentration may be reduced, although the partial pressure of arterial oxygen may be elevated secondary to alveolar hyperventilation. In addition, there is an increase in oxygen consumption. By term, the enlarging gravid uterus causes a 4 cm elevation of the diaphragm and an increase in transverse chest diameter. This is associated with a 10–25% reduction in functional residual capacity.
These changes increase the risk of hypoxaemia in situations of apnoea or ventilation-perfusion mismatch. In addition, the immediate buffering capacity of blood in response to acidosis is reduced. Separately, increases in abdominal pressure and decreases in oesophageal sphincter tone place the pregnant woman at increased risk of aspiration and associated respiratory infection.
Incidence
The incidence of acute respiratory infections (ARIs) in healthy women of child-bearing age (16–39 years) in the UK is approximately 70 per 1000 population per year.1 Data for pregnant women are few. In a US study, nearly 50% of 4967 women reported symptoms in keeping with a respiratory tract infection during their pregnancy.2 In an Australian study of women at least 20 weeks pregnant, the commonest self-reported acute infection was an ARI (weekly prevalence 2.6%); on average 21% of women with an infection saw a healthcare professional and 65% took some type of medication to treat the infection.3
Most ARIs are upper respiratory tract infections (URTIs); these include sinusitis, pharyngitis and laryngitis. Lower respiratory tract infections (LRTIs) include pneumonia and acute bronchitis; the latter if occurring in patients with chronic lung disease (e.g. asthma) is usually considered an acute exacerbation of disease.
Upper Respiratory Tract Infections
Pharyngitis
Pharyngitis is a common respiratory infection. In the USA, it accounts for over 12 million ambulatory healthcare visits annually.4 It is not considered that pregnancy alters the susceptibility to this condition. Viruses are the commonest cause of pharyngitis in adults. Occasionally, bacteria, especially group A β-haemolytic streptococci, may be implicated (Table 6.1).5
Table 6.1 Common respiratory pathogens in pharyngitis
| Viruses |
|
| Bacteria |
|
| Fungi |
|
Clinical features of pharyngitis include sore throat, fever, pharyngeal erythema and tonsillar enlargement with an exudate. It can be difficult to distinguish between viral and bacterial pharyngitis. Features of a viral pharyngitis include rhinorrhea, cough and oral ulcers; occasionally cervical lymphadenopathy may be present.
In Group A streptocococcal pharyngitis, suppurative complications may occur; these include peritonsillar/retropharyngeal abscesses and otitis media. Rarer complications, such as pneumonia, meningitis and venous sinus thromboses, occur due to extension via local or haematogenous spread. Throat swabs for rapid antigen detection tests and culture help with diagnosing Group A streptococci disease. Antistreptococcal antibody titres are not recommended in acute pharyngitis.
Most cases of viral and bacterial pharyngitis are self-limiting. Antimicrobial therapy is not indicated in patients with viral pharyngitis. Patients with a positive Group A streptococci antigen test or culture should be commenced on antibiotic therapy; penicillin or amoxicillin is considered appropriate first-line therapy. Outcomes are not thought to differ in pregnant compared to non-pregnant patients.
Sinusitis and Rhinosinusitis
Pregnancy-induced rhinitis is a common disease, observed in nearly 40% of pregnant women.6 It is defined as nasal congestion without other signs of an upper respiratory tract infection or a recognized allergic precipitant that resolves within two weeks of delivery. Sinusitis should be excluded before making a diagnosis of pregnancy-induced rhinitis.
Treatment of pregnancy-induced rhinitis is conservative, with non-pharmacological measures: education, nasal irrigation and exercise. Decongestants may be considered in severe disease, although evidence of safety in pregnancy is limited.7 Some evidence suggests an association between pregnancy-induced rhinitis and maternal and fetal morbidity (obstructive sleep apnoea syndrome, pre-eclampsia, intrauterine growth retardation and low APGAR scores).
The common cold is frequently associated with rhinitis and pharyngitis. It is caused predominantly by respiratory viruses and is usually a mild illness that is self-limiting. Acetaminophen/paracetamol for symptom relief from fever, headache and sore throat should be considered; fever (particularly in the first trimester) can carry risks for the fetus.
Sinusitis occurs due to obstruction of the sinus ostia, usually from mucosal swelling due to an infective cause. Sinusitis rarely occurs in isolation and there is usually concomitant inflammation of the nasal mucosa i.e. rhinosinusitis (Table 6.2).
Table 6.2 Features of rhinosinusitis8,9
| Inflammation of the nose and the paranasal sinuses characterized by ALL of: |
|
The commonest pathogens implicated are respiratory viruses. Viral infections increase mucus secretion whilst reducing mucociliary clearance. This may pre-dispose to stasis. Secondary bacterial infection occurs in 0.5–2.0% of cases.10 The predominant bacterial pathogens isolated are Streptocococcus pneumoniae and Haemophilus influenzae. Also implicated are other streptococcal species (Streptococcus pyogenes, non-Group A streptococci), Staphylococcus aureus and anaerobic bacteria.
Uncommon sequelae of acute bacterial rhinosinusitis include: meningitis, peri-orbital infections, epidural and brain abscesses, cavernous and sagittal sinus thrombosis. Complication rates are higher in sinusitis involving the frontal, ethmoid or sphenoid sinus than those involving the maxillary sinus, due to anatomical positions and local extension.
Pregnant women may not present with all the usual features of rhinosinusitis, and differentiating viral from bacterial disease can be challenging. The Infectious Disease Society of America (IDSA) recommends that the presence of any of the following criteria should warrant diagnosis and treatment for bacterial rhinosinusitis:9
1. Signs or symptoms compatible with acute rhinosinusitis, lasting for ≥10 days without any evidence of clinical improvement
2. Severe symptoms or signs of high fever (≥39 °C) and purulent nasal discharge or facial pain lasting for at least three to four consecutive days at illness onset
3. ‘Double sickening’ – New onset of fever, headache or increase in nasal discharge following symptoms of a typical viral upper respiratory infection that lasted five to six days and were initially improving.
Management
Treatment is generally supportive in nature with analgesics and antipyretics. Uncomplicated acute viral rhinosinusitis typically resolves in seven to ten days. Antimicrobial therapy is recommended for those where bacterial rhinosinusitis is suspected, although there is conflicting data supporting the benefit of antibiotic therapy in disease.11 Amoxicillin or amoxicillin-clavulanic acid will target commonly implicated pathogens.
There is weak evidence to suggest that adjunctive saline nasal irrigation and intranasal corticosteroid therapy may be of some additional benefit. Individuals with typical symptoms do not need routine sinus imaging and can be managed on an empirical basis based on clinical symptoms.
For patients who fail to respond to treatment or whose clinical condition deteriorates, CT imaging of the sinuses is required to assess for the presence of structural abnormalities and complications. Sinus aspirates for culture may be necessary to identify antibiotic-resistant pathogens.
Lower Respiratory Tract Infections
Acute Bronchitis
Bronchitis is characterized by non-specific inflammation of the bronchial tree, which may be due to a variety of causes. Acute infective bronchitis is a specific clinical entity which manifests as an acute-subacute illness with a duration of up to three weeks. Cough is the cardinal symptom. It can be dry or productive (clear, mucoid, purulent). Other symptoms include sore throat, rhinorrhoea, fever, wheezing (less common in the absence of asthma) and chest pain (uncommon).
The diagnosis is made by the presence of typical clinical features, and importantly by excluding the presence of pneumonia. Whilst chest X-ray (CXR) is the reference standard for diagnosis of pneumonia, it is not considered necessary to perform CXR in every patient with an acute cough. The absence of focal chest signs or constitutional symptoms (e.g. tachycardia and fever) may be used as a surrogate to exclude pneumonia (see Pneumonia: Diagnosis; Table 6.5).12
Viruses contribute to the majority of disease, including:13
Influenza A and B viruses – they are the commonest viral pathogens implicated during winter months in temperate regions
Parainfluenza virus
Adenovirus
Respiratory syncytial virus
Rhinovirus
Coronovirus
Metapneumovirus.
In the less common cases of bacterial acute bronchitis, the most frequently implicated pathogens are Mycoplasma pneumoniae, Chlamydia pneumoniae and Bordetella pertussis. The presence of purulent sputum is common, even in viral-related acute bronchitis and does not always indicate a bacterial infection.
Treatment
Management is mainly supportive. Symptomatic treatment with cough suppressants or expectorants lack convincing data to support their use, although they are frequently tried.14 Inhaled β2 agonists are not considered effective.15 Antibiotic treatment is associated with:16
Shorter mean cough duration (mean difference (MD) –0.46 days)
Being more likely to be improved according to a clinician’s global assessment (RR 0.61; number needed to treat for an additional beneficial outcome (NNTB) 11)
Being less likely to have an abnormal lung examination (RR 0.54; NNTB 6)
Fewer days feeling ill (MD –0.64 days)
Fewer days with impaired activity (MD –0.49 days)
More adverse effects (RR 1.20; NNT for an additional harmful outcome 24).
Taken together, these data from a Cochrane review of 17 trials comprising 5099 participants suggest a limited beneficial effect from antibiotics which needs to be balanced against the potential for side effects, medicalization for a self-limiting condition and promotion of antimicrobial resistance. There have been no trials specifically in pregnant women.
Influenza
Influenza is an ARI characterized by an abrupt onset of fever and a cough which is usually non-productive in nature. Other symptoms commonly associated with influenza infection include headache, generalized myalgia, malaise, sore throat and rhinitis.
Many of these symptoms are also common in ARIs caused by non-influenza pathogens, particularly other respiratory viruses. Epidemiologically, two forms of influenza are recognized. Seasonal (or epidemic) influenza is caused by antigen-drifted influenza A and B viruses, while pandemic influenza is caused by novel antigen-shifted influenza A viruses. In temperate countries, seasonal influenza occurs fairly predictably over two to four months during winter, spreading rapidly through populations with an average reproductive number of 1.28 and an attack rate of 10–20%, depending on host factors, such as age;17 a median of 70% of influenza cases occurs during a three-month peak. In tropical regions, a distinct seasonality in influenza cases is observed in only a few countries. Instead, the distribution of influenza cases is flatter, seasonal influenza activity lasts longer (up to 10 months in Kenya between 2010–2014) and the peaks of influenza A and B infections coincide less frequently than in temperate regions.18 Taking these epidemiological features into consideration is important when making a clinical diagnosis of influenza infection. In one US study, influenza infection among pregnant women caused more severe symptoms compared to non-influenza ARIs, including more feverishness and fever >38.9 °C, myalgia, cough and chill. In addition, influenza was more likely to lead patients to seek medical care within two days of illness onset compared to other ARIs (53% vs 35%).19
Whether pregnant women are more likely to acquire influenza infection compared to non-pregnant women is difficult to ascertain due to a scarcity of reliable data. A systematic review to assess the incidence of laboratory-confirmed influenza illness among pregnant women found a wide range;20 0.10 to 6.6 cases of symptomatic influenza per 10 000 pregnancies during the 2009 H1N1 pandemic compared with 371 cases of seasonal influenza per 10 000 pregnancies among HIV-uninfected women in South Africa.
Uncomplicated influenza is usually a self-limiting illness with alleviation of most major symptoms occurring in about five days. Cough and malaise may take longer to resolve completely. Complications from influenza include exacerbations of chronic underlying diseases such as asthma, or secondary bacterial pneumonia. The commonest secondary bacterial pathogens implicated are Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae.21
Historically, influenza in pregnant women has been considered to cause a more severe disease compared to non-pregnant women. During the 1918 pandemic, maternal mortality was 30%, rising to 50% when complicated by pneumonia. Data from the H1N1 pandemic in the USA demonstrated that pregnant women accounted for 5% of reported deaths from pandemic influenza, whilst accounting for only 1% of the total population; mortality was highest for patients in the third trimester.22 A systematic review and meta-analysis of observational studies (up till 2014) that reported on pregnancy as a risk factor for severe outcomes from influenza found that:23
Influenza infection in pregnant women was significantly more likely to be associated with increased risk for hospitalization compared to non-pregnant women (OR 2.44, 95% CI 1.22–4.87)
There was no significant difference in all-cause mortality (OR 1.04, 95% CI 0.81–1.33)
There was no significant difference in ICU admission related to influenza (OR 0.85, 96% CI 0.62–1.17).
A lower threshold for hospitalization of pregnant women may explain these results. Ecological studies describe a higher risk of death and ICU admission in pregnancy-associated influenza, but may be subject to greater biases.
Treatment
Matrix 2 ion channel inhibitors (amantadine and rimantadine) are licensed in the EU and the USA for the treatment of influenza. However, all prevailing seasonal influenza viruses are resistant to these agents, limiting their use.
Neuraminidase inhibitors (NIs) are the current agents of choice. During the 2009 H1N1 pandemic, despite limited data on safety in pregnancy at the time, both oral oseltamivir and inhaled zanamivir were recommended for the treatment of influenza and as post-exposure prophylaxis. Various studies since then, including a large population-based European registry study involving over 5800 pregnant women exposed to NIs, have found no increased risks of adverse neonatal outcomes or congenital malformations associated with NI exposure during embryo-fetal life.24 In the USA, oseltamivir and zanamivir are ‘Pregnancy Category C’ medications, indicating that no clinical studies have been conducted to assess the safety of these medications for pregnant women.
The effectiveness of NIs in the treatment of influenza is a subject of ongoing debate. In uncomplicated influenza, NIs started within 48 hours of illness onset reduce the duration of symptoms by several hours; evidence base from RCTs and meta-analyses.25 Evidence for a reduction in severe outcomes, such as pneumonia, ICU admission or death, is less certain, being based mainly on observational data.26
Until stronger (clinical trial) evidence emerges, in the setting of severe infection, limited treatment options and reasonable safety profiles, oseltamivir and zanamivir remain valid treatment options to consider.27 The US Centers for Disease Control and Prevention (CDC) recommends that for treatment of pregnant women or women who are up to two weeks post-partum with suspected or confirmed influenza, oral oseltamivir is currently preferred (2016–2017 season).28 Data on the safety in pregnancy of newer NIs, such as intravenous peramivir and inhaled laninamivir, are limited.
Prevention
In 2012, the World Health Organization (WHO) recommended for the first time that pregnant women be prioritized, over other high-risk groups, for influenza vaccination in countries initiating or expanding influenza immunization programmes.29 There is strong evidence from randomized controlled trials (RCTs) that maternal immunization prevents influenza infection in pregnant women (vaccine effectiveness (VE) 31–70%) and their infants up to 6 months of age (VE 30–63%).30 There are no good data on prevention of severe outcomes from influenza.30
The available evidence on maternal immunization in relation to adverse birth outcomes raises no safety concerns; no studies suggest an increased risk of adverse birth outcomes following maternal immunization. Studies generally report either no association or significant risk reduction for pre-term birth (14–37%) and late fetal death (34–56%), though methodological issues caution confidence in these results.31
In the USA during the 2016–2017 influenza season, vaccine uptake was about 54%, similar to the previous four years. Women who received both a provider recommendation for, and offer of, influenza vaccination were more likely to be vaccinated (70.5%) compared to women who received a provider recommendation but no offer (43.7%) and women who received no recommendation for vaccination (14.8%).32
The role of post-exposure antiviral prophylaxis for pregnant women who have been in close contact with someone with influenza is less certain. The US CDC advises that post-exposure prophylaxis with NIs can be considered for pregnant women and women who are up to two weeks post-partum. Zanamivir may be preferable to oseltamivir due to its limited systemic absorption. However, potential adverse effects related to its inhaled route of administration need to be considered. The duration of post-exposure prophylaxis is seven days after the last known exposure.
Table 6.3 summarizes the recommended treatment doses for commonly used neuraminidase inhibitors.
Table 6.3 Antiviral medication: doses and adverse effects
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