Respiratory disease in [614112]

Respiratory disease in
pregnancy
Himabindu Annamraju
Katherine Robertson
Lucy Mackillop
Abstract
Physiological changes to the respiratory system in pregnancy make
breathlessness a common symptom. However, it is still important toinvestigate symptoms of breathlessness to exclude pathologicalcauses. This review illustrates some unusual cases of women present-ing with breathlessness in pregnancy. Prompt recognition, investiga-tion and management of these women is essential as delays canimpact the mother and the neonate. Investigations should be used
appropriately and not withheld or delayed due to pregnancy. Effects
of respiratory conditions on pregnancy and the neonate are alsodiscussed.
Keywords breathlessness; dyspnoea of pregnancy; lung cancer;
myasthenia gravis; non-small cell adenocarcinoma; physiology of
respiratory system
Introduction
Breathlessness is a common symptom in pregnancy. This may be
due to the physiological changes in pregnancy, but may also besecondary to a pre-existing or a new medical condition.
In this review, we present several interesting cases of
breathlessness with rare diagnoses that the clinician should bealert to and their management.
Case 1
A 41-year-old lady of African descent presented to her localhospital with breathlessness, weight loss and abdominal pain at30 weeks’ gestation. She reported worsening breathlessness onmild to moderate exertion.
This was her third pregnancy and she booked late, attending
her first antenatal appointment at 23 weeks. Her BMI was raised.She had two episodes of breathlessness during the pregnancy -one at 25 weeks’ gestation, when she was treated with antibiotics
for a lower respiratory tract infection, and another self-limitingepisode of breathlessness at 28 weeks. She had no medical his-tory of note, other than gestational diabetes managed ondiet alone. Her only medications were prophylactic dalteparin(she was assessed as per RCOG guidelines to be at high risk forvenous thromboembolic disease in pregnancy due to age, parityand high BMI), and Aspirin 75 mg (as per NICE hypertension inpregnancy guidelines; due to her age and BMI being risk factors
for pre-eclampsia). She was a non-smoker.
On examination she was tachypnoeic with a respiratory rate
of 22/min, had oxygen saturation 96% on room air, pulse ratewas 84 beats per minute and blood pressure 125/80 mmHg. Ongeneral examination she was breathless and found it difficult tospeak in full sentences. Examination of the cardiovascular sys-tem and abdomen was unremarkable. Respiratory system ex-amination revealed reduced air entry bilaterally. Fetal monitoringwas normal. Investigations showed haemoglobin of 111 g/l,ferritin of 20 mg/l, normal B12, folate, renal function and normalliver function tests. Her ECG, chest X-ray, VQ (ventilation
perfusion) scan and echocardiogram were all normal. ANCA and
ANA were negative, complement levels were normal and viralscreen for HIV was also negative. Urine dipstick showed no ab-normalities. Her arterial blood gas is shown in Table 1 .
The high PaCO
2level was clearly concerning and her case was
discussed with the respiratory physicians. It was noted that 9months prior to presentation she had a high resolution CT chestwhich showed bilateral basal atelectasis/consolidation. Theimpression was that she was in compensated type 2 respiratoryfailure. In the context of hypoventilation as evidenced by higherPaCO
2,n o r m a lP a O 2and normal alveolar-arterial gradient, a
neurological cause was suspected by the respiratory physicians. The
patient was transferred to a tertiary centre with worsening type 2respiratory failure. Her lung function tests revealed a severerestrictivepattern. On further questioningshe disclosed weakness inarms and legs, difficulty in chewing and swallowing resulting in aweight loss of over 20 kg in 12 months. She had no visual symptoms,but she felt that ‘my neck does not support my head properly’. Aclinical diagnosis of myasthenia gravis (MG) was made.
She was commenced on non-invasive ventilation (NIV). She
was empirically started on Pyridostigmine and intravenous im-munoglobulins (IVIg). Steroids were considered but not given,
due to the potential worsening effects on MG in the acute setting.
Subsequently she tested positive for Anti-MuSK antibodies,which confirmed the diagnosis of myasthenia gravis. Sheresponded well to IVIg and showed improvements in herArterial blood gas readings
Arterial blood gas Patient value Normal reference ranges
pH 7.41 7.35 e7.45
PaO 2 11.0 kPa 10 e14 kPa
PaCO 2 7.0 kPa 4.5 e6k P a
HCO 3 33 mmol/L 22 e26 mmol/L
1k P a¼7.5 mmHg p stands for the ‘partial pressure of .’
Table 1
Himabindu Annamraju MRCOG is a Consultant Obstetrician and
Gynaecologist at Buckinghamshire Healthcare NHS Trust, Aylesbury,UK. Con flicts of interest: none declared.
Katherine Robertson
MRCOG is a Senior Specialty Trainee in
Obstetrics and Gynaecology in Health Education Thames Valley
(HETV), UK. Con flicts of interest: none declared.
Lucy Mackillop FRCP is a Consultant in Obstetric Medicine and
Honorary Senior Clinical Lecturer at Oxford University Hospitals NHSFoundation Trust, Oxford, UK. Con flicts of interest: Lucy Mackillop is
supported by the National Institute for Health Research (NIHR)
Oxford Biomedical Research Centre (BRC). Lucy Mackillop is
employed part-time by Sensyne Health plc.CASE-BASED LEARNING
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:5 152 Crown Copyright /C2112020 Published by Elsevier Ltd. All rights reserved.

spirometry, pCO 2and HCO 3. Her lung functions remained stable
and she continued the pregnancy to 35 ț5 weeks. She was
delivered by a caesarean section, due to a history of previousclassical caesarean section, and the baby did well. Postnatallyshe continued NIV in the short term and a course of prednisolonewas commenced. She subsequently recovered and was dis-charged home with a follow up plan.
Myasthenia Gravis
Myasthenia gravis (MG) is an autoimmune disorder of the ner-vous system, that causes fatigability and fluctuating weakness ofthe skeletal muscles. The main pathophysiology of MG is theproduction of antibodies against the acetylcholine receptors
(AChRs) on the postsynaptic membrane of the neuromuscular
junction (NMJ). Serologically, AChR antibodies (Abs) are foundin about 85% of patients with generalized MG. Antibodies tomuscle-specific tyrosine kinase (MuSK) are found in 35 e50%
patients who are negative for AChR Abs.
MG and pregnancy: women with MG considering pregnancy
should be referred to pre-pregnancy counselling, so that their
condition is stabilized and any teratogenic drugs are changed to
more appropriate ones. The pregnancy should be cared for by amulti-disciplinary team including a neurologist, an obstetricianwith special interest in maternal medicine and/or an obstetricphysician, specialist midwives, and an obstetric anaesthetist.Thyroid function should be tested early in the pregnancy. Maternalmonitoring of fetal movements should be encouraged and if thereare any concerns additional scans should be organized. Womenwith stable MG can be reassured that it is unlikely to worsen inpregnancy and it is unlikely to affect timing or mode of birth.
Drugs such as methotrexate and MMF (mycophenolate mofetil)
are not recommended during pregnancy. Azathioprine, ciclo-
sporin and pyridostigmine can be used in pregnancy, when ben-efits outweigh risks. Steroids can be used for rapid improvement ofMG. However, it is important to note that high dose steroids cantemporarily exacerbate MG in some patients. Magnesium sulphateis contraindicated in MG as it can precipitate myasthenia crisis.
The plan for delivery should involve the multidisciplinary
team including a neonatologist, and delivery should be in a unitwith neonatal intensive care facilities. In women with wellcontrolled MG vaginal delivery with spontaneous onset of labourshould be the aim. Caesarean section should be performed for
obstetric indications only.
Transient neonatal myasthenia gravis (TNMG) is a recognised
complication of maternal MG in around 12 e20% babies. It
happens when antibodies common in myasthenia gravis crossthe placenta to the fetus. Onset of TNMG may be delayed up toseveral hours or days and manifests as weakness, poor suck andbreathing problems. Hence inpatient observation is recom-mended for at least 48 h. The condition is usually temporarylasting only a few weeks and treatment is usually supportive.
Breastfeeding is not contraindicated with MG medications.
Women should seek advice for any symptoms of deterioration
and should have routine follow up.
Case 2
A 30-year-old woman presented at 32 weeks’ gestation to her
local hospital with breathlessness, nausea, diarrhoea, itchyhands, headache and blurred vision. She was assessed as low
risk at booking with normal dating and anomaly scans. Her onlypast medical history was asthma for which she used salbutamolinhalers as required. She was a lifelong non-smoker.
On admission, her observations were normal with a pulse rate
of 88 beats per minute, blood pressure of 129/70 mmHg and
oxygen saturation of 97% on room air. The fetal monitoring wassatisfactory. The cardiovascular, abdominal and neurologicalexaminations were unremarkable. Respiratory examinationrevealed bilateral basal crepitations. ECG showed a sinusrhythm. Arterial blood gas showed marked hypoxia with a PaO
2
of 9.5 kPa (normal reference range: 10 e14 kPa). Haemoglobin
was 113 g/L (normal reference range: 110 e138 g/L) and CRP 37
mg/L (normal reference range: <3 mg/L). The urinalysis showed
no abnormalities.
Chest X-ray ( Figure 1 ) showed increased air space opacities in
both lungs, more marked on the left than the right. She then had
a CTPA which showed widespread inflammatory nodulesconsistent with metastatic malignancy of an unknown primary.She was transferred to a tertiary centre, where she had an ul-trasound guided lymph node biopsy. She was commenced onsupportive therapy with oxygen, but ventilatory functioncontinued to worsen. Repeat chest X-ray ( Figure 2 ) showed left
sided pleural effusion with left lower lobe collapse. She hadtherapeutic pleural aspiration of 700mls, patient controlledanalgesia and steroids for fetal lung maturation. Further in-vestigations ruled out metastasis in the spine and a showed a
small pericardial effusion on an echocardiogram without hae-
modynamic significance. Fetal growth scan was normal.
She was delivered by a caesarean section at 34 weeks due to
worsening respiratory function, and the baby was admitted tospecial care baby unit.
Biopsy from the lymph node confirmed non-small cell lung
adenocarcinoma. She was subsequently discharged with homeoxygen and a plan to commence chemotherapy once thecaesarean incision had healed.
Lung cancer in pregnancy
Lung cancer in pregnancy is rare. Risk factors for lung cancer inpregnancy are similar to the non-pregnant population including
smoking, asbestos, radon, family history and dietary factors.Practice Points: Myasthenia Gravis
CMG is an autoimmune neurological condition.
COptimization of the condition and drugs pre-pregnancy is crucial,
as stable MG is unlikely to worsen in pregnancy.
CMultidisciplinary care for the pregnancy in a tertiary centre isessential.
CMode of birth should be decided based on obstetric indications.
CMagnesium sulphate is contraindicated in MG.
CHigh dose steroids can temporarily exacerbate MG and should beused with caution.
CBreastfeeding is not contraindicated with MG drugs.
CTransient Neonatal Myasthenia Gravis is a recognized conditionand the neonate needs inpatient observation for 48 h.CASE-BASED LEARNING
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The most common histological subtype of lung cancer diag-
nosed in pregnancy is non-small cell lung cancer (NSCLC) ofadenocarcinoma type accounting for 80% cases. One study re-ported that up to 5% of women of reproductive age diagnosedwith NSCLC were diagnosed during pregnancy. Most of thesecases are diagnosed with a locally advanced or metastaticdisease.
Cancers in pregnancy occur in 1 in 1000 pregnancies and may
present with lung metastases. Invasion of the placenta or fetus is
a rare complication in pregnant women with cancer. Most in-stances of mother to child transmission of metastatic diseaserelate to melanoma, leukaemia or lymphoma, and lung cancerhas also recently been recognized as one of the tumours with ahigher risk.Diagnosis may be delayed in pregnancy due to low clinical
suspicion and is more likely to be advanced stage cancer atdiagnosis, resulting in a poorer prognosis. After a diagnosis oflung cancer or lung metastases in pregnancy, multidisciplinarymanagement is essential, involving surgeons, oncologists, ob-stetricians and neonatologists. Consideration should be given tothe gestational age, maternal prognosis, fetal toxicity of treat-ments, and also the impact of delayed treatment on maternalprognosis and the risk of neoplastic cells being transmitted to thefetus.
Psychological support is vital and patients may opt to termi-
nate the pregnancy, particularly if diagnosed at an early gesta-
tion. Chemotherapy can be given from 12 weeks’ gestation whenthe risks of fetal malformations is lower. Pregnancy outcomeshave been reported as generally good but there is an increasedrisk of fetal growth restriction and preterm birth. Term deliveryshould be the aim and if chemotherapy is ongoing, deliveryshould ideally be planned at least three weeks after the last cycleto avoid drug accumulation in the neonate, and to avoid prob-lems associated with haematopoietic suppression around thetime of delivery and in the neonate. Breastfeeding duringchemotherapy is contraindicated due to excretion in breast milk.
Thomboembolism is a serious and frequent complication in
malignancy associated with mortality. Systematic assessment ofthe risk of thromboembolism for these patients should be donebased on RCOG guidelines and appropriate prophylaxis shouldbe used.
Case 3
A 22-year-old lady presented to her local hospital with recurrentpostpartum pyrexia after the birth of her first child. Antenatally,her pregnancy was uncomplicated. Serial ultrasound scans forlow PAPP-A at booking showed normal fetal growth. She wastreated with oral iron for mild antenatal anaemia but had noantenatal respiratory symptoms. She was induced at 37 weeks’gestation for prolonged rupture of membranes and developedintrapartum sepsis with pyrexia and maternal tachycardia whichwas treated with intravenous cefuroxime and metronidazole forpresumed chorioamnionitis. She had an emergency caesareansection at 4 cm for failure to progress and suspected fetal
compromise with an estimated blood loss of 550 ml.
Postnatally, she remained significantly tachycardic with pulse
rate of 120 bpm. Initially this was attributed to ongoing sepsisand postnatal anaemia with Hb of 88 but her WCC and CRP werenoted to be rising on day 5 postnatally. She reported a new onsetof throat soreness but no other respiratory symptoms and after
Figure 1 Chest X-ray showing air space opacities in both lungs, more
marked on the left than the right.
Figure 2 Left sided moderate pleural effusion. Ongoing left lower lobe
collapse/consolidation with volume loss in the left hemithorax. Bilateral
lung nodules grossly unchanged from previous. The right pleuralspace remains clear. Dilated bowel loops in the left upper quadrant.Practice points: Lung carcinoma
CImaging and further investigations should not be delayed if ma-
lignancy is suspected in pregnancy.
CThe timing of delivery should be individualized.
CThe placenta should be sent for histology after delivery to exclude
metastatic disease.
CThromboprophylaxis is essential for women with malignancy inpregnancy.CASE-BASED LEARNING
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discussion with microbiology, her antibiotic regimen was
changed to tazocin. Blood cultures and throat swabs showed nosignificant growth. She became pyrexial on day 7 with a tem-perature of 39C. A further septic screen was performed, includingrepeat blood cultures, sputum cultures, chest X-ray, low vaginalswabs, urinanalysis and EBV serology. An ultrasound scan of theabdomen showed a small anechoic collection that was notthought to be clinically significant. She was discharged home on
oral coamoxiclav on day 9 postnatally having been afebrile for
more than 48 h.
She represented on day 15 postnatally with ongoing symp-
toms of pyrexia and feeling generally unwell. Her recent chest X-ray was noted to be significant abnormal with widespread patchyconsolidation and perihilar cavitation suggestive of possiblemilitary tuberculosis ( Figure 3 ).
Further investigations were done including urinary Legionella
antigen, urinary pneumococcal antigen and three sputum cul-tures for mycobacteria 24 h apart. The sputum samples wereshown to be smear positive for acid fast bacilli and a diagnosis of
smear positive pulmonary tuberculosis was made. She was
reviewed by the respiratory team and commenced on rifampicinand ethambutol. She retrospectively reported symptoms of coughand weight loss over the preceding six months. She underwenthospital and home isolation for 14 days and Public Health noti-fication was done. Postnatally she tolerated medication well butwas advised not to fly until the chest X-ray abnormalities hadresolved.
Tuberculosis and pregnancy
Tuberculosis (TB) in pregnancy and postnatal period should beconsidered in women with non-resolving pneumonias. Bloodtests to ascertain normal live rf u n c t i o np r i o rt oc o m m e n c i n g
treatment is important while liaison with respiratory physi-
cians and the TB team is crucial. First line recommendedtreatment is two months of Isoniazid, Rifampicin and Etham-butol, followed by seven months of Isoniazid and Rifampicin.Streptomycin should be avoided due to risk of ototoxicity to thefetus.The first-line anti-tuberculous drugs associated with hepato-
toxicity are isoniazid, rifampicin and pyrazinamide. Rifampicinmay be associated with elevated alkaline phosphatase and serumbilirubin, while isoniazid and pyrazinamide may be associatedwith elevated serum transaminase. Elevated serum transaminaseand bile salts in pregnancy can also be associated with obstetriccholestasis. Hence discussions between the obstetricians and therespiratory team are essential to ensure appropriate treatment toboth conditions while preventing hepatic injury.
The decision for chemoprophylaxis for the neonate depends
on several factors such as history of duration and detection of
maternal TB, type of TB and compliance with treatment. For a
new maternal diagnosis of TB in the postnatal period, theneonate would need chemoprophylaxis with Isoniazid. Theduration of treatment is guided by Mantoux test or interferon-gamma release assay and symptoms of active TB. The neonatewould also need referral to a TB specialist.
A
FURTHER READING
Mitrou S, Petrakis D, Fotopoulos G, Zarkavelis G, Pavlidis N. Lung
cancer during pregnancy: a narrative review. J Adv Res 2016; 7:
571e4.https://doi.org/10.1016/j.jare.2015.12.004 .
Norwood F, Dhanjal M, Hill M, et al. Myasthenia in pregnancy: best
practice guidelines from a UK multispecialty working group.J Neurol Neurosurg Psychiatr 2014; 85:538e43.https://doi.org/10.
1136/jnnp-2013-305572 .
Santos E, Braga A, Gabriel D, et al. MuSK myasthenia gravis and
pregnancy. Neuromuscul Disord 2018; 28:150e3.https://doi.org/
10.1016/j.nmd.2017.11.014 .
Sieb JP. Myasthenia gravis: an update for the clinician. Clin Exp
Immunol 2014; 175: 408e18.https://doi.org/10.1111/cei.12217 .
Acknowledgements
The authors acknowledge the previous contributions to this review
of:
Lauren Green MRCOG is a subspecialty trainee in Maternal fetal
medicine at Oxford University hospitals NHS Trust.
Samantha Chessell is a specialty trainee (ST2) in Obstetrics and
Gynaecology in HETV.
Charlie Frise MRCP is an Obstetric Physician at the Oxford Uni-
versity Hospitals NHS Trust.
Figure 3 Chest X-ray showing widespread patchy consolidation and
perihilar cavitation.
Practice points: Tuberculosis in pregnancy
CActive TB in pregnancy and postnatal period should be investi-
gated and treated as in a non-pregnant adult. Streptomycin
should be avoided due to risk of ototoxicity to the fetus.
CFirst line anti-tuberculous treatment can cause hepatotoxicity,
which can be confused with Obstetric Cholestasis.
CClose liaison between the obstetricians, the respiratory physiciansand TB nurses is vital.CASE-BASED LEARNING
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 30:5 155 Crown Copyright /C2112020 Published by Elsevier Ltd. All rights reserved.