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Clinmed 17 3 251
The prevalence of medical problems in pregnancy is increasing Intensive Care National Audit and Research Centre (ICNARC)
ABSTRACT
because of a complex interplay between demographic and show that the admission rate to critical care during the period
lifestyle factors, and developments in modern medicine. 2009–12 was 290 per 100,000 maternities, compared to a
Maternal mortality and morbidity resulting from treatable maternal mortality rate of less than 11 per 100,000 over the
medical conditions, such as venous thromboembolism, epilepsy same period.1
and autoimmune disease, have not decreased in recent years. Maternal deaths can be classified as direct (‘obstetric’) or
This is despite a marked decrease in overall maternal mortality. indirect (‘medical’) (Box 1). As Fig 2 illustrates, there has
It is vital that all physicians acquire a basic knowledge and been a worrying increase in the rate of indirect deaths over
understanding of medical problems in pregnancy. This includes the last 25 years and while this has plateaued, direct death
prepregnancy measures such as counselling and optimisation rates continue to fall. Medical conditions now dominate the
of medical therapy, as well as multidisciplinary management list of leading causes of maternal death (Fig 3). Therefore,
throughout pregnancy and the postpartum period. Prompt it is vital that all physicians acquire a basic knowledge and
recognition and treatment of acute and chronic illness is understanding of medical problems in pregnancy.
of clear benefit, and most drugs and many radiological The approach to managing medical problems in pregnancy
investigations may be used in pregnancy. is summarised in Fig 4. The process should begin before
conception, and all physicians should consider delivering
KEYWORDS: Biologics, maternal mortality, obstetric medicine, prepregnancy counselling as part of their routine inpatient or
pregnancy outpatient consultations with women of reproductive age. The
MBRRACE reports call for action to ‘ensure that physicians are
appropriately trained in… the care of pregnant women, and
Introduction that services are designed for women with medical conditions…
including pre-pregnancy, during pregnancy and delivery, and
The prevalence of medical problems in pregnancy is increasing
postpartum’. This is clearly a very broad subject, and this article
because of a complex interplay between demographic and
aims to provide a snapshot. We discuss a few of the important
lifestyle factors, and developments in modern medicine.
causes of maternal mortality, as well as some common medical
Women are delaying childbearing until later in life. Older
causes of morbidity that present particular diagnostic and
women are more likely to have acquired medical disorders,
therapeutic challenges in pregnancy.
such as hypertension and obesity; they are also at higher risk
of gestational diabetes and venous thromboembolism. Medical
and surgical advances have enabled women to become pregnant Box 1. Definitions of maternal deaths (World Health
despite having chronic conditions that would previously have
Organization 2010).
precluded pregnancy. However, this is not without risk – the
MBRRACE (Confidential Enquiries into Maternal Deaths and Maternal death: Death of a woman while pregnant or within
Morbidity) report1 revealed that two-thirds of maternal deaths 42 days of the end of the pregnancy (the puerperium) from
in 2011–13 were in women with known medical comorbidities any cause related to or aggravated by the pregnancy or its
and 30% of mothers that died were obese (Fig 1). Additionally, management, but not from accidental or incidental causes.
for every maternal death, there are many others that suffer Direct: Deaths resulting from obstetric complications of the
severe morbidity during or soon after pregnancy. Data from the pregnant state (pregnancy, labour and puerperium), from
interventions, omissions, incorrect treatment or from a chain of
events resulting from any of the above. Examples include genital
tract sepsis, hypertensive disorders of pregnancy and thrombosis.
Authors: Aclinical fellow in obstetric medicine and specialty Indirect: Deaths resulting from previous existing disease, or
registrar in acute medicine and general internal medicine, Women’s disease that developed during pregnancy and which was not
Health Academic Centre, Guy’s and St Thomas’ Foundation Trust, the result of direct obstetric causes, but which was aggravated
London, UK; Bconsultant obstetric physician and professor of by the physiological effects of pregnancy. Examples include
obstetric medicine, Women’s Health Academic Centre, Guy’s and St cardiovascular disease, neurological disorders, non-genital
Thomas’ Foundation Trust, London, UK infections and psychiatric causes.
No medical
Obese 30%
comorbidity Normal
34% weight
Medical 48%
comorbidies
66%
Venous thromboembolism the left iliac vein by the right iliac artery and ovarian artery.
Venous thromboembolism (VTE) is the leading direct cause 85% of deep vein thrombosis in pregnancy are on the left side
of maternal death in the UK and the trend of falling mortality and 70% are ilio-femoral (which are more prone to lead to
rates from 2002 to 2008 has reversed in recent years. pulmonary embolism).3
The relative risk of VTE in pregnancy is increased four- to A thorough history and examination is important when
sixfold compared with the general population. This risk assessing for acute pulmonary embolism (PE) because the
increases with gestational age, reaching a maximum just differential diagnosis includes cardiac disease and aortic
after delivery. Caesarean section further increases this risk, dissection. A chest X-ray (CXR) should always be performed first
particularly if this is performed as an emergency.1 Certain (negligible radiation risk) as pneumonia and pneumothorax can
women are, because of medical or obstetric factors, at present similarly. If PE is still suspected, then a nuclear medicine
particularly high risk and therefore require antenatal and/or perfusion (VQ) scan or computerised tomography pulmonary
postpartum thromboprophylaxis with low molecular weight angiogram (CTPA) should be performed. Investigation should
heparin (LMWH). LMWH is safe and effective in pregnancy not be withheld simply because the patient is pregnant. The
and recent guidelines from the Royal College of Obstetricians maternal and perinatal risks of missing a diagnosis of VTE
and Gynaecologists (RCOG) provide a detailed approach to risk are thought to be greater than the risks associated with the
stratification.2 investigations; the risks to the fetus are small with either
As well as preventative measures, it is also important to imaging modality. Compared with CTPA, VQ may carry a very
promptly recognise and treat acute VTE in pregnancy. Venous slightly increased risk of childhood cancer (1/280,000 versus
stasis is more marked in the left leg because of compression of less than 1/1,000,000).4 However, CTPA is associated with a
16
14
Direct and indirect deaths
Mortality per 100,000 maternies
12
10
Indirect deaths
8
6
Fig 2. Direct and indirect maternal
mortality rates per 100,000 4 Direct deaths
maternities in the UK, 1985–2013
(preliminary data 2011–13).
Deaths from indirect causes have 2
risen and plateaued in recent years.
In contrast, deaths from direct causes 0
are falling. Adapted from the 2015 1985–87 1988–90 1991–93 1994–96 1994–99 2000–2 2003–5 2006–8 2009–11 2011–13
MBRRACE report.1 Triennium
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in reproductive hormonal fluctuation. However, around 10% small and the fetal exposure is negligible. However, magnetic
experience a worsening of symptoms and migraine may present resonance venogram is the preferred imaging modality to
de novo in pregnancy.11 detect cerebral venous thrombosis.
If clinical assessment supports a diagnosis of migraine or Reversible cerebral vasoconstriction syndrome is a recently
tension headache, then no further investigations are required. recognised disorder of cerebrovascular tone, which can cause
Lifestyle measures and simple analgesia are the first-line severe sudden onset headache and atypical subarachnoid
treatments. Patients should be advised to get adequate sleep haemorrhage in the postpartum period.14 It may be associated
and to avoid dietary triggers and dehydration. Paracetamol with hypertension. Diagnosis is on MRI angiography (with a
is acceptable for use in pregnancy and ibuprofen can be characteristic appearance of vascular beading) and treatment is
prescribed for short-term use in the first and second trimesters. with nimodipine. It usually resolves within 3 months.
Opiates are not harmful to the fetus but should be used
sparingly because of their side-effect profile and tendency
Inflammatory and autoimmune conditions
to cause rebound headaches. Metoclopramide, cyclizine or
prochlorperazine can be added to treat nausea and vomiting. Systemic inflammatory diseases, such as systemic lupus
There are increasing safety data on triptans to treat migraine erythromatosis, rheumatoid arthritis and inflammatory bowel
in pregnancy.12,13 Sumatriptan exposure has not been disease, are relatively common in women of childbearing age.
associated with fetal malformations or adverse outcomes and, The approach shown in Fig 4 is particularly relevant for women
if other treatments have failed, it may be used to treat acute with these conditions.
migraine attacks. Good disease control is of obvious benefit to the mother but
If attacks are frequent, then prophylactic medication it also reduces adverse fetal and neonatal outcomes as well as
should be considered. Low-dose aspirin is the first-line agent. improving fertility.15 A 2013 meta-analysis showed that women
β-blockers (eg propranolol) can be added and, if this is not who conceive with active inflammatory bowel disease have a
effective, then a tricyclic antidepressant (eg amitryptilline) can higher rate of active disease during pregnancy (46–55%) than
be used as a third-line option. those who conceive while in remission (23–29%).16 Similarly,
It is important to consider secondary causes in the differential systemic lupus erythromatosis flares during pregnancy are
diagnosis of headache, which may require urgent investigation. more common in those with active disease at conception.17
Pre-eclampsia may present with headache and meningitis A major source of uncertainty for patients and healthcare
presents as headache with fever and neck stiffness. Pregnancy professionals relates to the safe use of medications during
significantly increases the risk of subarachnoid haemorrhage pregnancy. Very few drugs are licensed for use in pregnancy,
and cerebral venous thrombosis. The risk is highest in the so safety information is often derived from animal studies,
puerperium (first 6 weeks post-delivery). case series, registry data and extrapolation from non-pregnant
Urgent imaging should be performed in patients who subjects. The US Food and Drug Administration recently
present with severe thunderclap headache, features of raised discontinued the traditional pregnancy categories A, B, C, D
intracranial pressure, neurological deficits or seizures. CT brain and X as they were often misinterpreted and misused. There is
is safe in pregnancy, readily available and indeed superior to growing evidence of drug safety in pregnancy and it is vital to
MRI in detecting acute haemorrhage. The radiation dose is avoid cessation of important medications because of theoretical
or unwarranted concerns. It is also important to note that there gestational age.22 A prospective study is currently underway to
is a background incidence of major congenital malformations further evaluate this.
(2–3%), miscarriage (10–20%) and stillbirths (0.5%).18 This is The calcineurin inhibitors ciclosporin and tacrolimus are
irrespective of any drug exposure. This section aims to provide also safe for use in pregnancy. However, drug levels should be
an update on the pharmacological treatment of inflammatory monitored closely as drug metabolism and clearance may vary
disorders in pregnancy. during and after pregnancy. Maternal blood pressure, blood
glucose and renal function should also be checked regularly.
Corticosteroids The drugs that should be avoided in pregnancy are
methotrexate, mycophenolate mofetil, leflunomide and
Prednisolone and methylprednisolone are extensively cyclophosphamide. Adequate contraception is imperative.
metabolised by the placenta and less than 10% reaches the fetus. These drugs should be stopped prior to conception and changed
Several large studies have not found any significant adverse to an alternative medication. It is important to address this
effect (major malformations, prematurity, low birthweight) in prepregnancy counselling and to aim for optimal disease
attributable to these drugs19 although there is an increased control on the new drug prior to conception. In exceptional
maternal risk of gestational hypertension and diabetes. circumstances, cyclophosphamide may be used in the second
Prednisolone should be used in preference to fluorinated and third trimesters for conditions such as breast cancer and
steroids, such as dexamethasone, as the latter cross the placenta rapidly progressive interstitial lung disease.23
to a greater degree.
Corticosteroids play a key role in the treatment of disease Biologics
flares in patients with rheumatological conditions or
inflammatory bowel disease as well as acute asthma. They ‘Biologic’ anti-TNFα drugs, such as infliximab, adalimumab
should be used at any stage of pregnancy if clinically indicated. and etanercept, have revolutionised the treatment of systemic
There is evidence that physicians under prescribe systemic inflammatory disorders. All three can be safely used in early
steroids when managing pregnant patients with asthma, pregnancy; they do not cross the placenta until after 16 weeks of
resulting in worse outcomes for these women;20 it is important gestation. There are no significant associations with a particular
to avoid this error when managing pregnant patients with any pattern of congenital malformations or adverse pregnancy
condition requiring steroid treatment. outcomes. Beyond 16 weeks, decisions about continuation
are individualised based on the drug clearance rate, degree of
placental transfer and the patient's clinical condition.
Immunomodulators and immunosuppressants
Infliximab and adalimumab are immunoglobulin G
Many of the drugs used in autoimmune, rheumatological and antibodies and are therefore actively transported across the
inflammatory bowel disease can be used in pregnancy. Table 2 placenta from 16 weeks, resulting in higher drug levels in the
shows a summary for commonly used drugs and counselling neonate than in the mother. Etanercept appears to have a lower
about pregnancy should be undertaken when these drugs are rate of placental transfer.
initiated. There are good safety data for hydroxychloroquine, To minimise neonatal levels at birth, these drugs should
sulfalazine, mesalazine and azathioprine, none of which are be discontinued, if possible, by 20 weeks for infliximab and
associated with any increase in congenital malformation rates 28 weeks for adalimumab or etanercept. However, in some
or pregnancy loss. Although azathioprine was, in one study,21 patients with active inflammatory disease, it is acceptable and
associated with neonatal anaemia, this was a small uncontrolled indeed necessary to continue treatment throughout pregnancy.
study and the results were not significant after adjustment for The British Society of Rheumatologists and European League
Against Rheumatism have recently issued detailed guidance24,25
on this topic.
Table 2. Immunosuppressants in pregnancy If infliximab is used throughout pregnancy, it can take up to
Acceptable at Acceptable in early Avoid in all stages 7 months for blood levels to become undetectable in the infant.
all stages of pregnancy (but of pregnancy Adalimumab has a slightly shorter duration of action and takes
pregnancy can be continued if up to 11 weeks to become undetectable. The effect on the neonate
required for disease is unclear and there are theoretical concerns about neonatal
control) immunosuppression. However, data from the PIANO registry26
are reassuring: third trimester anti-TNFα use had no effect on
Prednisolone Infliximab – stop at Methotrexate infant growth, development and immune development in the
20 weeks if possible first year of life and a systematic review27 found no increased risk
Ciclosporin Adalimumab – stop at Leflunomide of infections up to 1 year of age. There has been a single isolated
28 weeks if possible case of fatal disseminated Bacillus Calmett-Guerin (BCG) in an
Tacrolimus Mycophenolate infliximab-exposed infant who received the vaccine at 3 months
of age. It is therefore recommended that infants exposed to anti-
Hydroxychloroquine Etanercept – stop at Cyclophosphamide TNFα drugs should not receive live vaccines in the first 6 months
28 weeks if possible of life. All of these drugs may be detectable in breast milk at very
Sulfasalazine low levels, but they are very poorly absorbed via the oral route so
Mesalazine breastfeeding is considered safe.
There are a number of newer anti-TNFα drugs, some of
Azathioprine which have been modified to alter the pharmacokinetic profile.
Certolizumab pegol is an antigen-binding fragment of a Therefore, a pregnancy history should be taken when assessing
monoclonal anti-TNFα antibody (lacking the Fc region) that cardiovascular risk in women.
has been conjugated with poly-ethylene glycol. It has low rates It is common practice to aim for target blood pressure lower
of placental transfer and early data suggest that it is compatible than 150/100 mmHg in pregnancy and this is consistent with
with all three trimesters of pregnancy. the 2010 National Institute for Health and Care Excellence
guidelines.29 There were theoretical concerns that lower targets
Hypertensive disorders of pregnancy might compromise uteroplacental circulation. However,
recent evidence from the CHIPS trial30 showed that neonatal
Hypertension is the most common medical problem in outcomes are no different with a target diastolic blood pressure
pregnancy. In normal pregnancy, blood pressure falls of 81–85 mmHg compared with 100–104 mmHg and severe
by around 10 mmHg in the first half of pregnancy, and maternal hypertension was more frequent in the less tight
then gradually returns to prepregnancy levels by term. control (100–104 mmHg) group. Therefore, when treating
Hypertension in pregnancy increases the risk of pre- hypertension in pregnancy, the aim should now be tight
eclampsia, preterm delivery, fetal growth restriction, placental control, with a target diastolic blood pressure of 81–85 mmHg.
abruption and perinatal death. Women may have pre-existing If pharmacological treatment is required, labetalol (non-
hypertension or gestational hypertension (developing after selective α- and β-blocker) or modified-release nifedipine
20 weeks of gestation). Pre-eclampsia is a disease specific to (calcium channel blocker) are the first-line drugs in pregnancy
pregnancy and can be defined as new/worsening hypertension (Table 3). Methyldopa and amlodipine are second-line options.
with significant proteinuria or organ dysfunction (Fig 5).28 Importantly, angiotensin-converting enzyme inhibitors,
Pre-eclampsia often occurs de novo, but women with pre- angiotensin II receptor blockers and spironolactone are
existing hypertension may develop superimposed pre- contraindicated in pregnancy and should be switched (ideally
eclampsia, and gestational hypertension may also evolve pre-conception) to an alternative agent. However, angiotensin-
into pre-eclampsia. It requires hospital admission for close converting enzyme inhibitors can be reintroduced postpartum
monitoring and the only cure is delivery, which may be and are safe when breastfeeding.31
required urgently in severe cases. Pre-eclampsia is associated
with a doubling of the lifetime risk of developing hypertension, Conclusions
coronary artery disease, cerebrovascular disease and chronic
kidney disease. In women with early-onset pre-eclampsia Maternal mortality and morbidity resulting from treatable
(before 34 weeks), the risk is increased up to eightfold. medical conditions have not decreased in recent years, despite
a marked decrease in overall maternal mortality. Part of
the solution is to improve the training of physicians in the
Eclampsia (seizures)
management of pregnant patients, including pre-conception
Cerebral haemorrhage counselling. Prompt recognition of acute illness and optimal
treatment of chronic conditions is of clear benefit, and most drugs
and many radiological investigations can be used in pregnancy. ■
2 Royal College of Obstetricians and Gynaecologists. Reducing the risk 18 UK Teratology Information Service. Available online at www.uktis.org/
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Address for correspondence: Professor C Nelson-Piercy,
patients with inflammatory bowel disease. Aliment Pharmacol Ther Women's Health Academic Centre, Guy's and St Thomas’
2013;38:4606. Foundation Trust, 10th Floor, North Wing, St Thomas’
17 Soh M, Nelson-Piercy C. High-risk pregnancy and the rheumatologist. Hospital, Westminster Bridge Road, London SE1 7EH, UK.
Rheumatology 2015;54:572–87. Email: [email protected]