Oxford Handbook of Obstetrics and Gynaecology (3 edn)
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Epilepsy: overview
0.6% of pregnancies occur in women with epilepsy.
Most women have been diagnosed before conception.
If the first seizure occurs in pregnancy there is a wide differential diagnosis (see Box 5.1).
Seizure frequency can ↑ (37%), ↓ (13%), or remain unchanged (50%).
Poorly controlled epileptics and those who stop medication are at the highest risk of ↑ seizure frequency.
Eclampsia.
Epilepsy.
Infection:
meningitis
encephalitis
abscess.
Metabolic:
drug or alcohol withdrawal
drug toxicity
hypoglycaemia
electrolyte imbalance (i Na, ↓ Na, ↑ Ca).
Severe hypoxia.
Space-occupying lesion.
Vascular:
cerebral vein thrombosis
thrombotic thrombocytopaenic purpura (TTP)
cerebral infarction or haemorrhage.
All patients who present with their first seizure in pregnancy should have imaging of the brain with CT or, preferably, MRI and be reviewed by a neurologist.
The fetus usually tolerates seizures without long-term sequelae, but there is ↑ risk of fetal demise with status epilepticus.
Fetal risks
There is an increased risk of major congenital anomalies (2–5%)1 in women with epilepsy. Most of this risk is due to anticonvulsant medication; however, women not on antiepileptic drugs still have a higher risk than the general population. The use of multiple drugs carries a higher risk to the fetus than monotherapy. Higher doses lead to increased risk. Dividing doses and reducing peak blood levels may be beneficial. Any change in anticonvulsant therapy should be undertaken before pregnancy. Once pregnancy is diagnosed the woman should continue on her anticonvulsant drugs, and not change, as teratogenic risk exposure has already occurred. Folic acid (5mg) reduces the risk of some anomalies.
Teratogenicity: congenital anomalies or fetal anticonvulsant syndrome.
Neonatal withdrawal.
Vitamin K deficiency (enzyme inducers)→haemorrhagic disease of newborn.
Developmental delay and behavioural problems.
Drugs used in treatment of epilepsy
These have varying risks of congenital anomalies and can be divided according to their ability to induce liver enzymes.
Carbamazepine.
Topiramate.
Phenytoin.
Phenobarbital.
Primidone.
Lamotrigine.
Levetiracetam.
Valproate. Doctors in the EU are now advised not to prescribe valproate for epilepsy or bipolar disorder in pregnant women, in women who can become pregnant, or in girls, unless other treatments are ineffective or not tolerated. Those for whom valproate is the only option for epilepsy or bipolar disorder should be advised on the use of effective contraception, and treatment should be started and supervised by a doctor experienced in treating these conditions.2
Gabapentin.
Ethosuximide.
Neural tube defects: ↑ 10-fold (1–2%).
Genitourinary anomalies (hypospadias).
Cardiac anomalies.
Facial clefts.
Neurodevelopmental delay: ↑ 3.5-fold.
Neural tube defects (0.5–1%).
Cardiac anomalies.
Facial clefts.
Facial clefts: ↑ 5-fold.
Cardiac anomalies.
References
2. European Medicines Agency. Valproate and related substances. Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Valproate_and_related_substances/hu-man_referral_prac_000032.jsp&mid=WC0b01ac05805c516f.
Epilepsy: management
Prepregnancy counselling
Involve a neurologist to confirm diagnosis is epilepsy.
Optimize treatment, achieve seizure control, and educate patient.
Use the least number of drugs at the lowest dose to control seizures to minimize risk of congenital anomalies.
Consider stopping drugs if seizure free for >2yrs (warn of risk of seizures and implications for driving).
All women should take folic acid 5mg for at least 12wks before conception and continue until delivery (d risk of neural tube defects).
Risk of epilepsy in the child (4% if one parent affected, 15% if both parents affected).
Antenatal care
Do not change medication in pregnancy if well controlled, and stress the importance of compliance with medication.
Prenatal screening:
α-fetoprotein (neural tube defects)
detailed anomaly scan (facial clefts and cardiac abnormalities).
Consider fetal echocardiography at 22–24wks.
Consider vitamin K 10mg/day for the last 4wks of pregnancy (hepatic enzyme-inducing drugs may lead to neonatal coagulopathy).
General advice (showers rather than baths, avoid sleep deprivation).
The levels of newer antiepileptics, particularly lamotrigine, may fall precipitously and usually require a 30–50% rise in dose by 12–20wks.3
There is no role for routine monitoring of drug levels (it may be useful in women with increased seizure frequency, suspected non-compliance, concern over toxic side effects, or polypharmacy).
Intrapartum care
Aim for vaginal delivery (CS should be for obstetric indications; seizures are not an indication unless in status epilepticus).
Labour is associated with increased risk of seizures due to sleep deprivation, reduced absorption of drugs, and hyperventilation.
Control seizures with benzodiazepines.
Ensure usual anticonvulsants are taken at the correct time.
Neonatal vitamin K to ↓ risk of haemorrhagic disease of the newborn.
Breast-feeding is not contraindicated (anticonvulsants reach breast milk and thus slow withdrawal occurs, although phenobarbital and benzodiazepines may cause sedation in the baby).
If the anticonvulsant dose was increased in pregnancy it should be reduced back to prepregnancy levels slowly post-partum.
Contraception with enzyme-inducing drugs:
COCP containing 50 micrograms oestrogen with a shorter pill-free interval
progestogen-only pill (POP) is less effective
intrauterine contraceptive device (IUCD) is ideal.
General advice (bathing and feeding) to minimize risk of harm to baby from seizures.
References
Further reading
Epilepsy Foundation. Available at: http://www.epilepsy.com.
Epilepsy Society. Available at: http://www.epilepsysociety.org.uk/.
Cerebrovascular accident
Cerebrovascular accidents (CVAs) are rare in women of reproductive age, but there is an ↑ risk in the post-partum period. There is a 9-fold ↑ risk for infarcts and 28-fold ↑ for haemorrhagic stroke in the first 6wks post-partum compared with non-pregnant women. Symptoms include:
Abrupt onset of weakness.
Sensory loss.
Dysphasia.
Common risk factors for strokes at all ages include:
Smoking.
Diabetes.
Hypertension.
Hypercholesterolaemia.
Cryptogenic stoke is more common in young people often from emboli phenomenon, the origin of which is never found. Patients who have previously had a stroke are unlikely to have a further event in pregnancy, unless stroke was caused by dissection (usually vertebral artery).
Management
Treatment depends on the cause (see Box 5.2).
Anticoagulation may be appropriate.
Pre-eclampsia/eclampsia.
Central nervous system (CNS) vasculitis.
Carotid artery dissection.
Emboli:
mitral stenosis
peripartum cardiomyopathy
endocarditis
paradoxical emboli.
Coagulopathies:
thrombophilia
antiphospholipid syndrome.
Thrombotic thrombocytopaenic purpura.
Cerebral vein thrombosis.
Pre-eclampsia/eclampsia.
DIC.
AVM.
Ruptured berry aneurysm.
CNS vasculitis.
Subarachnoid haemorrhage
Outside pregnancy the commonest cause is a ruptured berry aneurysm, but arteriovenous malformations (AVMs) may dilate in pregnancy due to the effect of oestrogen, resulting in a similar incidence.
Presentation
Headache.
Vomiting.
Loss of or impaired consciousness.
Neck stiffness.
Focal neurological signs.
Management
Early treatment is recommended to reduce the chance of subsequent bleeding (the risk is high for AVM).
Surgery is usually recommended, excision of the AVM, coiling, or clipping.
Interventional radiology is associated with exposure of the fetus to radiation.
Nimodipine is used to decrease vasospasm.
Delivery:
labour is a high-risk time for bleeding, so elective CS should be recommended if the lesion is inoperable
epidural anaesthesia is contraindicated with a recent subarachnoid haemorrhage (SAH) due to raised intracranial pressure
if the lesion has been successfully treated, vaginal delivery is recommended (a longer passive 2nd stage with early use of assisted delivery may reduce the risk of rebleeding).
A neurologist should be involved in the investigation and management.
MRI or CT scan of head.
Cerebral angiography +/– venography.
Echocardiogram.
Carotid Dopplers.
Thrombophilia screen and antiphospholipid antibodies.
Homocystine level/methylenetetrahydrofolate reductase (MTHFR) screen.
Cardiac disease: management
The pattern of heart disease in pregnancy has changed over the past few decades. CHD is now more common than rheumatic heart disease and ischaemic heart disease has become a common cardiac cause of death in pregnancy.
Normal pregnancy is associated with significant haemodynamic changes. These may not be tolerated in women with heart disease.
Antenatal management
Multidisciplinary management with an obstetrician, cardiologist, anaesthetist, and, occasionally, cardiothoracic surgeon.
Preconception counselling should be offered to:
optimize maternal cardiovascular status (may involve surgery)
modify medication
discuss maternal and fetal risks of pregnancy.
The ability of a woman to tolerate pregnancy depends on:
exercise tolerance (New York Heart Association (NYHA) class)
presence of pulmonary hypertension or left heart obstruction
presence of cyanosis.
Decide if termination recommended (e.g.
pulmonary hypertension).
Correct factors that may lead to decompensation (anaemia, infection, hypertension, and arrhythmias).
Monitor for signs of heart failure and consider serial maternal echos.
Monitor fetal growth by serial ultrasound as risk of IUGR and death in utero, especially with maternal cyanosis.
Risk of CHD in fetus is 3–5% if either parent is affected. Some conditions carry higher risk. It is higher if mother rather than father is affected. Arrange for fetal echocardiography at 22wks.
Intrapartum and post-partum management
A clear intrapartum care plan should be agreed before labour.
Aim for a vaginal delivery usually with a short active 2nd stage (CS is indicated if aortic root >4.5cm, left ventricular ejection fraction (LVEF) <30%, aortic dissection or aneurysm).
In labour, maternal cardiac ± invasive monitoring may be required (the fetus should be continuously monitored).
Avoid aortocaval compression.
Decide on need for endocarditis prophylaxis.
Blood loss should be minimized by active management of 3rd stage followed by an infusion of oxytocin, but ergometrine and prostaglandin F2α (PGF2α, dinoprost) should be avoided.
Epidural analgesia may reduce changes in heart rate and BP associated with pain (low-dose epidural is usually well tolerated, but may cause serious complications with restricted cardiac output).
Strict fluid balance is mandatory as there is a much higher risk of pulmonary oedema the first few days post-partum.
Discuss contraception before discharge.
Peripheral vasodilatation leads to a fall in systemic vascular resistance.
Cardiac output increases by:
40% during pregnancy (↑heart rate and↑stroke volume)
15% in the 1st stage of labour
50% in the 2nd stage of labour.
Following delivery there is further increased cardiac output due to increased venous return from:
relief of vena caval obstruction
tonic uterine contraction (expels blood into systemic circulation).
Blood pressure falls in pregnancy and reaches a nadir around 24wks.
Colloid osmotic pressure falls leading to increased susceptibility to pulmonary oedema.
Hypercoagulability.
2 These changes start in early pregnancy.
Level of risk of maternal mortality (absolute risk level depends on the degree of the condition in the individual)Pulmonary hypertension.
Aortic dissection.
Complicated aortic coarctation.
Marfan’s syndrome with significant aortic root involvement.
Myocardial infarction.
Mitral stenosis NYHA class 3 or 4.
Severe aortic stenosis.
Mechanical heart valves.
ASD.
VSD.
PDA.
Corrected tetralogy of Fallot.
Tissue valve prosthesis.
Pulmonary and tricuspid valve disease.
Mild mitral stenosis.
Arrhythmias.
Artificial heart valves
Women with artificial heart valves often have near-normal cardiac function and therefore tolerate pregnancy well. The main maternal and fetal risk is from anticoagulation, which must be continued throughout pregnancy as without it there is a high morbidity (stroke) and mortality (valve thrombosis). The choice of anticoagulant should be made after discussion with the patient. Warfarin better protects against valve thrombosis, therefore is better for the mother, but heparin is better for the fetus.
Less maternal bleeding.
No risk to fetus (does not cross the placenta).
Increased risk of embolic events.
Increased risk of valve thrombosis—may require emergency valve replacement and has a high mortality.
Osteoporosis and heparin-induced thrombocytopenia.
Increased risk of miscarriage.
Risk of warfarin embryopathy (risk dose dependent: ↑ if >5mg/day).
Maternal and neonatal bleeding.
Long half-life.
There is a 4–12% risk of an embolic event per pregnancy.
Management
Antenatally there are two options:
continue warfarin throughout pregnancy—aim for an international normalized ratio (INR) of 3.0
conceive on warfarin, change to LMWH from 6–12wks to minimize risk of warfarin embryopathy, then use warfarin from 12 to 36wks.
Risk of bleeding in labour with warfarin (mother and baby) is high:
all patients should be changed to LMWH at 36wks (or earlier if preterm risk)
LMWH should be stopped in labour and restarted after delivery
warfarin should be restarted 7–10 days post-partum.
Reversal in the event of life-threatening bleeding:
warfarin—fresh frozen plasma, vitamin K, and prothrombin complex concentrates (PCCs)
LMWH—protamine sulphate.
Heparin and warfarin can safely be given to breast-feeding mothers.
Low-dose aspirin should be given with LMWH because of its anti-thrombotic effects and relative safety.
Titrate LMWH optimal dose based on anti-Xa effect, both trough (predose) and 4hrs peak levels; check anti-Xa every 2–3wks.4
Tissue valves
Bio-prosthetic or homograft valves do not require anticoagulation.
They have a shorter life expectancy than mechanical valves, so structural deterioration may occur in pregnancy.
Anticoagulation would still be required with arrhythmias, e.g. atrial fibrillation.
Endocarditis prophylaxis should be given to the following two groups:
Prosthetic heart valves (mechanical or tissue).
Previous bacterial endocarditis.
Complex cyanotic heart disease (Fallot’s tetralogy, transposition).
Surgically constructed systemic/pulmonary shunts.
Hypertrophic cardiomyopathy.
Acquired valvular lesions.
Mitral valve prolapse with severe regurgitation.
Other congenital cardiac malformations.
Prophylaxis is not recommended for:
Isolated secundum ASD.
Surgically repaired ASD or VSD.
Cardiac pacemakers.
Mitral valve prolapse without severe regurgitation.
▶ Recommended antibiotics:
Amoxicillin 1g IV plus gentamicin 120mg IV at onset of labour or rupture of membranes, then amoxicillin 500mg orally 6h later.
Vancomycin 1g IV or teicoplanin 400mg IV if penicillin allergy with gentamicin 120mg IV.
References
Acquired heart disease
Mitral stenosis
This is the most common lesion of rheumatic heart disease (90%).
↑ Risk of pulmonary oedema in pregnancy, greatest in labour:
↑ in heart rate in pregnancy, ↓ ventricular filling time, and ↑ pulmonary blood volume leading to pulmonary oedema
first line treatment for pulmonary oedema in pregnancy should be diuretics. β-blockers also used to slow heart rate and improve left atrial emptying (add digoxin if in atrial fibrillation (AF)).
Mitral stenosis is the most likely lesion to require treatment for pulmonary oedema, heart failure or surgery in pregnancy.
With severe mitral stenosis, consider surgery before pregnancy.
The risk of thromboembolism is ~1.5% in pregnancy, higher with left atrial enlargement and AF (treat with LMWH).
Mitral regurgitation is well tolerated in pregnancy; heart failure and endocarditis are rare.
Aortic stenosis
Aortic valve disease is less common than mitral valve disease (it is less likely to be 2° to rheumatic disease, more likely to be due to a congenital bicuspid valve).
The severity and risk of complications is dependent on the gradient across the valve: >100mmHg in the non-pregnant state is severe.
Associated symptoms are chest pain, syncope, and sudden death.
Pulmonary hypertension and Eisenmenger’s syndrome
1° pulmonary hypertension is an idiopathic abnormality of the pulmonary vasculature. In Eisenmenger’s syndrome there is pulmonary hypertension with reversal of the initial left-to-right shunt and consequent cyanosis. There is a fixed high pulmonary vascular resistance and inability to increase pulmonary blood flow. This leads to slowly worsening hypoxaemia.
Maternal mortality is high (25%) but has improved. Death classically occurs in the first few days post-partum.
Women should be advised to avoid getting pregnant and termination offered if pregnancy occurs.
Pregnancy should be managed in a pulmonary hypertension centre with multidisciplinary care from cardiologists, obstetricians, and anaesthetists.
Antenatal care includes anticoagulation, oxygen, bed rest, and serial assessment of fetal growth.
Avoid manoevures that suddenly increase vagal tone (with resultant bradycardia) and venous return, e.g. ergometrine.
Avoid PGF2α which is associated with pulmonary vasoconstriction and pulmonary hypertensive crisis.
Delivery should be in a high dependency unit with tight control of blood pressure, fluid balance, and oxygen saturations.
Mode of delivery and epidural use are controversial.
Myocardial infarction and cardiomyopathy
Myocardial infarction
Remains rare in pregnancy, but incidence has been increasing due to increased age at pregnancy and lifestyle factors. Mortality high (20% immediate, 32% overall); highest in puerperium.
Risk factors include smoking, hypertension, diabetes, hypercholesterolaemia, family history, and obesity.
There may be atypical symptoms, such as abdominal or epigastric pain, and vomiting or dizziness.
Diagnosis is based on history, electrocardiograph (ECG) changes, and elevated troponin.
Single normal ECG especially in a pain-free patient does not rule out ischaemia. Serial ECGs should be considered.
Patient should be managed on a coronary care unit by cardiologists.
1° percutaneous coronary intervention (PCI) is the treatment of choice in the pregnant patient.
Thrombolysis is associated with higher fetal loss rates, but should be considered if primary PCI is not available.
Delivery: aim for a vaginal delivery with a short 2nd stage (avoid ergometrine as it can cause coronary artery spasm).
Women with a past history of myocardial infarction (MI) should have a prepregnancy assessment of cardiac function (echo and exercise test) with counselling on the basis of the results, and aspirin should be continued in pregnancy.
Peripartum cardiomyopathy
This is a rare condition—incidence <1:2000.
It occurs between 32wks and 6mths after delivery.
Risk factors:
increasing maternal age
multiparity
multiple pregnancy
Afro-Caribbean ethnicity
poor socio-economic class
hypertension in pregnancy.
Presentation: breathlessness, palpitations, oedema, poor exercise tolerance, and embolic phenomena.
Diagnosis: global dilatation of all four chambers of the heart (seen on echo) with exclusion of other causes of cardiomyopathy.
Management: supportive; should include angiotensin-converting enzyme inhibitors (ACEIs) and anticoagulation ( immunosuppression has been tried).
If the diagnosis is made antenatally, delivery is indicated.
Consider heart transplantation if there is heart failure despite optimal medical therapy.
Mortality 25–50% (long-term survival likely if patient survives initial episode).
Recurrence risk high (up to 50%). Avoid further pregnancies if cardiac function does not return to normal.
Congenital heart disease
The most common CHDs in pregnancy are PDA, ASD, and VSD. They are generally well tolerated in pregnancy.
Marfan’s syndrome This is an autosomal dominant condition (chromosome 15) caused by a defect in fibrillin synthesis (genetic testing is available). The main risk is of aortic dissection and rupture. This risk increases if there is a family history of rupture and/or there is evidence of aortic root dilatation.
Management
Monthly maternal echo for aortic dimensions until 8wks post-partum.
β-Blockers should be given for hypertension or aortic dilatation as they are shown to reduce rate of dilatation and risk of dissection.
Aim for vaginal delivery with a short 2nd stage (if aortic root dilatation is present, deliver by CS).
Mortality
<1% if aortic root <4cm.
>25% if aortic root >4cm.
Pregnancy is contraindicated with an aortic root >4.5cm until aortic root replacement.
Coarctation of aorta
This has usually been corrected before pregnancy. The main risk is of aortic dissection; this risk is highest if there is hypertension present (usually treated with β-blockers). Condition is also associated with berry aneurysms, which can bleed in pregnancy causing cerebral haemorrhage.
If uncorrected or recurrent, coarctation risks include:
hypertension
heart failure
angina.
Avoid balloon angioplasty in pregnancy (↑ risk of dissection).
Deliver by CS if there is associated aortic dilatation.
Fallot’s tetralogy
The majority of women with Fallot’s will have had surgery and the risk to their pregnancy will depend on not only the type of surgery but also its level of success.
There are two main risks in pregnancy:
paradoxical emboli can pass from right-to-left through the shunt causing strokes
cyanosis affects the fetus leading to increased risk of miscarriage, IUGR, prematurity, and death in utero.
Risks are minimized by anticoagulation (prophylactic dose LMWH), bed rest, and oxygen.
Further reading
European Society of Cardiology. ESC Guidelines on the management of cardiovascular diseases during pregnancy. Available at: http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/Guidelines-Pregnancy-FT.pdf.
Anaemia
Plasma volume expansion (50%) greater than red cell mass↑(25%).
This leads to physiological dilution with↓Hb and haematocrit.
Anaemia is diagnosed if Hb <10.5 g/dL in pregnancy.
There should be no change in mean corpuscular volume (MCV) or mean corpuscular haemoglobin concentration (MCHC) in normal pregnancies.
Normally pregnancy has:
2–3-fold increase in iron requirements
10–20-fold increase in folate requirements in pregnancy.
Iron-deficiency anaemia
The most common cause of anaemia in pregnancy (90% of cases).
Diagnosis: ↓ MCV, ↓ MCHC, and ↓ ferritin.
Often asymptomatic and detected on screening.
Treat by oral iron supplementation: vitamin C (orange juice) ↑ absorption, tea ↓ absorption.
Parenteral iron should be considered in those who do not tolerate the oral preparations (corrects the anaemia more rapidly).
The expected improvement in haemoglobin is ~1g/dL/wk.
In situations such as multiple pregnancy or known depletion of iron stores, consider prophylactic supplementation even if no anaemia.
If severe iron-deficiency anaemia (Hb <7g/dL) is diagnosed near term, blood transfusion may be considered.
Folate deficiency
Also common in pregnancy (5% of cases of anaemia).
Risk factors:
poor nutritional status
haematological problems with a rapid turnover of blood cells, e.g. haemolytic anaemia and haemoglobinopathies
drug interaction with folate metabolism, e.g. antiepileptics.
Diagnosis:↑ MCV, ↓ serum, and ↓ red cell folate.
Folic acid given preconception and in early pregnancy to reduce risk of neural tube defects (400 micrograms/day for general population).
Women with high risk of neural tube defects should take 5mg folic acid daily. The high-risk group includes those women:
on anticonvulsants
with a previous child affected with a neural tube defect
with demonstrated deficiency
with diabetes
with a BMI >35
with sickle cell disease.
Vitamin B12 deficiency
Occurs in pernicious anaemia, terminal ileum disease, and strict vegans.
It is uncommon to make a new diagnosis in pregnancy.
Women with a previous diagnosis should continue treatment throughout pregnancy.
Further reading
Pavord S, et al.
Sickle cell disease
Inheritance is autosomal recessive. Most commonly seen in people of Afro-Caribbean origin, but also occurs in those from the Middle East, Mediterranean, and Indian subcontinent. As diagnosis has usually been made in childhood, it is rare to make a new diagnosis in pregnancy.
Pathophysiology
Results in distortion of the shape of red cells into a rigid sickle shape. This leads to microvascular blockage, stasis, and infarction in any organ in the body. Crises can be precipitated by infection, dehydration, hypoxia, and cold.
Risks in pregnancy
Crises are more common during pregnancy.
↑ Risk of pre-eclampsia.
↑ Risk of delivery by CS 2° to fetal distress.
Haemolytic anaemia.
Painful crises.
Hyposplenism (chronic damage to the spleen results in atrophy).
Increased risk of infection (UTI, pyelonephritis, pneumonia, puerperal sepsis).
Avascular necrosis of bone.
Increased risk of thromboembolic disease (pulmonary embolism (PE), stroke).
Acute chest syndrome (fever, chest pain, tachypnoea, iWCC, pulmonary infiltrates).
Iron overload:leads to cardiomyopathy.
Maternal mortality 2%.
Management
Multidisciplinary care with an obstetrician and haematologist.
Prepregnancy counselling should involve screening of the partner (if the partner is a carrier, consider prenatal diagnosis).
Stop iron-chelating agents before pregnancy.
If there is a history of iron overload, arrange a maternal echo.
Give folic acid 5mg/day and penicillin prophylaxis for hyposplenism.
Monitor Hb and HbS percentage and arrange transfusion if necessary (may have red cell antibodies from multiple transfusions).
Screen for urine infection each visit.
Treatment of a crisis involves adequate analgesia, oxygen, rehydration, and antibiotics if infection suspected (exchange transfusion may be required in severe crises).
Regular assessment of fetal growth with ultrasound, including Doppler.
Aim for vaginal delivery ensuring adequate hydration and avoiding hypoxia (continuous fetal monitoring as increased risk of fetal distress).
Consider antenatal and postnatal thromboprophylaxis.
The use of prophylactic antibiotics is controversial.
Miscarriage.
IUGR.
Prematurity.
Stillbirth.
Perinatal mortality is increased 4–6-fold compared to the general population.
Further reading
Royal College of Obstetricians and Gynaecologists (2011). Management of Sickle Cell Disease in Pregnancy, Green-top Guideline no. 61. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_61.pdf.
Thalassaemia
Adult haemoglobin is made up from two α- and two β-globin chains associated with a haem complex. There are four genes for α-globin and two for β-globin chain production. An adult’s blood is normally made up of HbA (α2β2, 97%), HbA2 (α2δ2, 1.5–3.5%), and HbF (α2γ2, <1%). Thalassaemia is a group of genetic conditions leading to impaired production of the globin chains and resulting in red cells with inadequate haemoglobin content. Fetal haemoglobin consists of 2α and 2γ chains, so a fetus cannot be affected by β-thalassaemia.
α-Thalassaemia
Caused by defects in 1–4 of the α-globin genes.
Most common in individuals from South-east Asia.
α-Thalassaemia trait has two (α0) or three (α+) normal genes: women are usually asymptomatic, but may become anaemic in pregnancy.
In HbH there are three defective genes:
unstable haemoglobin is formed by tetramers of the β chain
chronic haemolysis results and iron overload is common
offspring will have either α0 or α+ thalassaemia.
α-Thalassaemia major (Hb Barts) has no functional α genes and is incompatible with life:
fetuses are often hydropic and born prematurely
severe early-onset pre-eclampsia often complicates the pregnancy.
β-Thalassaemia
β-Thalassaemia trait has one defective gene and women are asymptomatic but may become anaemic in pregnancy.
It is most common in individuals from Cyprus and Asia.
Incidence of β-thalassaemia minor is 1:10 000 in the UK compared with 1:7 in Cyprus: offspring have a 1:4 chance of β-thalassaemia major.
β-Thalassaemia major has two defective genes and women are often transfusion dependent:
iron overload can occur
puberty is often delayed
there is subfertility and only very few pregnancies have been reported.
Repeated transfusions cause iron overload, leading to endocrine, hepatic, and cardiac dysfunction:
heart failure is the most common cause of death
iron-chelating therapy can reduce the incidence of iron overload
the condition can be cured by bone marrow transplant.
Check ferritin in early pregnancy: give iron supplements only if iron deficient.
Women need folic acid 5mg daily:
if failure to respond to folate PO, then IM (and oral iron if needed); a blood transfusion may be required
parenteral iron should be avoided.
If the woman has thalassaemia, the partner needs screening:
if positive, the couple need counselling on the risk of pregnancy with thalassaemia major
prenatal diagnosis should be offered.
Screen all women of Mediterranean, Middle Eastern, Indian, Asian, African, or West Indian ethnic origin by haemoglobin electrophoresis at booking.
Inα0 andα+ thalassaemia no abnormal haemoglobin is made and there is no excess in HbA2or HbF:
Hb electrophoresis is normal
the diagnosis can be confirmed by globin chain synthesis studies or DNA analysis of nucleated cells.
Inα-thalassaemia there is a raised concentration of HbA2and/or HbF.
Suspect the diagnosis of thalassaemia in the presence of:
low MCV
low MCHC
microcytic anaemia with normal MCHC (which differs from iron deficiency where the MCHC is also low).
Haemophilia
X-linked inherited deficiency of clotting factor VIII and IX that causes problems with bleeding. Haemophilia A (factor VIII deficiency) is 4 times more common than haemophilia B (factor IX deficiency). Can vary in severity depending on the clotting factor levels: mild (>5% to <40%), moderate (1–5%), or severe (<1%). Severity tends to be similar within members of one family. The use of prophylactic recombinant factor replacement from childhood has now drastically changed the outlook and life expectancy for affected children.
Incidence
15:100 000 males.
Female carriers have one abnormal gene and do not usually have significant bleeding problems, but the clotting factor level is around 1/2 normal (occasionally clotting factors may be much lower because of lyonization).
Female carriers have a 50% chance of having an affected son and a 50% chance of having carrier daughters.
An affected male will produce carrier daughters and unaffected sons.
1/3 of newly diagnosed infants has no family history and are the result of a new mutation.
Prenatal diagnosis and antenatal care
Manage jointly with haematologist.
Genetic counselling and prenatal diagnosis (if the mutation is known by DNA-based family studies) should be offered to affected families.
Fetal sexing can be done if the mutation is not known, with fetal cell free DNA testing from a maternal blood sample.
Check hepatitis serology as previous exposure to blood products.
Maternal coagulation factor activity should be checked at booking, 28, and 34wks, and when clinically indicated (e.g. bleeding, before surgery).
There is increased risk of post-partum haemorrhage (factor VIII, but not factor IX, increases in pregnancy in normal women and haemophilia carriers. Therefore, women with factor IX deficiency are most at risk while pregnant. There is a rapid ↓ to prepregnancy levels after delivery).
Intrapartum and post-partum care
Aim for vaginal delivery.
Check maternal coagulation factor activity (factor VIII or factor IX), aiming for levels >50IU/L (give appropriate clotting factors if lower than this).
Also send FBC, clotting screen, and group and save when in labour.
Avoid fetal scalp electrodes, fetal blood sampling, ventouse, and rotational forceps deliveries in affected or male fetuses with unknown status.
Epidural anaesthesia can be used if normal coagulation screen, platelet count >100 × 109/L, normal bleeding time, and clotting factor >50IU/L.
Maintain clotting factors >50IU/l and give tranexamic acid for 5 days post-partum to reduce risk of post-partum haemorrhage.
Avoid IM injections in neonate with possible clotting disorder.
Send cord blood of males for clotting factor VIII or IX levels (refer to haemophilia centre if diagnosis is confirmed).
Autosomal dominant (types 1 and 2).
Autosomal recessive (type 3)—more uncommon and severe.
Stabilizes factor VIII and helps adherence of platelets to vessel wall.
Diagnosis by measuring:
von Willebrand’s factor (vWF) antigen
factor VIII
ristocetin cofactor activity.
Levels of vWF and factor VIII increase in pregnancy and fall rapidly post-partum.
Main risk is post-partum haemorrhage.
Desmopressin can be used in some type 1 cases (it stimulates the release of vWF from endothelial cells).
Further reading
British Committee for Standards in Haematology guideline (2010). Management of haemophilia in the fetus and neonate. Available at: http://www.bcshguidelines.com/documents/NeonatalGuidelineFinalNov2010.pdf.
United Kingdom Haemophilia Centre Doctors’ Organization (2014). Guideline for the diagnosis and management of the rare coagulation disorders. Available at: http://onlinelibrary.wiley.com/doi/10.1111/bjh.13058/pdf.
Autoimmune idiopathic thrombocytopaenic purpura
Caused by antibodies to surface antigens on platelets, leading to platelet destruction.
Incidence 1–3:1000 pregnancies.
Diagnosis is by exclusion of other causes of thrombocytopenia.
Pregnancy does not affect the disease, but due to a lower median platelet count in pregnancy, the platelet count of women with idiopathic thrombocytopaenic purpura (ITP) usually falls further in pregnancy.
Fetal risks
IgG antiplatelet antibodies can cross the placenta and cause fetal thrombocytopaenia.
Difficult to predict which fetus will be affected (it has no relation to maternal platelet count).
Can lead to antenatal and intrapartum intracranial haemorrhage:
<2% with a history of ITP before pregnancy
risk is highest if there has been a previously affected child.
Management
FBC every 2–4wks.
Bleeding is unlikely if platelet count is >50 × 109/L (treatment is not required at this level).
Patients with bleeding or platelet count <50 × 109/L should be started on oral steroids, >75% respond within 3wks.
Patients who fail to respond to steroids can be treated with iv immunoglobulin.
Splenectomy is rarely performed in pregnancy.
Platelet transfusions may be required if rapid response is needed.
In labour, avoid:
fetal scalp electrodes
fetal blood sampling
ventouse delivery
rotational forceps delivery.
No fetal benefit from delivery by CS, but ↑ maternal risks.
Cord platelet count should be taken at birth:
the count reaches a nadir at around day 4
the neonate may require IV immunoglobulin.
Spurious.
Gestational thrombocytopaenia.
Pre-eclampsia.
Idiopathic thrombocytopaenic purpura.
Thrombotic thrombocytopaenic purpura.
Disseminated intravascular coagulopathy.
Systemic lupus erythematosus.
Bone marrow suppression.
Further reading
American Society of Hematology (2013). 2013 Clinical Practice Guide on Thrombocytopenia in Pregnancy. Available at: http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Reference.aspx.
Asthma
This is the most common respiratory disease encountered in pregnancy and affects 1–4% of women of childbearing age. It is caused by reversible bronchoconstriction of smooth muscle in the airways, with inflammation and excess mucus production. Diagnosis is based on recurrent episodes of wheeze, shortness of breath, chest tightness, or cough, and variation in peak expiratory flow rate (PEFR) of >15% after treatment with bronchodilators. Pregnancy outcomes in women with asthma are usually good.
Effect of pregnancy on asthma
1/3 of patients show no change in their asthma, 1/3 show improvement, and 1/3 deteriorate, usually in those with more poorly controlled asthma at conception. Deterioration occurs most often between 24 and 36wks. There may be a different effect in different pregnancies. Deterioration may be caused by cessation of maintenance therapy.
Effect of asthma on pregnancy
Usually there is no effect on the fetus or course of the pregnancy, but poorly controlled asthma may be associated with low birth weight and preterm labour.
Management
Current therapy should continue in pregnancy, and women educated and reassured of the safety of the medication and warned not to stop their treatment.
Women should continue to monitor their PEFR (↑ diurnal variation with ↓ PEFR in the night or early morning may be an early sign of worsening of asthma).
Chronic and acute severe asthma should be treated as in the non-pregnant state (aim for O2 sats >95% and administer O2 if required).
Magnesium sulfate is readily available in maternity services and may be used for acute severe asthma when there has not been a good initial response to inhaled bronchodilator therapy.
Advise cessation of smoking.
Chest radiograph (CXR) should be considered to exclude pneumothorax.
↑ Risk of gestational diabetes in women on long-term oral steroids.
Asthma attacks are rare during labour; inhaled β-agonists can be used (there is no evidence that they interfere with uterine activity).
Women on long-term oral steroids (prednisolone >7.5mg/day for >2wks) theoretically are at risk of Addisonian collapse during labour—give hydrocortisone 100mg every 8h.
PGF2α should only be used in cases of life-threatening post-partum haemorrhage because of its bronchoconstriction action.
Breast-feeding should be encouraged as it may give the child some protection against developing allergies in later life.
The fetus is at greater risk from undertreated asthma than from the drugs used in its treatment.
Step 1: inhaled short-actingβ-agonists: salbutamol or terbutaline.
Step 2: inhaled steroids (up to 800 micrograms/day): beclometasone, budesonide.
Step 3: long acting beta-agonist: salmeterol or formoterol.
Step 4: high-dose inhaled steroid (up to 2000 micrograms/day): oral slow-release theophylline, leukotriene antagonists.
Step 5: oral steroids: review by respiratory physician if oral steroids commenced.
Leukotriene receptor antagonists should not be commenced in pregnancy but can be continued in women who have demonstrated significant improvement in asthma control that was not achievable by other medication.
Medication:
nebulized bronchodilators
IV steroids
nebulized ipratropium
IV aminophylline or IV salbutamol
+/– antibiotics if evidence of infection.
Clinical findings:
heart rate >110 beats/min
respiratory rate >25/min
pulsus paradoxus >20mmHg
PEFR <50% predicted
accessory muscle use
unable to complete sentences.
Silent chest with very little wheeze may be a sign of life-threatening asthma.
Further reading
Scottish Intercollegiate Guidelines Network (2014). British guideline on the management of asthma. Available at: http://sign.ac.uk/pdf/SIGN141.pdf.
Cystic fibrosis
This is one of the commonest genetic conditions, affecting 1:2000 people of European origin with a gene frequency of around 1:25. Transmission is autosomal recessive and disease is caused by defective function of the cystic fibrosis (CF) transmembrane conductance regulation (CFTR) chloride channel. The condition affects the lungs, gastrointestinal tract, pancreas, hepatobiliary system, and reproductive organs. Recurrent chest infections lead to bronchial damage and respiratory failure.
Life expectancy is improving (currently 41yrs) and women with CF are now having families. However, most men are infertile owing to congenital absence of the vas deferens and women are subfertile because of unfavourable mucus, reduced BMI, and anovulation.
Prenatal counselling
Offspring will definitely receive one affected gene from the mother, so paternal status should be ascertained. There are many different gene mutations, but screening will detect ~90% of mutations. Risk of an affected child is 2–2.5% for unknown paternal carrier status. If the father’s screen is negative the risk of an affected child falls to 1:500. If the father is a carrier the chance of an affected child is 1:2. Chorionic villus sampling can then be performed to check the fetus for affected genes.
Management of pregnancy with CF
Care involves a multidisciplinary team with chest physician (CF unit), obstetrician, dietitian, and physiotherapist.
Principles of care involve control of respiratory infections, avoidance of hypoxia, maintaining nutrition, and fetal surveillance.
Chest physiotherapy should continue as in the non-pregnant state.
Watch for signs of chest infection; treat aggressively with antibiotics, tailored according to sputum culture results.
Avoid tetracyclines and parenteral aminoglycosides, which may cause ototoxicity in high doses.
Cardiac status should be checked by echocardiography.
In the later stages of pregnancy patients can become breathless even without infections (if oxygen saturations are ≤90% at rest, hospital admission for oxygen therapy is indicated).
High calorie intake with pancreatic enzyme supplementation is required.
8% of pregnant women with CF have pre-existing diabetes and 20% have diabetes by term.
Fetal monitoring with regular growth scans (fetal risks are IUGR due to maternal hypoxaemia and preterm labour).
Aim for a vaginal delivery (limit the 2nd stage, as pneumothoraces can occur with prolonged or repeated Valsalva manoevures).
Avoid general anaesthesia and inhalational analgesia if possible.
Same thing applies with PGF2α as many CFs have an element of obstructive airways disease.
Breast-feeding is recommended (ensure continued nutritional supplementation).
Hypoxaemia: PaO2<60mmHg free from infection.
Cyanosis.
Pulmonary hypertension.
Poor prepregnancy lung function: forced expiratory volume in 1s (FEV1) <60% predicted.
Pancreatic insufficiency (especially diabetes) and malnutrition.
Lung colonization withBurkholderia cepacia.
Further reading
European Cystic Fibrosis Society (ECFS) (2008). Guidelines for the management of pregnancy in women with cystic fibrosis, 2008. Available at: https://www.ecfs.eu/files/webfm/webfiles/File/documents/Pregnancy.pdf.
Respiratory infections
Pneumonia
This has the same incidence as in the non-pregnant population: 1–2:1000 pregnancies.
Risk factors include smoking, chronic lung disease, and immunosuppression.
Clinical features: fever, cough, purulent sputum, chest pain, and breathlessness.
Investigations: FBC, CRP, CXR, sputum culture, serology (mycoplasma, Legionella, and viral titres), and arterial blood gases.
Fetal risks are preterm labour and possibly IUGR.
Treatment involves physiotherapy, adequate oxygenation, hydration, and appropriate antibiotics.
Varicella infection (chickenpox) causes pneumonia in 10% of cases in pregnancy. Mortality is ~10% and is highest in the latter stages of pregnancy. Women who develop varicella in pregnancy should be treated with aciclovir; they should be hospitalized if respiratory signs develop (on a non-obstetric ward with barrier nursing).
Tuberculosis
The incidence of tuberculosis (TB) is increasing in the UK, especially in the immunosuppressed (HIV) and immigrant population. It is uncommon in pregnancy, but does not adversely affect the outcome if it is diagnosed and treated appropriately in the first 20wks or so.
Clinical features: cough, haemoptysis, fever, weight loss, chest pain, and night sweats.
Diagnosis may be delayed by an unnecessary reluctance to perform investigations such as CXR in pregnancy.
Investigations: screening (active or latent infection): Mantoux subcutaneous test (BCG vaccination may cause false positives) or in vitro blood test based on interferon gamma release assay (QuantiFERON® or T-SPOT®; BCG vaccination does not cause false positives). CXR (classically calcification and upper lobe abnormalities), sputum microscopy with a Ziehl–Nielsen stain, sputum culture (can take 6wks), bronchoscopy if no sputum, and tissue biopsies for extrapulmonary TB.
There is increased risk of prematurity and IUGR if treatment is inadequate or delayed (transplacental spread of infection is rare).
Neonatal considerations
Transmission from mother to baby after delivery (or to other caregivers) can occur if the mother remains infective (smear +ve). Women usually become non-infectious (smear −ve) within 2wks of starting treatment. The baby should be given Bacillus Calmette–Guerin (BCG) vaccination and, if smear +ve, prophylaxis with isoniazid for 3mths.
Amoxicillin for community-acquired pneumonia. Use higher dose in pregnancy because of increased renal clearance (1000mg tds).
Erythromycin if penicillin allergy.
Add erythromycin or clarithromycin if atypical organisms suspected.
Cephalosporin for hospital-acquired pneumonia.
No cause found in substantial proportion of patients.
Streptococcus pneumoniae (>50% of cases).
Haemophilus influenzae.
Staphylococcus aureus (often after a viral infection).
Klebsiella (more common with chronic lung disease).
Pseudomonas aeruginosa (more common with chronic lung disease).
Mycoplasma pneumoniae (atypical organism).
Legionella pneumoniae (atypical organism).
Chlamydia psittaci (atypical organism).
Gram −ve organisms (secondary to aspiration).
Pneumocystis carinii (immunosuppressed).
Fungal.
Viral: influenza, varicella-zoster.
Respiratory physician and microbiologist involvement is essential.
Treatment should be supervised to encourage and confirm compliance.
A minimum of 6mth course of treatment is required.
A typical treatment regime for pulmonary TB would involve an initial phase of therapy with isoniazid, rifampicin, ethambutol, +/– pyrazinamide for 2mths, followed by a continuation phase of 4mths of isoniazid and rifampicin (and based on drug sensitivities):
isoniazid—can cause demyelination and peripheral neuropathy. If given with pyridoxine considered safe in pregnancy; risk of hepatitis is increased in pregnancy so monitor liver function monthly
rifampicin—can be safely used in pregnancy. It is a liver enzyme inducer; therefore, give vitamin K to the mother in the last 4wks of pregnancy to prevent haemorrhagic disease of the newborn
ethambutol—is safe in pregnancy
streptomycin—10% risk of deafness in fetus due to damage to the 8th cranial nerve; should not be used in pregnancy
pyrazinamide—considered safe after the 1st trimester, occasionally used before 14wks.
Inflammatory bowel disease
Ulcerative colitis (UC) affects women more than men.
Crohn’s disease is equally distributed between the sexes.
Clinical features are diarrhoea, abdominal pain, rectal bleeding, and weight loss.
Effect of inflammatory bowel disease on pregnancy
Fertility, miscarriage, stillbirth, and fetal anomaly rates are not affected in women with quiescent or well-controlled disease.
Active disease at conception, first presentation in pregnancy, colonic rather than small bowel disease alone, active disease after resection, and severe disease treated by surgery are all associated with increased risk of miscarriage, stillbirth, prematurity, and low birth weight.
Effect of pregnancy on inflammatory bowel disease
If the condition is quiescent at conception the risk of relapse is the same as in non-pregnant women.
Conception occurring at a time of active disease is associated with persistent activity during pregnancy.
Management of inflammatory bowel disease in pregnancy
Acute flares carry a high risk of adverse outcome, and are best treated aggressively.
▶ Most drugs used for inflammatory bowel disease (IBD) are considered low risk during pregnancy.
However, methotrexate and thalidomide are contraindicated.
High-dose folic acid (2-5mg/day) should be given before conception to women on sulfasalazine, to protect against neural tube defects, as the drug impairs the metabolism of folate.
Management is similar to the non-pregnant state. Maintenance therapy usually includes sulfasalazine, other 5-aminosalicylic acid derivatives, and/or steroids (available orally or rectally).
Active disease should be investigated by stool culture to exclude infection (including parasites), inflammatory markers, and sigmoidoscopy to assess disease activity in colitis (manage by rehydration and drug therapy with sulfasalazine or steroids).
If the active disease is refractory to steroids, then azathioprine, 6-mercaptopurine, or ciclosporin may be useful.
The new biologic therapies such as infliximab and adalimumab are probably safe but limited data are so far available.5
Surgery is occasionally required in pregnancy when complications occur such as intestinal obstruction, haemorrhage, perforation, fistula, abscess formation, or toxic megacolon.
Caesarean section is usually reserved for obstetric reasons but may be considered with severe perianal Crohn’s disease, as a scarred perineum is inelastic and tears may result in fistula formation.
Caesarean section should also be considered in UC patients with a pouch or patients with poorly controlled UC that will probably need a pouch in the future.
Breast-feeding is safe in women on steroids, sulfasalazine, other 5-aminosalicylic acid derivatives, and azathioprine, and probably on anti-TNFa (such as infliximab, etanercept, and adalimumab).
Oral 5-aminosalicylates
Topical 5-aminosalicylates
Sulfasalazine
Corticosteroids
Azathioprine
6-Mercaptopurine
Infliximab
Adalimumab
Etanercept
Certolizumab
Ciclosporin
Tacrolimus
Budesonide
Metronidazole
Ciprofloxacin
Methotrexate
Thalidomide
6-Thioguanine (no data)
References
Further reading
van der Woude CJ et al.
Obstetric cholestasis
Obstetric cholestasis affects 0.7% of pregnancies in the UK. It is more common in women of Asian ethnicity and there is geographical variation in prevalence. 1/3 of patients have a family history of the condition. It usually occurs in the 3rd trimester and resolves spontaneously after delivery.
Symptoms
Pruritus of the trunk and limbs, without a skin rash (often worse at night).
Anorexia and malaise.
Epigastric discomfort, steatorrhoea, and dark urine (less common).
Diagnosis
Full investigation is required as it is a diagnosis of exclusion, but is usually made on the history, abnormal LFTs, and raised bile acids in the absence of any other cause for hepatic dysfunction.
Risks
Maternal risks
Vitamin K deficiency (potentially leading to post-partum haemorrhage).
Fetal risks
Preterm labour (including iatrogenic).
Stillbirth (actual ↑ risk has yet to be determined but is likely to be small).
↑ Risk of meconium (delivery in a consultant-led unit is recommended).
Management of obstetric cholestasis
Send LFTs and bile acids for all woman itching, without a rash.
If normal, they should be repeated every 1–2wks if symptoms persist, as itching can predate abnormal LFTs.
Exclude other causes of pruritus and liver dysfunction.
Water-soluble vitamin K should be commenced from diagnosis.
Symptoms may be alleviated by topical emollients (antihistamines cause sedation but do not improve pruritus).
Ursodeoxycholic acid (8–12mg/kg daily in two divided doses; probably safe up to 20–30mg/kg/d) reduces pruritus between 1 and 7 days after starting, but there is no proven benefit for fetal adverse effects.
Fetal surveillance with ultrasound and CTG monitoring are commonly used but of no proven benefit.
Postnatal resolution of symptoms and LFTs should be established.
Recurrence risk in subsequent pregnancy is 45–70% (it can also recur with the combined contraceptive pill).
Intrauterine death is usually sudden and cannot be predicted by biochemical results, CTG findings, or on USS.
Timing of delivery is controversial as there is an increased risk of perinatal and maternal morbidity with early intervention; therefore this should be discussed with the woman on an individual basis. Women with severe obstetric cholestasis should have a consultant-led decision made regarding the need for IOL at 37wks gestation onwards.
Gallstones.
Acute or chronic viral hepatitis.
Primary biliary cirrhosis (antimitochondrial antibody +ve).
Chronic active hepatitis (antismooth muscle antibody +ve).
LFTs:
2–3-fold ↑ in ALT, AST, gamma-glutamyltransferase (γGT), or alkaline phosphatase
use pregnancy-specific reference ranges.
Clotting screen.
Bile acids.
Ultrasound of the liver and biliary tree.
Viral serology (hepatitis A, B, C, CMV, EBV).
Autoimmune screen (antimitochondrial and antismooth muscle antibodies).
References
Further reading
Royal College of Obstetricians and Gynaecologists. (2011). Obstetric cholestasis. Green-top Guideline No. 43. Available at: http://www.rcog.org.uk/womens-health/clinical-guidance/obstetric-cholestasis-green-top-43.
Acute fatty liver of pregnancy
This is a rare condition affecting 1:10 000 pregnancies. It typically presents in the third trimester and can occur at any parity. It is associated with twin pregnancy (9–25%), a male fetus (♂:♀ ratio 3:1), and mild pre-eclampsia (30–60%).
Acute fatty liver of pregnancy (AFLP) has a maternal mortality of 18%, higher if diagnosis is delayed, and fetal mortality of 23%.
Abdominal pain.
Nausea and vomiting.
Jaundice.
Headache.
Fever.
Confusion.
Coma.
Diagnosis is based on the Swansea criteria (see Box 5.3).
Can progress rapidly to fulminant liver failure, DIC, and renal failure.
Hypoglycaemia is common.
Some women have polyuria 2° to transient diabetes insipidus.
Investigations: FBC and film, clotting, U&E, urate, LFT, glucose, blood gases.
Six or more are required in the absence of another cause:
Vomiting.
Abdominal pain.
Polydipsia/ polyuria.
Encephalopathy.
Elevated bilirubin >14μmol/L.
Hypoglycaemia <4mmol/L.
Elevated urea >340μmol/L.
Leucocytosis >11×109/L.
Ascites or bright liver on USS.
Elevated transaminases aspartate aminotransferase (AAT) or alanine transaminase (ALT) >42IU/L.
Elevated ammonia >47μmol/L.
Renal impairment; creatinine >150μmol/L
Coagulopathy; prothrombin time >14s or APPT >34s.
Microvesicular steatosis on liver biopsy.
Differentiating AFLP from HELLP syndrome
Distinctive features of AFLP
Mild hypertension and proteinuria only.
Early coagulopathy.
Profound and persistent hypoglycaemia.
Marked hyperuricaemia.
Fatty infiltration on imaging the liver (may also be normal).
Management of AFLP
This should be in a high dependency or intensive care setting with a multidisciplinary team.
Management should involve:
treatment of hypoglycaemia
correction of coagulopathy with IV vitamin K and fresh frozen plasma (FFP)
strict control of BP and fluid balance.
Delivery should follow stabilization (regional anaesthesia is contra-indicated in presence of thrombocytopaenia (<80) or deranged clotting).
Bleeding complications are common.
Fluid balance may require central line.
Following delivery, care is supportive, and most women improve rapidly after delivery with no long-term liver damage.
Some patients with fulminant hepatic failure may require transfer to a specialist liver unit, who should be informed as soon as the diagnosis is suspected.
Recurrence rate is unknown but may be greater than that of HELLP.
Haemolysis
Gilbert’s syndrome
Viral hepatitis (hepatitis A, B, C, E, EBV, CMV)
Autoimmune hepatitis (primary biliary cirrhosis, chronic active hepatitis, sclerosing cholangitis)
Gallstones
Cirrhosis
Drug-induced hepatotoxicity
Malignancy.
Hyperemesis gravidarum
Pre-eclampsia/HELLP syndrome
AFLP
Obstetric cholestasis.
Renal tract infections
More common in pregnancy because of dilatation of upper renal tract and urinary stasis. Asymptomatic bacteriuria affects 5–10% of pregnant women; untreated it can lead to symptomatic infection in 40% of cases.
Cystitis complicates 1% of pregnancies.
Pyelonephritis occurs in 1–2% of pregnant women and is associated with preterm labour.
Women should be screened for asymptomatic bacteriuria with MSU sample at booking. If this is −ve, the chance of developing a urinary infection in pregnancy is <2%.
Symptoms
Cystitis: urinary frequency, urgency, dysuria, haematuria, proteinuria, and suprapubic pain.
Pyelonephritis: fever, rigors, vomiting, loin and abdominal pain.
Consider the diagnosis of pyelonephritis in women presenting with hyperemesis or threatened preterm labour.
Investigations
Urinalysis: the most useful markers are nitrites and leukocytes but they may be poor predictors of positive culture in asymptomatic bacteriuria.
MSU: a positive result is confirmed with a culture of >100000 organisms/mL. Mixed growth or non-significant culture—repeat MSU.
Bloods: blood cultures, FBC, U&E, and CRP in a pyrexial patient.
Renal USS: after a single episode of pyelonephritis or ≥2UTI, to exclude hydronephrosis, congenital abnormality, and calculi.
20% of pregnant women with pyelonephritis have an abnormal renal tract.
Monthly MSU should be sent in women with culture-proven urinary infection to prove eradication. 15% develop recurrent bacteriuria and require further treatment.
Treatment
Oral antibiotics are recommended in asymptomatic bacteriuria and cystitis to prevent pyelonephritis and preterm labour.
Pyelonephritis should be treated with IV antibiotics until the pyrexia settles and vomiting stop. IV fluids and antipyretics should also be given (manage in hospital because of risk of preterm labour).
Duration of treatment
Asymptomatic bacteriuria: 3 days.
Cystitis: 7 days.
Pyelonephritis: 10–14 days.
Prevention
Increase fluid intake.
Double voiding and emptying bladder after sexual intercourse.
Cranberry juice: proven in non-pregnant population to ↓ bacteriuria.
Prophylactic antibiotics: if ≥2 culture +ve urine infections + 1 risk factor.
Previous infection (in previous pregnancy or outside pregnancy).
Renal stones.
Diabetes mellitus.
Immunosuppression.
Polycystic kidneys.
Congenital anomalies of renal tract (e.g. Duplex system).
Neuropathic bladder.
Prolonged labour.
Prolonged 2nd stage.
CS.
Pre-eclampsia.
Depends on antibiotic sensitivities. Options include:
Penicillin, amoxicillin.
Cephalosporin.
Gentamicin: monitor levels to minimize risk of ototoxicity.
Trimethoprim: avoid in 1st trimester as it is a folate antagonist.
Nitrofurantoin: avoid in late 3rd trimester as risk of haemolytic anaemia in neonate with glucose-6-phosphate dehydrogenase deficiency.
Sulfonamides: avoid in 3rd trimester as risk of kernicterus in neonate due to displacement of protein binding of bilirubin.
Tetracyclines: cause permanent staining of teeth and problems with skeletal development.
Ciprofloxacin: may causes skeletal problems.
Chronic renal disease
There are increased maternal and fetal risks to pregnancy with renal disease. This is dependent upon:
The underlying cause.
The degree of renal impairment.
The presence and control of hypertension.
The amount of proteinuria.
As renal function deteriorates, so does the ability to conceive and sustain a pregnancy. Successful pregnancies are rare with a serum creatinine >275µmol/L.
Accelerated, and possibly permanent, deterioration in renal function; this is more likely if there is also hypertension and proteinuria and significant renal impairment at conception.
Hypertension.
Proteinuria.
Pre-eclampsia.
Venous thromboembolism (if nephrotic level of proteinuria).
UTI.
Miscarriage.
IUGR.
Spontaneous and iatrogenic preterm delivery.
Fetal death.
Management
Multidisciplinary care involving a renal physician.
Baseline investigations, ideally before conception, include FBC, U&E, urate, 24h protein, and creatinine clearance.
Prepregnancy counselling (genetic counselling if a familial disorder).
Early and regular antenatal care is advised with the following aims;
control BP—tight control lessens chance of renal function declining
monitor renal function and proteinuria
assess fetal size and well-being with serial growth scans + Doppler
early detection of complication—anaemia, UTI, pre-eclampsia, IUGR.
Medication should be reviewed and may need altering. ACEIs should be stopped as soon as pregnancy is confirmed.
Prophylactic low-dose aspirin may reduce the risk of pre-eclampsia.
Erythropoetin may be required with significant renal impairment.
Hospital admission should be considered with ↑ proteinuria or hypertension, deteriorating renal function, or symptoms of pre-eclampsia.
Look for an underlying cause of deterioration in renal function: UTI, obstruction, dehydration, pre-eclampsia, renal vein thrombosis.
It can be difficult to differentiate between pre-eclampsia and deterioration of renal impairment. Thrombocytopaenia, IUGR, and abnormal LFTs suggest the former diagnosis. Aim for vaginal delivery, but rates of CS are increased.
Reflux nephropathy.1
Diabetes.
Lupus nephritis.
Chronic glomerulonephritides.
Polycystic kidneys.2
1 Condition may be familial.
2 Adult polycystic kidney disease is inherited in an autosomal dominant manner.
A successful outcome is achieved in 90% of cases.
Increasing proteinuria is common (>50% of pregnancies) and can be in nephrotic range.
25% of women experience an accelerated decline in renal function.
Preterm delivery rate is up to 50%, and 1/3 have IUGR.
A successful outcome is achieved in 60–90% of cases.
The risk of maternal complications is significantly higher than the chance of successful pregnancy; advise against pregnancy.
There is reduced fertility due to amenorrhoea.
Permanent deterioration in renal function can occur in up to 25%.
Preterm delivery rate is >70%, and the rate of IUGR is 30%.
Creatinine level is dependent on muscle mass as well as renal function so patients may have significantly different creatinine clearance on 24h urine collection, despite similar blood results. The latter is a more accurate reflection of renal function.
Hypertension is an important predictor of outcome regardless of renal function.
Pregnancy after renal transplantation
Menstruation, ovulation, and fertility return after transplantation. Women should be informed of this and contraception discussed. Those who wish to conceive should be advised to wait at least 1yr after transplantation, until stabilization of renal function has been achieved and immunosuppression is at maintenance levels. The best outcomes are seen with:
Well-controlled BP.
No proteinuria.
No evidence of graft rejection.
Plasma creatinine <180, preferably <125µmol/L.
Management of pregnancy in a transplant recipient
Multidisciplinary management with a renal physician.
Antenatal care should be at fortnightly intervals. The aim is:
serial assessment of renal function: deterioration may be caused by infection, dehydration, pre-eclampsia, drug toxicity, or rejection
diagnosis and treatment of graft rejection
BP control (avoid ACEIs)
prevention, early diagnosis, and treatment of anaemia
detection and treatment of any infection
serial assessment of fetus (risk of IUGR).
All women will be on immunosuppressive therapy, which must be continued; commonly used are prednisolone, azathioprine, and tacrolimus.
Aim for vaginal delivery with continuous fetal monitoring (parenteral steroids are necessary to cover labour, due to adrenal suppression).
Prophylactic antibiotics are recommended for obstetric procedures.
A transplanted kidney does not obstruct labour; CS should be for obstetric reasons—the current rate is 40% (patients with pelvic osteodystrophy may need elective CS).
Mycophenalate mofetil is associated with congenital abnormalities and should be stopped before conception.
Increased risk of ectopic pregnancy: as a result of pelvic adhesions 2° to surgery, peritoneal dialysis, and pelvic infection.
15% develop significant deterioration in renal function, which may be permanent.
In most cases pregnancy has no effect on graft survival or function.
Graft rejection ~5%: same as in non-pregnant women.
Hypertension, proteinuria, and pre-eclampsia: 30–40%.
Infections, especially urinary tract: up to 40%.
Miscarriage and congenital anomaly rates are unchanged.
IUGR 30%, higher if the mother is on ciclosporin.
Preterm delivery 45–60%: may be iatrogenic, spontaneous, or 2° to preterm rupture of membranes.
If maternal complications occur before 28wks the chance of a successful pregnancy outcome falls from 95% to 75%.
FBC, U&E, urate.
MSU.
PCR.
USS for fetal growth and Doppler studies.
Calcium, phosphate, albumin, and LFTs.
Single sample for protein/creatinine ratio, or 24h urine for creatinine clearance and protein.
Consider the diagnosis if there is deteriorating renal function with:
Fever.
Oliguria.
Renal enlargement and tenderness.
▶ It can be difficult to diagnose and a renal biopsy may be required.
Blood transfusion should be avoided if possible as it increases likelihood of sensitization making graft rejection more of a problem.
Further reading
Davison J, Nelson-Piercy C, Kehoe S, Baker P (eds) (
http://www.rcog.org.uk/womens-health/clinical-guidance/renal-disease-pregnancy.Acute renal failure
Characterized by oliguria (<400mL/day), ↑ urea and creatinine, hyperkalaemia, and metabolic acidosis. Rare in pregnancy, typically complicating the post-partum period. There are three phases:
Oliguria: few days to several weeks.
Polyuria: 2 days to 2wks, dilute urine is produced, and as waste products are still not excreted, renal function still deteriorates.
Recovery: urine volume returns to normal with a gradual improvement in renal function.
Management of acute renal failure
Seek advice from a physician or nephrologist.
Most cases are reversible with appropriate management (permanent problems more likely with pre-existing renal disease).
Assessment should include the following investigations:
FBC, coagulation, U&E, plasma osmolality, glucose, albumin
blood cultures, MSU, HVS
urinalysis and urine osmolality and electrolytes
ECG (looking for changes due to ↑ K+) and arterial blood gases (ABG)
fetal assessment with CTG and USS
renal USS if obstruction suspected.
Interventions should include catheterization, central venous line, and renal biopsy if improvement is delayed; only a minority require dialysis.
Replace fluid/blood loss but avoid fluid overload as there is a significant risk of pulmonary oedema (accurate documentation of input/output, daily weight, and central venous pressure monitoring).
Maintain BP at levels that allow adequate renal perfusion.
Review medication and stop nephrotoxic drugs.
Correct hyperkalaemia, coagulopathy, and give antibiotics if infection suspected.
Dialysis is required for persistent hyperkalaemia, acidosis, pulmonary oedema, or uraemia.
Haemorrhage:
antepartum (abruption, placenta praevia, etc.)
post-partum (uterine atony, genital tract trauma, etc.)
Hyperemesis.
Septic shock.
Acute fatty liver of pregnancy.
Pre-eclampsia.
HELLP syndrome.
Sepsis (Gram −ve, etc.).
Drug reaction.
Amniotic fluid embolus.
Obstruction
Ureteric damage.
Pelvic or broad ligament haematoma.
Non-pregnancy-related problems may also be the cause.
10mL calcium gluconate (10%) IV slowly, for cardioprotection.
15U soluble insulin with 50g of glucose 50% IV over 20min.
Consider use of Calcium Resonium®.
These are only temporary measures; dialysis may be required.
Systemic lupus erythematosus
More common in women than men (9:1) with a higher prevalence in the Afro-Caribbean population than in whites (5:1). The incidence is 1:1000 and onset during the reproductive age is common. It is a connective tissue disease of relapses (flares) and remissions. Diagnosis is based on the four features from the American Rheumatism Society Criteria present either consecutively or concurrently.
Monitoring disease severity in pregnancy
Flare-ups can be difficult to diagnose as similar symptoms occur in normal pregnancy, e.g. fatigue, hair loss, joint aches, anaemia.
ESR is raised in normal pregnancy and CRP is not a marker of disease activity
C3(d) or anti-DNA levels (i) are an objective index of disease activity.
Renal disease can also be difficult to distinguish from pre-eclampsia, as hypertension, proteinuria, and thrombocytopaenia are common to both conditions:
raised urate and liver transaminases are not features of systemic lupus erythematosus (SLE)
falling C3 and rising anti-DNA levels suggest lupus nephritis
renal biopsy is diagnostic, but rarely performed in pregnancy.
Maternal risks
Long-term prognosis is not affected by pregnancy.
There is increased risk of flare-up, especially in the puerperium.
Hypertension, pre-eclampsia, and placental abruption are more common.
Do not stop hydroxychloroquine as this may precipitate a flare.
Fetal risks
Increased risk of miscarriage, preterm delivery, preterm rupture of membranes, IUGR, and in utero fetal death.
These risks are due to anticardiolipin antibodies, lupus anticoagulant, renal impairment, or hypertension. Risk is low if all these are absent.
Congenital heart block may occur in women with anti-Ro (or La) antibodies, which cross the placenta (risk of occurrence if anti-Ro +ve is 2%, increasing to 18% if previously affected child).
Transient skin lesions similar to cutaneous lupus can occur in neonates (usually in first 2wks of life).
Management
Multidisciplinary team management.
Prepregnancy counselling of maternal and fetal risks based on BP, renal function, anti-Ro, and antiphospholipid antibody status.
Treat hypertension and modify medication if necessary (see 
Blood pressure in pregnancy: hypertension, p. 62).
Advise conception during periods of disease remission: less risk of flare.
Obtain objective evidence of flare-up.
Flare-ups should be treated by starting or ↑ dose, or steroids.
Assess fetal growth and well-being (uterine artery Doppler at 24wks is a useful screening test).
Diagnosis requires four of the following features, either simultaneously or following each other:
Facial butterfly rash.
Discoid lupus.
Photosensitivity of skin rash.
Oral or nasopharyngeal ulceration.
Arthritis: non-erosive, migratory of two or more peripheral joints.
Serositis: pleurisy or pericarditis.
Renal problems: proteinuria >500mg/day or cellular casts.
Neurological problem: psychosis or convulsions.
Haemotological problem: haemolytic anaemia, leucopaenia (<4×109/L), lymphopaenia (<1.5×109/L) or thrombocytopaenia (<100×109/L).
Anti-DNA, antinuclear antibodies (ANAs), chronic false +ve syphilis serology for >6mths, or +ve lupus erythematosus (LE) cell preparation.
Further reading
Bertsias G, et al.
http://ard.bmj.com/content/67/2/195.full.Antiphospholipid antibody syndrome
This condition is diagnosed on the basis of the presence of one or more clinical features and one or more positive laboratory findings. The condition may be complicated by hypertension, pulmonary hypertension, epilepsy, thrombocytopaenia, leg ulcers, and valvular problems. It is called 1° if features of connective tissue disease are absent or it can occur 2° to established connective tissue disease. Lupus anticoagulant is an inhibitor of the coagulation pathway, and anticardiolipins are antibodies against the phospholipid components of cell walls.
Vascular thrombosis: arterial or venous.
Three or more consecutive miscarriages (<10wks).
One or more fetal death >10wks.
One or more preterm delivery (<34wks) due to pre-eclampsia or placental insufficiency.
Anticardiolipin antibody (IgG or IgM) in medium or high titre (in titre >99th percentile), on at least two occasions >12wks apart.
β2-glycoprotein-1 antibody (IgG or IgM) in medium or high titre (in titre >99th percentile), on at least two occasions >12wks apart.
Lupus anticoagulant present on at least two occasions >6wks apart.
Maternal risks
These include thrombosis, thrombocytopenia, placental abruption and pre-eclampsia.
Previous poor obstetric history is an important predictor of outcome (the risk is less with just recurrent miscarriages).
Fetal risks
Risks include early and late miscarriage, in utero death, IUGR.
Fetal outcome may be improved by multidisciplinary management, fetal monitoring (including growth, umbilical and uterine artery Dopplers), appropriate drug therapy, and timely delivery.
Women with double or triple laboratory criteria positivity and/or previous thrombotic events are at highest risk of pregnancy complications.
Possible mechanisms of fetal injury are recurrent placental infarction and direct cellular injury.
Liaise with anaesthetist if the woman is on LMWH (regional anaesthesia is contraindicated within 12h of a prophylactic dose of heparin and 24h of therapeutic dose).
No thrombosis or pregnancy loss: no treatment or aspirin 75mg.
Previous thrombosis: aspirin + LMWH (therapeutic).
Previous recurrent 1st-trimester miscarriages: aspirin + LMWH (prophylactic dose).
Previous IUD or IUGR or severe pre-eclampsia: aspirin + LMWH (prophylactic dose).
Start aspirin (od, nocte) and LMWH when pregnancy confirmed.
Take home baby rate: 40% aspirin alone; 70% aspirin and LMWH.
Some studies have disputed improved pregnancy outcomes with LMWH compared with aspirin alone.
Consider stopping heparin if 24wk uterine artery Doppler is normal. The improved live birth rate is due to ↓ miscarriages.
Steroids are not recommended → less success and more side effects.
Further reading
Bertolaccini ML, et al.
de Jesus GR, et al.
Miyakis S, et al.
Rheumatoid arthritis
This is more common in women than men, with an incidence of 1:1000–2000 pregnancies. Characterized by symmetrical chronic inflammation and destruction of synovial joints. Autoantibodies are formed to immunoglobulins, which are deposited as immune complexes in the synovial fluid and elsewhere. 80–90% have rheumatoid factor and 20–30% are ANA +ve. It is a multisystem disorder with extra-articular features including anaemia, nodules, carpal tunnel syndrome, and eye and lung involvement.
Maternal risks
The condition improves in pregnancy in 50% of cases, but flare-up is common in the puerperium.
At this age atlantoaxial subluxation rarely causes problems during intubation.
Fetal risks
There is usually no adverse effect on pregnancy unless the woman is anti-Ro +ve or has antiphosphlipid antibodies (5–10%).
Paracetamol.
Steroids.
Hydroxychloroquine.
Sulfasalazine (in conjunction with 5mg folic acid).
Azathioprine.
Biological agents, such as etanercept, adalimumab, infliximab (until 3rd trimester as effect on neonatal immune system is unknown).
NSAIDs: oligohydramnios, premature closure of ductus arteriosus and neonatal haemorrhage especially with 3rd-trimester use.
Gold: teratogenic effect seen in animals only.
Penicillamine: connective tissue abnormalities only in high doses.
Cyclophosphamide (alkylating agent): risk of leukaemia.
Methotrexate (folate antagonist): causes miscarriage and congenital anomalies.
Myasthenia gravis
Uncommon condition; highest incidence in women of childbearing age. It is caused by autoimmune disruption of nicotinic acetylcholine receptors at the skeletal muscle motor end plate, leading to muscle weakness and fatigue. 90% have acetylcholine receptor antibodies. Muscles affected include eyes (ptosis, diplopia), face, neck, limbs, and trunk. Diagnosis confirmed by prompt, transient improvement in muscle strength with Tensilon test. Condition can be worsened by infection, hypokalaemia, exercise, emotion, and drugs (aminoglycosides, MgSO4, local anaesthetic, β-blockers, β-agonists, narcotics, and neuromuscular blocking drugs).
Effect of pregnancy on myasthenia
No change 60%, improvement 20%, deterioration 20%.
There is no consistent effect between pregnancies.
Symptoms commonly worsen post-partum.
Previous thymectomy associated with fewer exacerbations in pregnancy.
Hyperemesis, delayed gastric emptying, ↑ volume of distribution of drugs, ↑ renal clearance can lead to subtherapeutic drug levels.
Increased doses of anticholinesterases may be required as pregnancy advances; this is best achieved by decreasing dose intervals.
Parenteral anticholinesterases should be given in labour to avoid absorption problems.
Effect of myasthenia on pregnancy
Preterm delivery, polyhydramnios, and IUGR are all increased.
The 1st stage of labour is not prolonged (the smooth muscle of the myometrium is not affected by the condition).
In the 2nd stage there can be skeletal muscle fatigue; instrumental delivery may be required to prevent maternal exhaustion.
Neonatal myasthenia can occur following delivery in 10–20% of babies:
it results from transplacental passage of maternal antibodies
there is poor correlation between the condition and maternal disease activity or antibody levels
presentation is with generalized hypotonia, poor sucking/feeding, and a weak cry
onset is within 24h and the condition resolves by 2mths
treatment is with anticholinesterases.
MgSO4 is contraindicated for treatment of eclampsia in myasthenia.
Management
Inform neurologist, paediatrician, and anaesthetist of pregnancy.
The usual treatment options have all been used in pregnancy:
long-acting anticholinesterases (e.g. pyridostigmine)
immunosuppression: steroids, azathioprine
immunoglobulins
plasmapheresis
thymectomy.
Further reading
Norwood F, et al.
Diabetes: established disease in pregnancy
Established diabetes affects 1–2% of pregnancies.
Without good glycaemic control there is increased fetal and neonatal morbidity and mortality.
Management should be by a multidisciplinary team including:
obstetrician
physician/diabetologist
diabetic specialist nurse/midwife
dietitian.
Glucose metabolism is altered by pregnancy.
Many pregnancy hormones are diabetogenic (human placental lactogen, cortisol, glucagon, oestrogen, and progesterone).
Insulin requirements ↑ throughout and are maximal at term.
Effect of diabetes on pregnancy
Maternal hyperglycaemia: leads to fetal hyperglycaemia.
Fetal hyperglycaemia: leads to hyperinsulinaemia (through β-cell hyperplasia in fetal pancreatic cells). Insulin acts as a growth promoter:
macrosomia
organomegaly
↑ erythropoiesis
fetal polyuria (polyhydramnios).
Neonatal hypoglycaemia: caused by the removal of maternal glucose supply at birth from a hyperinsulinaemic fetus.
Respiratory distress syndrome: more common in babies born to diabetic mothers due to surfactant deficiency occurring through reduced production of pulmonary phospholipids.
Effect of pregnancy on diabetes
Ketoacidosis: may be associated with hyperemesis, infection, tocolysis (β-sympathomimetics), or steroid therapy.
Retinopathy: there is a two-fold increased risk of development or progression of existing disease. Rapid improvement in glycaemic control leads to increased retinal blood flow, which can cause retinopathy. All diabetic women should have assessment for retinopathy in pregnancy, and proliferative retinopathy requires treatment. Early changes usually revert after delivery.
Nephropathy: affects 5–10% of women. Renal function and proteinuria may worsen during pregnancy. This is usually temporary. There is increased maternal risk of pre-eclampsia and fetal risk of IUGR in this population and increased surveillance is required.
Ischaemic heart disease: pregnancy increases cardiac workload. Women with symptoms should be assessed by a cardiologist before conception.
UTI.
Recurrent vulvovaginal candidiasis.
Pregnancy-induced hypertension/pre-eclampsia.
Obstructed labour.
Operative deliveries: CS and assisted vaginal deliveries.
↑ Retinopathy (15%).
↑ Nephropathy.
Cardiac disease.
Polycythaemia.
Jaundice.
Hypoglycaemia.
Hypocalcaemia.
Hypomagnesaemia.
Hypothermia.
Cardiomegaly.
Birth trauma: shoulder dystocia, fractures, Erb’s palsy, asphyxia.
Respiratory distress syndrome.
.
In diabetics with poor control
Diabetes: antenatal management
Prepregnancy counselling
Offer to all diabetic women of reproductive age; include:
Achievement of optimal control: keep fasting blood glucose between 3.5 and 5.9mmol/L and 1h post-prandial <7.8mmol/L (↑ risk of miscarriage and congenital abnormalities with poor control).
Assessment of severity of diabetes: check for hypertension, retinopathy (fundoscopy, ophthalmology assessment), nephropathy (U&E, urinalysis, urinary protein:creatinine ratio, 24h urine for protein, creatinine clearance), neuropathy (clinical assessment), and cardiac disease.
Education: ensure understanding of effects of hyperglycaemia on fetus and need for tight control—instruct to inform doctor as soon as pregnancy confirmed; some drugs may need stopping (ACEIs).
General health: stop smoking, optimize weight (aim for a normal BMI), minimize alcohol (max 1–2U bd/wk).
Folic acid: ↑ risk of neural tube defects, so start on 5mg folic acid.
Rubella status: offer vaccination if not rubella immune.
Contraception: ensure effective contraception until good control achieved and pregnancy desired.
Antenatal care
Manage by a multidisciplinary team with a diabetologist.
Control: as for prepregnancy, aim for normoglycaemia. Monitor glucose at least 6 times/day, usually before and after meals for a tighter control. Women can alter their own insulin based on their glucose. Insulin can be given as SC injections 4 times/day or as a continuous infusion. The latter is no better than injections.
HbA1c every month: this gives an objective measurement of control over the preceding 2mths.
Dietitian review: low sugar, low fat, high fibre diet—low glycaemic index.
Dating ultrasound: to confirm viability and gestation.
Down’s syndrome screening: consider nuchal translucency or invasive testing. Serum screening is affected by diabetes (↓ AFP); therefore, less accurate unless appropriate normograms used.
Anomaly scan: 5–10-fold ↑ risk of congenital anomalies. Risk depends on glycaemic control prior to conception and early pregnancy.
Fetal echocardiography: at 20–24wks.
Antenatal surveillance: individualize care. Serial USS every 2–4wks to detect polyhydramnios, macrosomia, or IUGR. Increased surveillance if problems detected. The use of umbilical artery Doppler should be restricted to cases of IUGR; it is not of value as a screening test.
Hypoglycaemia: awareness of hypoglycaemia may be lost. Educate patient and family and supply with glucagon.
Diabetes: labour and post-partum care
Timing and mode of delivery should be individualized and based on EFW and obstetric factors (previous mode of delivery, gestation, glycaemic control, and antenatal complications).
Timing of delivery
Some obstetricians advise elective delivery by induction of labour at 38–39wks if there are no maternal or fetal complications and good glycaemic control. Outcomes may not be better than awaiting spontaneous labour. Delivery should be expedited if complications occur.
Mode of delivery
Vaginal delivery is preferred. Continuous electronic fetal monitoring is advised in labour. Consider elective CS if EFW is >4.5kg. If EFW is 4–4.5kg use obstetric factors to influence decision. CS rates are high: 50–60%. Give antibiotic and thromboprophylaxis if CS is carried out.
Shoulder dystocia is more common at all birth weights than in the non-diabetic population. Experienced obstetricians should perform instrumental deliveries because this is an independent risk factor.
Glycaemic control
Diet controlled: check blood glucose hourly. If glucose >6.0mmol/L, start sliding scale.
Insulin dependent: continue SC insulin until in established labour, then convert to insulin sliding scale (Table 5.1). If induction of labour or CS, continue normal insulin until day of procedure, then start sliding scale in early morning.
Blood glucose (mmol/L) | Insulin rate (mL/h) |
<3.0 | 0 |
3.1–4 | 0.5 |
4.1–6 | 1.0 |
6.1–8 | 1.5 |
8.1–11 | 2.0 |
11.1–15 | 3.0 |
>15.1 | Call doctor |
Blood glucose (mmol/L) | Insulin rate (mL/h) |
<3.0 | 0 |
3.1–4 | 0.5 |
4.1–6 | 1.0 |
6.1–8 | 1.5 |
8.1–11 | 2.0 |
11.1–15 | 3.0 |
>15.1 | Call doctor |
Prescription: 50U human actrapid in 50mL normal saline (sodium chloride 0.9%), via a continuous infusion pump.
Avoid maternal hyperglycaemia → causes fetal hypoglycaemia.
If steroids are given for threatened preterm labour, monitor glucose closely—hyperglycaemia should be anticipated.
Post-partum care
Encourage breast-feeding. Avoid oral hypoglycaemic drugs if breast-feeding—metformin and insulin are safe.
Baby needs early feeding and glucose monitoring.
Contraception
Avoid the COCP if breast-feeding or vascular complications. Progesterone-based contraception is safe and there are no contra-indications to an IUCD. This should be fitted from 6wks post-partum onwards. Sterilization or vasectomy should be considered if the family is complete.
Review sliding scale regularly.
Renew insulin syringe every 24h.
IV fluids should always be given with the sliding scale:
stable situations—5% glucose
high blood glucose—normal saline.
Insulin requirements fall dramatically after delivery of the placenta. Halve the sliding scale initially. Change back to SC insulin when eating and drinking. Start with the prepregnancy dose of SC insulin. If this is not known, it is roughly half the last dose. The dose may need to be further reduced if breast-feeding. Stop the sliding scale 1h after giving the SC dose.
▶ Aim for blood sugar monitoring (BM) 4–9mmol/L in the post-partum period.
Gestational diabetes
The World Health Organization (WHO) now includes gestational impaired glucose tolerance (IGT) with gestational diabetes. A proportion of women diagnosed in pregnancy will actually have previously unrecognized type 1 or 2 diabetes (20–30%). WHO does not advocate universal screening. Selective screening should be based on risk factors.
BMI above 30kg/m2.
Previous macrosomic baby weighing 4.5kg or above.
Previous gestational diabetes.
First-degree relative with diabetes.
Family origin with a high prevalence of diabetes (South Asian, black Caribbean, and Middle Eastern).
The diagnosis is based on an oral glucose tolerance test (OGTT) (Box 5.4), usually undertaken at 26–28wks gestation. A normal result in early pregnancy does not mean that gestational diabetes will not develop, and an OGTT should be repeated by 34wks if there are concerns.
Overnight fasting (8h minimum):
water only may be consumed during this time
no smoking.
75g Glucose load in 250–300mL water.
Plasma glucose measured fasting and at 1h and 2h.
Results
Gestational diabetes:
Fasting ≥5.1mmol/L (92mg/dL)
1hr ≥10.0mmol/L (180mg/dL)
2hrs ≥8.5mmol/L (153mg/dL)
Diabetes:
fasting glucose ≥7.0mmol/L
2h glucose ≥11.1mmol/L.
IGT:
fasting glucose >6.0mmol/L but <7.0mmol/L
2h ≥7.8 <11.0mmol/L.
Only one value needs to be abnormal to make the diagnosis.
Management
Management by a multidisciplinary team.
Measure glucose 4–6 times/day (1h post-prandial measurements may be more effective in preventing macrosomia than pre-meal glucose).
Diet should be first-line treatment:
aim for normoglycaemia and avoid ketosis.
weight should remain steady if diet followed
compliance is often poor—dietitian input may help.
Start metformin or start/add insulin if:
pre-meal glucose >6.0mmol/L
1h post-prandial glucose >7.5mmol/L.
AC >95th centile despite apparent good control.
There is no increased risk of miscarriage or congenital anomalies; other fetal and neonatal risks are similar to established diabetes (IUGR is less likely).
Antenatal and intrapartum care as for established diabetes.
Post-partum:
stop metformin, insulin, and glucose infusions
check glucose prior to discharge to ensure normal (risk of previously undiagnosed type 2 diabetes)
arrange OGTT at 6wks post-partum
education—50% risk of developing type 2 diabetes mellitus over next 25yrs (this risk can be reduced by maintaining physical activity and avoiding obesity).
Further reading
Coustan DR, et al.
National Institute for Health and Care Excellence (2008). Diabetes in pregnancy: Management of diabetes and its complications from pre-conception to the postnatal period. Available at: https://www.nice.org.uk/guidance/cg63.
Thyrotoxicosis
Thyrotoxicosis occurs in 1:500 pregnancies. The most common cause is Graves’ disease (95%). This is an autoimmune disease characterized by the production of TSH receptor stimulating antibodies. Most women have been diagnosed before pregnancy and may be on treatment. Many symptoms and signs occur in normal pregnancy. The most discriminatory features are weight loss, tremor, persistent tachycardia, and eye signs. Diagnosis is made by a low TSH and high free T4 or free T3 levels.
2 Use pregnancy-specific reference ranges for each trimester. See Table 5.2.
Non-pregnant | 1st trimester | 2nd trimester | 3rd trimester | |
TSH (µ/l) | 0.3–4.2 | 0–5.5 | 0.5–3.5 | 0.5–4 |
Free T4 (pmol/L) | 9–26 | 10–16 | 9–15.5 | 8–14.5 |
Free T3 (pmol/L) | 2.6–5.7 | 3–7 | 3–5.5 | 2.5–5.5 |
Non-pregnant | 1st trimester | 2nd trimester | 3rd trimester | |
TSH (µ/l) | 0.3–4.2 | 0–5.5 | 0.5–3.5 | 0.5–4 |
Free T4 (pmol/L) | 9–26 | 10–16 | 9–15.5 | 8–14.5 |
Free T3 (pmol/L) | 2.6–5.7 | 3–7 | 3–5.5 | 2.5–5.5 |
Effect of pregnancy on thyrotoxicosis
Usually improves in the 2nd and 3rd trimester.
Pregnancy is a state of relative immunodeficiency, but with return of normal immunity in the puerperium it is likely to deteriorate.
Effect of thyrotoxicosis on pregnancy
Maternal and fetal outcome usually good if disease is controlled.
Untreated or poorly controlled thyrotoxicosis is associated with sub-fertility (amenorrhoea due to weight loss), ↑ risk of miscarriage, IUGR, and premature delivery.
With the stress of infection, labour, or operative delivery a ‘thyroid storm’ can occur in poorly controlled patients. This is a medical emergency, characterized by pyrexia, confusion, and cardiac failure. Neonatal/fetal thyrotoxicosis occurs in up to 10% of babies born to women with current or past history of Graves’ disease (transplacental passage of thyroid receptor stimulating antibodies).
2 Check antibody levels in all women with a history of Graves’ disease.
If antibodies are present, monitor by fetal heart rate, and serial USS for growth and fetal goitre (treatments include antithyroid drugs titrated to fetal heart rate, or delivery).
Antibodies have a half-life of around 3wks, therefore transient neonatal hyperthyroidism may occur.
Treatment
Antithyroid drugs: carbimazole and propylthiouracil (PTU) are the two drugs used. The aim of treatment is to achieve clinical euthyroid with T4 at the upper limit of normal. Use the lowest dose of drug to achieve this. Both drugs cross the placenta and may cause fetal hypothyroidism in high doses. PTU is preferred for new cases diagnosed before 9wk gestation, because of inferior teratogenic risk. β-blockers may safely be used for symptom relief in new cases for a short period of time.
Surgery: thyroidectomy can be safely done in pregnancy. Indications include dysphagia, stridor, suspected carcinoma, and allergies to both antithyroid drugs.
Radioactive iodine is contraindicated in pregnancy and breast-feeding.
Graves’ disease.
Toxic multinodular goitre.
Toxic adenoma.
Carcinoma.
Subacute thyroiditis.
Amiodarone.
Lithium.
Women with hyperemesis or a molar pregnancy may mimic biochemical hyperthyroidism as hCG, at high levels, can stimulate TSH receptors. They usually have no clinical signs of thyrotoxicosis and should not be treated.
Graves’ disease often improves in pregnancy, but relapses post-partum.
With treatment the outlook is good for mother and baby.
Untreated thyrotoxicosis is dangerous for mother and baby.
PTU and carbimazole may be used as treatment; both cross the placenta.
Avoid radioactive iodine.
Check for TSH receptor stimulating antibodies.
Monitor thyroid function every 4–6wks in new cases, less frequently in stable cases.
Monitor fetus by fetal heart rate and serial USS for growth and presence of goitre.
Breast-feeding is safe with moderate doses of PTU and carbimazole. Monitor TFTs in baby at higher doses.
Hypothyroidism
Hypothyroidism complicates around 1% of pregnancies. Most cases have been diagnosed previously and patients are on replacement therapy. New diagnosis in pregnancy is rare. The commonest cause is autoimmune and may be associated with other autoimmune conditions.
Classical symptoms and signs may be seen in normal pregnancy. The most discriminatory features are cold intolerance, bradycardia, and slow relaxation of tendon reflexes.
The diagnosis is made by a low free T4. TSH is also raised, but in isolation is not diagnostic.
2 Use pregnancy-specific reference ranges for each trimester (Table 5.2). Free T4 levels are normally lower in the 2nd and 3rd trimester. TSH level is most useful.
Effect of pregnancy on hypothyroidism
No effect usually. Most women do not need to alter their dose of levothyroxine. The most common reason for increasing levothyroxine is an inadequate prepregnancy dose.
Effect of hypothyroidism on pregnancy
Untreated hypothyroidism is associated with anovulatory infertility.
Severe or untreated hypothyroidism in pregnancy is associated with increased risk of miscarriage, fetal loss, pre-eclampsia, and low birth weight.
Hypothyroidism is also associated with gestational diabetes.
The fetus requires maternal T4 for normal brain development before 12wks (inadequate replacement may lead to reduced IQ in the offspring); after this time T3/T4/TSH do not cross the placenta.
2 Aim for optimal control before conception.
Women on adequate replacement therapy are euthyroid at the onset of pregnancy and have good maternal and fetal outcomes.
Neonatal/fetal hypothyroidism is very rare and caused by the transplacental transfer of TSH receptor blocking antibodies, which may be seen in atrophic thyroiditis.
Treatment
Most women should continue their maintenance dose of levothyroxine; the dose should only be increased if they are under-replaced (shown by TSH level).
TSH levels need to be checked before conception and every 6–8wks through pregnancy, unless there has been a dose adjustment, in which case it should be repeated in 4–6wks.
If the diagnosis is made in pregnancy, in the absence of cardiac disease, consider a starting dose of 25–50 micrograms daily.
In practice, aim for a TSH level of <2.5–3µ/L in the first trimester.
Levothyroxine can be safely taken during breast-feeding.
Hashimoto’s thyroiditis.
Atrophic thyroiditis.
Congenital absence of thyroid.
Iatrogenic:
thyroidectomy
radioiodine
drugs (amiodarone, lithium, iodine, antithyroid drugs).
Pituitary cause (rare).
Other thyroid diseases
Post-partum thyroiditis
This is an autoimmune condition causing destructive thyroiditis. It presents post-partum due to return to normal immunity after the relative immunosuppression of pregnancy. Preformed T4 is released, which may cause transient hyperthyroid symptoms followed by hypothyroidism as the reserve of T4 is used up.
It can present for up to a year after delivery, but usually occurs 3–4mths post-partum. The incidence varies (5–10%) and it may manifest as transient hypothyroidism (40%), hyperthyroidism (40%), or biphasic with first hyperthyroidism then hypothyroidism (20%). There may be a family history of thyroid disease in 25% of cases. Many women are asymptomatic and often symptoms are vague and may be attributed to the post-partum state. Initiation of treatment should be based on symptoms and not biochemical results. Some women may not require any treatment. Most recover spontaneously. Risk of recurrence in future pregnancy is 70%. Risk of permanent hypothyroidism is 5%/yr for antibody-positive women (90% of patients have thyroid peroxidase antibodies).
The hyperthyroid phase should be treated with β-blockers (not antithyroid drugs).
Differential diagnosis: Graves’ disease.
The hypothyroid state should be treated with thyroxine; treatment should be withdrawn after 6mths to check for recovery.
Differential diagnosis: Hashimoto’s thyroiditis or Sheehan’s syndrome.
2 Long-term follow-up should be with annual TFT.
Thyroid nodules
Thyroid nodules are common, affecting 5% of women in their reproductive years.
A small proportion of thyroid nodules are malignant.
Differential diagnosis is a solitary toxic nodule, subacute (de Quervain’s) thyroiditis, or a bleed into a cystic lesion.
Investigations:
TFT and thyroid antibodies
thyroglobulin level: suggests malignancy if >100 micrograms/L
USS—cystic nodules are more likely to be benign than solid nodules
fine needle aspiration for cytology (cystic lesion)
biopsy (solid lesion).
Radioiodine is contraindicated in pregnancy.
Malignant lesions can be surgically treated in the 2nd and 3rd trimesters, and postoperatively thyroxine can be safely given to completely suppress TSH in TSH-dependent tumours.
Past history of radiation to neck or chest.
Fixed lump.
Lymphadenopathy.
Rapid growth of painless nodule.
Voice change.
Neurological involvement such as Horner’s syndrome.
Further reading
De Groot L, et al.
Phaeochromocytoma
This is a tumour of the adrenal medulla that causes excess secretion of catecholamines. They are bilateral in 10% of cases and malignant in 10%. In non-pregnant hypertensive patients the incidence is around 1:1000; it is exceedingly rare in pregnancy. A high index of clinical suspicion is required to make the diagnosis—the condition should be considered in hypertensive pregnant women if there are atypical features. Untreated, mortality is high: maternal mortality ~17% and fetal mortality ~26%. Maternal mortality can be reduced to ~4% with treatment.
Hypertension.
Sweating.
Palpitations.
Anxiety.
Headache.
Vomiting.
Symptoms may mimic pre-eclampsia and may be paroxysmal.
Investigations
Raised 24h urinary catecholamines or their metabolites, such as vanillylmandelic acid (VMA) confirm the diagnosis—a level twice normal is highly suggestive and 3 times normal diagnostic (methyldopa and labetalol can interfere with the results). Plasma metanephrines can also be used for screening.
Imaging is required to localize the tumour (USS, CT, or MRI are all used but MRI is preferable in pregnancy).
Management
Multidisciplinary management including endocrine physician and surgeon.
The main risk from this condition is potentially fatal hypertensive crises that can cause strokes, congestive cardiac failure, and arrhythmias.
Patients should be commenced on α-blockers (phenoxybenzamine) to control BP, then β-blockers (propranolol) to control tachycardia.
Do not start β-blockers until a few days after α-blockers or a hypertensive crisis may ensue.
Surgery is the only cure for the condition and should only be undertaken once pharmacological blockade has been achieved (if the diagnosis is made after 24wks, surgery should be delayed until fetal maturity is achieved).
CS is preferred for delivery as it minimizes potential catecholamine surges (removal of the adrenal tumour can be done at the time of CS or later).
Anaesthetic experience is vital as the patient may have a catecholamine surge during delivery due to inadequate pharmacological blockade.
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Congenital adrenal hyperplasia
This is an autosomal recessive disorder affecting the synthesis of glucocorticoids and mineralocorticoids. In response to low levels of these hormones, the pituitary gland produces large amounts of ACTH and this results in excessive production of sex steroids. A number of enzyme deficiencies can lead to this condition: the commonest is 21-hydroxylase deficiency. Many different gene mutations exist, which result in variable clinical presentations. Treatment is replacement with corticosteroid +/– fludrocortisone.
Affected individuals present in several ways:
Salt-losing crisis in neonate.
Masculinization of female fetus (ambiguous genitalia at birth).
Precocious puberty in boy.
2 If a couple has an affected child, risk in subsequent pregnancies is 1:4.
Maternal and fetal risks
Pregnancies in women with congenital adrenal hyperplasia (CAH), diagnosed in infancy, are uncommon. Many are subfertile due to anovulation; others have psychosexual and emotional difficulties or anatomical problems related to corrective surgery for virilization.
↑ Risk of miscarriage, pre-eclampsia, and IUGR.
↑ Risk of CS due to android-shaped pelvis.
Management
Maternal steroid therapy should be continued at same dose throughout pregnancy.
Genetic counselling should be offered to all couples after the birth of an affected child; antenatal diagnosis can be untaken in subsequent pregnancies, but the female fetus is at risk of virilization before these tests can be undertaken,
2 Start dexamethasone, 1.5mg/day, as soon as pregnancy confirmed, and before 5wks gestation (dexamethasone crosses placenta and suppresses excessive fetal ACTH production, which prevents masculinization and neuroendocrine effects to female fetus).
Usually CVS is the preferred method of antenatal diagnosis.
If the fetus is male, or an unaffected female, stop dexamethasone.
If the fetus is an affected female options include continuation of dexamethasone throughout pregnancy or termination of pregnancy.
Mother needs to be monitored for gestational diabetes and ↑ BP.
If invasive testing is declined, dexamethasone should be given and fetal sex determined by USS.
Suppression of virilization with dexamethasone is not always successful and parents should be appropriately counselled.
During labour increase steroid dose—hydrocortisone 100mg IV every 6h.
Postnatally the child needs to be reviewed by a paediatrician and evidence of virilization sought; replacement glucocorticoid and mineralocorticoid therapy should be continued.
Amniocentesis (≥16wks):
Fetal sex.
17-Hydroxyprogesterone and androgen levels in amniotic fluid.
Human leucocyte antigen (HLA) typing of amniotic cells.
Chorionic villus sampling (≥10wks):
fetal sex
gene probe for specific mutations of 21-hydroxylase.
PCR of fetal cells in maternal blood may help determine fetal sex.
Addison’s, Conn’s, and Cushing’s syndromes
Addison’s disease
Adrenocortical failure with deficiency of glucocorticoids and mineralocorticoids; may be associated with other autoimmune conditions: pernicious anaemia, diabetes, or thyroid disease. Most common cause in the UK is autoimmune destruction of the adrenals. Worldwide, TB is an important cause. It is rare to make a new diagnosis in pregnancy.
Diagnosis is based on δ cortisol, ↓ ACTH, and poor response to tetracosactide (synthetic ACTH).
2 Cortisol measurements are normally higher in pregnancy; therefore, care should be taken in interpreting results.
Pregnancy does not affect the course of Addison’s disease and if the condition is treated there are no adverse fetal effects.
Patients should continue with their usual steroid doses (hydrocortisone 20–30mg/day and fludrocortisone 100 micrograms/day) throughout pregnancy.
Increased or IV doses of steroids are required to cover periods of stress, such as infection, hyperemesis, labour, or surgery.
In the puerperium physiological diuresis can cause profound hypotension; therefore tail steroids down to maintenance over several days.
Breast-feeding is safe.
Conn’s syndrome
This is a rare cause of hypertension in pregnancy. Primary hyperaldosteronism is caused by adrenal aldosterone-secreting adenoma or carcinoma or bilateral adrenal hyperplasia.
Clinical features are hypokalaemia (K+ <3.0mmol/L) and hypertension.
Diagnosis is based on ↓ K+, ↑ plasma aldosterone, ↓ renin.
Treat hypertension as usual (but avoid spironolactone which is used outside pregnancy) and give potassium supplements.
Cushing’s syndrome
This is a condition of glucocorticoid excess; very rare in pregnancy as anovulation leads to infertility. Causes in pregnancy are excessive pituitary ACTH secretion (44%), adrenal adenoma (44%), and adrenal carcinoma (12%).
Diagnosis based on ↑ cortisol, which fails to suppress with high dose dexamethasone suppression test (ACTH levels depend on cause).
Maternal morbidity and mortality are raised: specific risks include pre-eclampsia, diabetes, and poor wound healing.
Fetal loss, prematurity, and perinatal mortality are increased and adrenal insufficiency can occur in the neonate.
Surgery is the treatment of choice for adrenal and pituitary causes, and it may be successfully performed in pregnancy.
Limited knowledge of use of drugs in pregnancy. Medical treatment include drugs that suppress cortisol production (metyrapone) or ACTH activity (cyproheptadine).
Avoid breast-feeding.
Weight loss.
Vomiting.
Postural hypotension and syncope.
Weakness.
Hyperpigmentation (skin folds, scars, mouth).
Bruising.
Myopathy.
Hypertension.
Excessive weight gain/oedema.
Hirsutism.
Excessive striae.
Headaches.
Acne.
Obesity.
Impaired glucose tolerance/diabetes.
Hyperprolactinaemia
Prolactinomas are the commonest pituitary tumours seen in pregnancy. They can be classified according to their size into microprolactinoma (<1cm) and macroprolactinoma (>1cm). Outside pregnancy, diagnosis is based on a raised serum prolactin level in conjunction with imaging of the pituitary fossa by CT or MRI. In pregnancy, there is a 10-fold physiological rise in prolactin levels, so prolactin level is not a useful test in diagnosis or follow-up.
Amenorrhoea.
Galactorrhoea.
Headache.
Visual field defects (bitemporal hemianopia).
Diabetes insipidus.
Effect of pregnancy on prolactinoma
There is a possibility that prolactinomas will increase in size in pregnancy and cause symptoms. The highest risk (15%) is in the 3rd trimester with macroprolactinomas. Pregnancy should be delayed until tumour shrinkage has occurred with drug therapy. This reduces the risk of symptomatic tumour expansion to 4%. The risk is small for microprolactinomas (1.6%).
Effect of prolactinoma on pregnancy
Untreated, high prolactin levels lead to infertility. With preconception treatment fertility can be restored. Most cases have no complications in pregnancy. Breast-feeding is not contraindicated.
Management
Outside pregnancy dopamine receptor agonists (cabergoline and bromocriptine) reduce prolactin levels; these could be stopped upon confirmation of pregnancy.
The patient should report symptoms that might suggest tumour expansion—headache, visual disturbance, thirst, and polyuria; this should then be investigated by CT or, preferably, MRI of the pituitary.
Formal visual field testing is recommended in pregnancy for symptomatic and asymptomatic patients with macroprolactinomas.
Bromocriptine can safely be restarted if there is concern regarding tumour expansion and can be continued during breast-feeding, but may suppress milk production.
Surgery is reserved for macroprolactinomas that fail to shrink despite drug therapy, but is usually delayed until after delivery.
Normal pregnancy and breast-feeding.
Pituitary adenomas.
Hypothalamus or pituitary stalk lesions.
Empty sella syndrome.
Hypothyroidism.
Chronic renal failure.
Drugs: phenothiazines, metoclopramide, methyldopa.
Hypopituitarism
This is anterior pituitary failure. Diagnosis is based on reduced levels of anterior pituitary and target organ hormone levels: thyroxine, TSH, cortisol, ACTH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and growth hormone. There is also a failed response to an insulin stress test with lack of increase in growth hormone, ACTH, and prolactin levels.
Pituitary surgery.
Radiotherapy.
Pituitary or hypothalamic tumours.
Post-partum pituitary infarction (Sheehan’s syndrome).
Autoimmune lymphocytic hypophysitis.
Imaging of the pituitary area, by MRI or CT, should be undertaken to exclude a space-occupying lesion.
Pregnancy is possible, but may require ovulation induction with gonadotrophins.
Once pregnancy is achieved the feto-placental unit can sustain pregnancy by sufficient production of oestradiol and progesterone.
Maternal and fetal outcome is normal if the condition is adequately treated.
Inadequately treated cases are at increased risk of adverse outcomes including maternal hypotension, hypoglycaemia, and mortality, miscarriage, and stillbirth.
Treatment involves replacement therapy with levothyroxine and hydrocortisone (additional IV hydrocortisone is required in labour).
Milk production may be impaired because of prolactin deficiency.
Sheehan’s syndrome
This is caused by avascular necrosis of the pituitary, as a result of hypotension usually secondary to a post-partum haemorrhage. The pituitary is particularly vulnerable in pregnancy due to its 2–3-fold increase in size. Partial or complete pituitary failure can occur. The posterior pituitary is unaffected as it has a different blood supply. Treatment is as above. Pregnancies have been reported following this diagnosis.
Failure of lactation.
Persistent amenorrhoea.
Loss of pubic and axillary hair.
Hypothyroidism.
Adrenal insufficiency (vomiting, hypotension, hypoglycaemia).
Incidence 1:15 000 pregnancies.
Caused by a lack of antidiuretic hormone (ADH).
Four types:
central —lack of ADH production by the posterior pituitary caused by expanding tumours
nephrogenic —ADH resistance in the kidney
transient —production of an enzyme by the placenta that results in increased breakdown of ADH, occurs in association with pre-eclampsia or acute fatty liver of pregnancy
psychogenic —compulsive water drinking.
Clinical features: excessive thirst and polyuria.
Pregnancy may unmask the condition or make it worse (60%).
Treatment is with desmopressin intranasally.
Obesity in pregnancy: maternal risks
Obesity is an increasing problem in the developed world.
The WHO definition of normal weight is a BMI between 18.5 and 24.9:
overweight is BMI between 25.0 and 29.9
obese is BMI ≥30.
1 in 5 pregnant women in the UK are now obese.
The 2006–8 Confidential Enquiry unit Maternal and Child Health (CEMACH) report identified that obesity carries a greater risk of maternal death.
Maternal risks associated with obesity
Hypertension and pre-eclampsia
Over twice as likely to develop gestational hypertension.
Women with a BMI >30 have a significantly ↑ risk of pre-eclampsia.
Excessive weight gain in pregnancy is associated with higher rates of pre-eclampsia in already overweight women.
Gestational diabetes
Over 3 times more likely to develop gestational diabetes compared with women with a normal BMI.
Thromboembolism
The incidence of thromboembolic disease in pregnancy is doubled in obese women.
Antenatal requirements for obese women
5mg folic acid pre-conception and until 12wks.
400 micrograms vitamin D.
VTE risk assessment.
Referral for consultant care.
Anaesthetic referral.
GTT at 24–28wks.
It may be difficult to palpate the uterus in obese women, leading to:
Missed diagnosis of breech presentation.
Missed diagnosis of IUGR or macrosomia.
Unsuccessful ECV attempts.
USS is also technically difficult and may be inaccurate.
Postnatal complications associated with obesity
Increased rates of postoperative complications also occur, including:
wound infection and endometritis
lower respiratory tract infection
PPH.
Also associated with a reduction in breast-feeding frequency.
Difficulty in siting regional anaesthesia due to body habitus.
If a general anaesthesia (GA) is needed:
intubation is technically more difficult
↑risk of aspiration.
Difficulty monitoring both the fetus and uterine contractions.
Higher rate of:
induction of labour
failed induction
CS.
If vaginal delivery, there is an↑rate of:
instrumental deliveries
shoulder dystocia
3rd and 4th degree perineal tears.
High prepregnancy BMI and weight gain in the interpregnancy interval has been shown to↓the success of VBAC by 50%.
Counselling regarding weight loss and lifestyle changes prepregnancy would be ideal.
Increased vigilance for pre-eclampsia:
regular antenatal checks with urine dipstick analysis (low threshold for quantifying proteinuria)
measure arm circumference to ensure the correct size BP cuff.
Increased vigilance for diabetes:
consider random blood sugar at booking
urine dipstick analysis at each visit for glycosuria
GTT at 24–28wks (NICE).
Increased vigilance for both macrosomia and IUGR: may need serial USS to monitor growth as SFH measurement may not be accurate.
May require USS at 36wks gestation for presentation (to prevent an undiagnosed breech) if unable to palpate the fetus accurately.
Further weight gain during the pregnancy should be discouraged.
Obesity in pregnancy: fetal risks
Miscarriage
Overweight women have a significantly ↑ rate of early miscarriage (both spontaneous and IVF pregnancies); this is thought to be related to ↓ insulin sensitivity.
Congenital abnormalities
There is conflicting evidence regarding obesity and congenital abnormalities.
Some groups have reported an ↑ rate of neural tube defects, heart, and intestinal abnormalities, with increased serum insulin, triglycerides, uric acid, and oestrogens; in addition to increased insulin resistance, hypoxia and hypercapnia have been proposed as mechanisms for these effects.
Stillbirth
Significant risk factor for antepartum stillbirth:
Risk of stillbirth ↑ consistently with ↑ prepregnancy BMI.
Morbidly obese women are 3 times more likely to have a stillbirth than women with normal BMI.
Macrosomia
Well-recognized risk factor for fetal macrosomia (independent of maternal diabetes) which carries ↑ risk of:
Instrumental delivery.
CS.
3rd degree perineal tears.
PPH.
Maternal weight is an independent determinant of childhood obesity.
Macrosomic fetuses have an↑risk of adolescent and adult obesity related to an↑incidence of the metabolic syndrome.
Maternal death or severe morbidity.
Cardiac disease.
Spontaneous 1st trimester or recurrent miscarriage.
Pre-eclampsia.
Gestational diabetes.
Thromboembolism.
Post-CS wound infection.
Infection from other causes.
PPH.
Low breast-feeding rates.
Stillbirth and neonatal death.
Congenital abnormalities.
Prematurity.
Further reading
Centre for Maternal and Child Enquiries and the Royal College of Obstetricians and Gynaecologists (2010). Management of women with obesity in pregnancy. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/cmacercogjointguidelinemanagementwomenobesitypregnancya.pdf.
National Institute for Health and Care Excellence (2010). Weight management before, during and after pregnancy. Available at: https://www.nice.org.uk/guidance/ph27.
Drugs in pregnancy
Prescribing in pregnancy requires the clinician to walk a delicate line between benefit (usually for the mother) and potential harm (usually to the fetus). This tends to generate anxiety and at its worst may lead to the omission of necessary treatment with significant adverse effects.
Most drugs cross the placenta to a certain extent and therefore are potentially teratogenic or fetotoxic. The exception is very large molecules, such as heparin and insulin. As women delay becoming pregnant until later life, more and more will become pregnant whilst taking medication for common conditions such as essential hypertension. Similarly, some women with conditions that were once thought incompatible with pregnancy are now becoming pregnant due to improved medication (e.g. women with CF, transplant recipients).
Timing of exposure
Drugs can cause teratogenesis in the fetus. This is defined as dysgenesis of fetal organs in terms of either structure or function. Other manifestations include IUGR and fetal death.
The timing of exposure is critical. There are three main phases of human development:
Pre-embryonic:
conception to 17 days after (implantation and blastocyst formation)
adverse effects usually result in miscarriage.
Embryonic:
day 17 to day 55 after conception (organogenesis)
congenital malformations likely due to the rapidly dividing tissues
the earlier the timing of the insult, the greater the damage.
Fetal phase:
from 8wks after conception to term
any effects of drugs impact on fetal growth and function of organs.
The benefits from continuing medication in pregnancy and when breast-feeding often outweigh the potential risks.
Prepregnancy assessment should be offered to all women of childbearing age on regular medication with the option to change to alternative medication where possible.
Try to avoid 1st trimester use if possible.
Use drugs already used in pregnancy rather than new ones.
Use the minimum dose to achieve the desired effect.
The latest information on specific medications should be sought to enable the clinician to adequately assess the risks involved and allow the woman to make an informed choice.
▶ Help can be obtained from the Organization of Teratology Information Specialists (OTIS). This is funded by the Health Protection Agency to provide a 24h service on all aspects of toxicity of drugs and chemicals in pregnancy throughout the UK.
www.nyrdtc.nhs.uk/Services/teratology/teratology.html
