Venous thromboembolism (VTE) is the leading cause of direct maternal deaths in the UK (Royal College of Obstetricians and Gynaecologists (RCOG), 2015). A report published by MBRRACE-UK (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK) found that 30 out of 252 maternal deaths between 2009 and 2011 were attributed to VTE: 1.26 per 100 000 maternities (Knight et al, 2014). This mortality rate is more than double that attributed to haemorrhage, and almost three times that of pre-eclampsia and eclampsia.
This finding is not new. Confidential enquiry historical data prior to 2006 demonstrate that VTE has been the main direct cause of maternal deaths since 1985. In 2006–2008, VTE dropped to third place in the list of the most common causes of maternal death (0.79 per 100 000), behind genital sepsis, pre-eclampsia and eclampsia. Although there is no significant statistical difference between the change in the mortality rate of VTE over time, there have been improvements in the survival rates for other causes of maternal death, therefore VTE has returned as the leading direct cause of death in pregnant women. These figures, however, do not account for the large number of women who survive a VTE episode but go on to have a morbidity later in life.
What is VTE?
VTE encompasses two main conditions: deep vein thrombosis (DVT) and pulmonary embolus (PE). DVT is the formation of a blood clot (thrombus) in the deep veins, such as the femoral and popliteal veins, but the clot can form in any deep vein, including those of the upper limbs. The extent of the clot is variable: it may be small and non-occlusive, or occlusive and extend into the inferior vena cava, and, occasionally, up to the right atrium. Symptoms include pain and swelling of the affected area.
The principal concern with DVTs is the potential for clot embolisation through the venous system and the right side of the heart, lodging in the lung vasculature and forming a PE. Symptoms include chest pain and difficulty in breathing, and the ultimate consequence is death from respiratory and/or cardiac arrest. Associated morbidities include chronic hypoxia leading to long-term oxygen requirements, reduced exercise tolerance, pulmonary hypertension and right heart failure. Post-thrombotic syndrome describes a range of symptoms that can result from a DVT, including chronic swelling, chronic pain and skin ulceration of the leg.
During pregnancy, the relative risk of VTE is increased four-to six-fold, while the postpartum period is associated with an even greater risk (five-fold more than the antenatal risk) (Heit et al, 2005; Sultan et al, 2012). The overall risk of developing VTE during pregnancy has been estimated at around 2.5 per 1000 pregnancies conceived naturally, and is slightly higher with assisted conception methods (Henriksson et al, 2013).
Treatment of VTE
VTE is treated with anticoagulation for at least 3 months. The duration of the treatment depends on position of the clot and the woman's medical history. The treatment impairs the body's ability to clot blood, so that the existing clot will not extend, allowing the body to break down the clot. Therefore, the main side-effect of anticoagulants is bleeding. Warfarin is the agent mainly used, with intravenous heparin (continuous infusion), and subcutaneous low-molecular-weight heparin (LMWH), which is administered subcutaneously once or twice a day, reserved for the acute setting, or when warfarin is contraindicated. Warfarin is known to be teratogenic (although this teratogenicity is dose-dependent) if taken during the first trimester, and women on warfarin are usually advised to switch to LMWH by week 6 of pregnancy. There are some exceptions to this rule (women with metallic heart valves, for example); in such cases, LMWH is not considered a suitable alternative and counselling regarding the risk and benefit to the mother and fetus should be undertaken by a suitably qualified clinician (RCOG, 2015). Ultimately, the mother must consider the risks to herself (through inadequate anticoagulation, potentially leading to valve clots and heart failure) versus the risks to her unborn child (by teratogenesis with warfarin). Adequate time and information, ideally during pre-conception counselling, needs to be set aside for this. While a new generation of oral anticoagulants has been introduced, none are licensed for use in pregnancy, so women are again switched to LMWH for pregnancy. Both warfarin and LMWH, however, are safe to use while breastfeeding.
How can we prevent VTE?
The mainstay of VTE risk reduction is thromboprophylaxis with LMWH. The National Institute for Health and Care Excellence (NICE, 2012) estimates that LMWH reduces the risk of VTE in medical and surgical patients by 60% and 70%, respectively; it is reasonable to assume the risk in obstetric patients may also be reduced (RCOG, 2015). The dose (full treatment dose or partial prophylactic dose), timing and duration of LMWH depends on the woman's risk. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium, green-top guidance from RCOG (2015), provides a framework to risk-stratify women for VTE and suggests appropriate intervention. It recommends that all women are risk-stratified at least twice—for the first time in early pregnancy or at pre-pregnancy counselling, and again at intrapartum or immediately postpartum. Additional assessments are required for women admitted to hospital or those who develop other medical conditions that could further increase the risk of thrombosis.
Table 1 summarises the guidance from the RCOG. The recommendations for management, depending on the risk stratification, can be complicated and necessitate further discussions with obstetric medical or obstetric haematological specialists.
| Thrombophilia status | Risk factors | VTE status | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Nil | Single VTE | Recurrent VTE | |||||||
| All other single VTE | Related to major trauma or surgery | ||||||||
| Antenatal | Postnatal | Antenatal | Postnatal | Antenatal | Postnatal | Antenatal | Postnatal | ||
| Nil | Nil | Nil | Nil | Px LMWH | Px LMWH 6/52 | Px LMWH from 28/52 | Px LMWH 6/52 | Px LMWH—may need higher dose) | Px LMWH—higher dose 6/52 |
| 1 | Px LMWH | ||||||||
| 2 | Px LMWH 10/7 | ||||||||
| 3 | Px LMWH from 28/52 | Consider prolonging Px LMWH for 6/52 | |||||||
| 4 or more | Px LMWH | ||||||||
| Major: |
Px LMWH | Px LMWH 6/52 | Px LMWH—higher dose | Px LMWH—higher dose 6/52 | Px LMWH—higher dose | Px LMWH—higher dose 6/52 | |||
| Minor: |
Consider Px | Px LMWH 6/52 | Px LMWH | Px LMWH 6/52 | Px LMWH | Px LMWH 6/52 | |||
| Other: |
Nil | Nil | Nil | ||||||
| 1 | Px LMWH 10/7 | ||||||||
| 2 | Px LMWH from 28/52 | Px LMWH 6/52 | |||||||
| 3 or more | Px LMWH | Px LMWH 6/52 | |||||||
LMWH: low-molecular-weight heparin; Px: Prophylactic
The main factor determining risk is previous history of VTE (none, single or multiple VTE episodes). Single previous VTE is sub-divided into two groups:
Thrombophilia is not a single inherited condition. It may be undiagnosed, and women who fit certain criteria will need to be screened (see below). Some thrombophilias pose a greater risk for VTE than others. In an attempt to simplify the management pathway, thrombophilia status is divided into major, minor and other. This classification is rather crude, and from a genetic perspective, is not particularly accurate.
In addition, the list of thrombophilias is not exhaustive, and any uncertainty should be discussed with a specialist as incorrect classification can significantly alter the advice for the prevention of subsequent VTE.
Once VTE and thrombophilia status has been identified, where a patient fits on the table depends on how many additional risk factors (Table 2) they have. Broadly speaking, the greater the number of risk factors a woman has, the longer she will need LMWH, and women at a very high risk may need a higher dose.
| Pre-existing | Obstetric-related | New onset or transient |
|---|---|---|
| Age > 35 years | Current pre-eclampsia | Surgery |
| Obesity | Caesarean section | Hyperemesis or dehydration |
| Parity ≥ 3 | Prolonged labour (lasting longer than 24 hours) | Ovarian hyperstimulation syndrome |
| Medical co-morbidities (nephrotic syndrome, active inflammatory bowel disease, for example) | Mid-cavity or rotational operative delivery | In vitro fertilisation or assisted reproductive technology |
| Smoking | Stillbirth | Admission or immobility → 3 days |
| Gross varicose veins (symptomatic, above knee or associated skin changes/phlebitis) | Pre-term birth | Systemic infection (pyelonephritis, for example) |
| Paraplegia | Postpartum haemorrhage (loss of 500 ml or more of blood from the genital tract in the first 24 hours following delivery) | Long-haul flight or travel → 4 hours |
Points of note
Caveats for pregnant women
Caveats for postpartum women
Problems with anticoagulation in pregnancy
Anticoagulation, whether to treat or prophylactic, is not without risk. Recent large-scale retrospective studies have varied in their findings, but in general the risk of bleeding antenatally is low, although some women experience major bleeding at the time of emergency caesarean section (De Sancho et al, 2012; Khalifeh et al, 2014; Parent et al, 2015). Since LMWH does not cross the placenta, there is no increased risk of fetal bleeding. Pregnant women on LMWH should be advised to stop injections at the onset of labour and seek medical advice if they experience any vaginal bleeding.
The use of LMWH can also affect the analgesic options available at delivery—a patient should be 12 hours post the last dose of LMWH before a neuroaxial (spinal or epidural) procedure is performed. It is not an absolute contraindication to caesarean section, although ideally a 12-hour interval should be left before delivery.
Difficulties in implementing guidance for VTE
The biggest challenge clinicians face is to accurately risk-assess all pregnant women at booking and to remember to repeat risk stratification when circumstances change, including antenatal admission and postpartum. It can be easy to be distracted by the prime event that has caused the change in circumstances and forget about VTE. The risk of developing VTE increases approximately four-fold for those admitted to hospital for up to 3 days for a non-obstetric-related condition (Abdul Sultan et al, 2013), and this elevated risk of developing VTE remains for the 28 days following discharge.
The other main issue is the potential for the over-medicalisation of a potentially ‘normal’ pregnancy. Women with previous VTE ideally should have received pre-pregnancy counselling regarding their need for prophylactic LMWH from the time of a positive pregnancy test. Thrombophilia screening is expensive and rarely indicated. It should only be performed if the result will alter the woman's need for or dose of LMWH thromboprophylaxis. Women found to have low-risk heritable thrombophilias do not usually require LMWH unless they have other risk factors for VTE (Table 2).
Conclusions
The absolute risk of VTE in pregnancy is low, but the relative risk is high. Reducing the risk of VTEs in pregnant and puerperal women is an achievable target and is likely to have a significant effect on direct obstetric deaths and morbidity. Certain risk factors, such as age, obesity and caesarean section, are increasing in prevalence, meaning increased numbers of women are at significant risk and qualify for LMWH prophylaxis, which is costly and inconvenient. The accurate, repeated risk assessment for VTE and appropriate prescribing of LMWH, depending on the patient's weight and individual circumstances, are the main challenges faced by clinicians.