Results
A total of 34 articles published between 2000 and 2016 fulfilled the inclusion criteria.
The information was analyzed for the consistency of the data, the year of publication,
and the quality of the study.
Incidence of Venous Thromboembolism
Venous thromboembolism events, including deep venous thrombosis (DVT) and pulmonary
thromboembolism (PTE), are present in up to 3 out of 1,000 pregnancies, with pregnancy-associated
pulmonary embolism being a major cause of maternal morbidity and mortality in the
Western world.[4]
[5]
[6]
[7] In addition, VTE is considered one of the most serious complications of pregnancy,
accounting for 10% of maternal deaths in the United States through the occurrence
of PTE. In addition, pregnancy-related DVT causes significant morbidity, along with
a long-term risk of post-thrombotic syndrome (PTS), leg ulcers and a documented decrease
in quality of life.[8]
[9]
It has been found that the incidence of VTE increases about 4-5 times in pregnant
women and ∼ 20 times in the postpartum period.[5]
[6]
[7]
[9]
[10]
[11]
[12]
[13]
[14]
[15] This risk may be even higher: 1 study demonstrated a 60-fold increase in the risk
of VTE in the first 3 months after delivery compared with non-pregnant women.[16]
In developing countries, the incidence of VTE has increased, with a ratio of 1 case
per every 16 pregnancies per year. This represents an incidence rate of 1.4% of VTE,
with 1.1% manifesting as DVT and 0.3%, as PTE.[4]
[6]
[10]
[13]
[17]
Given the high maternal mortality due to PTE, early diagnosis and treatment should
be prioritized.[7]
Risk Factors
Thrombophilia is the most important risk factor for venous thrombosis during pregnancy.[5] Other risk factors include history of VTE, obesity, obstetric hemorrhage, presence
of varicose veins, heart disease, increased maternal age (≥ 35 years), eclampsia,
preeclampsia, intrauterine growth restriction, preterm labor, surgical history, multiparity
(≥ 3 children), anemia and smoking.[4]
[9]
[14]
[15]
[18]
[19]
Pathophysiology of the Thrombus
Pregnancy, due to hypercoagulability, venous stasis and endothelial injury, is considered
a typical example of the Virchow triad, with pregnant women having a potential 5-fold
higher possibility of developing a thrombogenic status when compared with non-pregnant
women of the same age group.[4]
[5]
[6] Hypercoagulability occurs due to the increase in coagulation factors such as fibrinogen,
factors II, VII, VIII and X, and the decrease in coagulation inhibitors, such as fibrinolytic
activity. Venous stasis occurs as a result of decreased venous return caused by compression
of the gravid uterus on the iliac veins and inferior vena cava, and endothelial injury
may occur during vaginal delivery, and it may be exacerbated during cesarean delivery.
All of this represents the physiological preparation to protect women from bleeding
during childbirth or abortion.[4]
[5]
[6]
[10]
In relation to the postpartum period, the type of delivery and postnatal mobility
are fundamental components in the pathophysiology of thromboembolism. The risk of
thromboembolism after vaginal delivery is ∼ 1 per 1,000, while this risk reaches 3
per 1,000 after elective cesarean section, and the mortality associated with VTE after
cesarean section is increased 10-fold compared with women who undergo vaginal delivery.[20]
[21] The reasons for such a difference in outcome between the different delivery routes
can be explained by several factors, among them, a greater immobility after cesarean
section when compared with vaginal delivery. A study even showed that on the 7th day,
postpartum women who underwent vaginal delivery were almost twice as mobile as those
who had undergone cesarean section.[16]
Regarding hemostatic differences in the puerperium, hypercoagulability is observed
for at least 2–3 weeks postpartum. Reactive thrombocytosis is a common occurrence
during the postpartum period, regardless of the chosen route of delivery, and it is
associated with an increased incidence of thrombosis.[22] There is also an increase in tissue factor (TF) levels in the postpartum period,
which is directly associated with an increase in activated factor VII (FVIIa) levels
and markers of thrombin generation. However, there is no significant difference between
vaginal delivery and cesarean section in the activation of TF-dependent coagulation.
The introduction of TF in the maternal blood leads to a rapid formation of the TF-FVIIa
complex, which is the main route of initiation of the hemostatic system. Through activation
of TF and factor X (FX), minimal amounts of thrombin can be formed, which results
in the activation of platelets and cofactors activated factor V (FVa) and activated
factor VIII (FVIIIa), causing a rapid amplification of the coagulation response. All
of this contributes to the development of thrombosis in the puerperium.[5]
In addition, an increase in the concentration of plasma homocysteine, which is responsible
for the inhibition of endothelial nitric oxide (NO) production and consequent endothelial
dysfunction, was observed in women after cesarean section as opposed to women after
vaginal delivery. Maternal erythrocyte glutathione levels, an indicator of oxidation
and reduction balance, have also been shown to increase significantly after full-term
vaginal delivery, while this has not occurred after elective cesarean delivery. Oxidative
stress through the production of oxygen-free radicals contributes to NO depletion
and eventually leads to endothelial dysfunction. These observations suggest that vaginal
delivery promotes endothelial function, while cesarean delivery impairs it.[23]
Another parameter to be analyzed is the mean platelet volume (MPV), a factor related
to cardiovascular complications, cerebrovascular disorders, and low-grade inflammatory
conditions. The increase in MPV contributes to the development of arterial and venous
thrombosis and to the pathogenesis of thromboembolic complications reported in patients
who gave birth by cesarean section and not by vaginal delivery.[24]
Groups of Higher and Lower Risk
Ethnic factors interfere with the risks of VTE in the postpartum period. Compared
with white women, black women have a 50% higher risk, and Asian women have a 30% lower
risk, while Hispanic women also have a lower risk. The increased risk of postpartum
VTE for black women is only observed after cesarean section, while the lower risk
for Hispanic women is apparent only after vaginal delivery.[8]
The postpartum thromboembolic mortality rate of African-American women is 4.5 times
higher than that of Caucasian women: 4.1/100,000 live births and 0.9/100,000 live
births respectively.[25]
Prophylaxis Techniques
After acknowledging the increase in maternal deaths due to thromboembolism and a widespread
failure of the clinicians to follow existing guidelines for prophylaxis based on identified
risk factors, experts have advocated universal prophylaxis for all women undergoing
cesarean section.[26]
Post-cesarean thromboprophylaxis has been shown to reduce maternal VTE-related morbidity
and mortality. Sequential mechanical compression devices, simple graduated compression
socks, low molecular weight heparin (LMWH), and fractionated heparin (FH) and unfractionated
heparin (UFH) demonstrated to be effective in this issue.[4]
[6]
[10]
[11]
[12]
[20]
[21]
[23]
[26]
[27]
[28]
[29]
In 2011, the American College of Obstetricians and Gynecologists (ACOG)[30] published an opinion supporting the routine use of perioperative pneumatic compression
devices during cesarean section. Sequential compression devices reduce the risk of
VTE by increasing femoral blood flow through mechanical compression of the lower limbs,
as well as by stimulating fibrinolysis through an increase in tissue plasminogen activator
concentration and a decrease in inhibitor levels. However, in order to effectively
prevent venous thrombosis, devices should be used continuously, since their beneficial
effects are lost within 10 minutes of their removal.[4]
[6]
[10]
[12]
[27]
[29]
The prophylactic use of LMWH in low-risk post-cesarean women is still controversial.
The current guidelines do not recommend LMWH thromboprophylaxis in this situation
without any additional risk factors. However, the “Confidential Inquiry into Maternal
Deaths” (CEMACH) report showed that risk factors were absent in more than 20% of women
who died from venous thromboembolism events.[21]
The Norwegian Society of Gynecology and Obstetrics recommends prophylaxis with low-molecular
weight heparin for 4 to 8 days after all cesarean sections. On the other hand, the
Royal College of Obstetrics and Gynecology (RCOG) classifies women who underwent cesarean
section in three degrees, and recommends thromboprophylaxis only for those women classified
as having a medium or high risk of thrombosis.[23]
According to the French College of Gynecology and Obstetrics,[20] for all cesarean sections, thromboprophylaxis by compression stockings from the
day of delivery until at least 7 days is recommended, with or without the addition
of LMWH, depending on the presence and type of risk (higher or lower). Considering
that the thromboembolic risk during an elective cesarean section is 3 per 1,000, and
that the anticoagulant treatment is indicated for any risk higher than 3%, it is important
to know the multiplicative factor of the risk, that is, the odds ratio (OR), for all
additional risk factors. Treatment is therefore considered necessary when the OR of
the combined risk factors is higher than 10, so that the theoretical risk of 3 per
1,000 for an elective cesarean section exceeds 3%. These additional risk factors were
well-studied in obstetric settings, and their ORs were evaluated. These data are presented
in [Table 1]. When there are several additional risk factors, their ORs are multiplicative. The
duration of the anticoagulant treatment depends on the number and, in particular,
on the type (major or minor) of associated risk factors: 1) in an emergency cesarean
section with no additional minor risk factor, thromboprophylaxis by compression stockings
is recommended alone for 7–14 days (by professional consensus); 2) in an emergency
cesarean with a minor additional risk factor (resulting in a cumulative OR > 10),
thromboprophylaxis by compression stockings plus a preventive dose of LMWH for 7–14
days is recommended (by professional consensus); 3) in an elective cesarean section
with no additional risk factors or only a minor one, thromboprophylaxis by compression
stockings for 7–14 days is recommended (by professional consensus); 4) in an elective
cesarean section with two additional minor risk factors (producing a cumulative OR > 10),
thromboprophylaxis with compression stockings and a preventive dose of LMWH for 7–14
days is recommended (by professional consensus); and 5) in all situations, particularly
those involving great risk or the presence of additional risk factors, this may result
in prolonging the duration of this medication prophylaxis for up to 6 weeks (by professional
consensus).[20]
[29]
Table 1
Simplified table describing the odds ratio of the main risk factors for venous thromboembolism
related to cesarean sections according to the French College of Gynecology and Obstetrics
|
Risk factor
|
Adjusted odds ratio
|
|
Major risk factors (odds ratio > 10)
|
|
History of thromboembolism with or without adjacent thrombophilia
|
> 20
|
|
High-risk asymptomatic thrombophiliaa
|
> 20
|
|
Asymptomatic antiphospholipid syndrome
|
> 20
|
|
Complete and prolonged immobility
|
11
|
|
Postpartum hemorrhage with consequent surgical procedure
|
12
|
|
Minor risk factors (odds ratio < 10)
|
|
Age > 35 years
|
1.4
|
|
Obesity (body mass index > 30) or weight > 120 kg
|
4
|
|
Parity > 3
|
2
|
|
Smoking (> 10 cigarettes/day before pregnancy or persistent smoking during pregnancy)
|
3
|
|
Significant varicose veins
|
2
|
|
Sickle cell anemia
|
4
|
|
Important heart disease
|
7
|
|
Disseminated lupus erythematosus
|
8
|
|
Inflammatory bowel disease
|
4
|
|
Low-risk asymptomatic thrombophiliab
|
3
|
|
Anemia or bleeding during pregnancy
|
3
|
|
Pregnancy obtained by assisted reproduction technique
|
4
|
|
Preeclampsia
|
3
|
|
Severe or fetal growth restrictive preeclampsia
|
4
|
|
Multiple pregnancies
|
4
|
|
Preterm birth < 37 weeks
|
3
|
|
Emergency cesarean section
|
3
|
|
Severe postpartum hemorrhage (bleeding > 1 L and/or blood transfusion)
|
3
|
|
Postpartum infection
|
4
|
Notes: aHigh-risk asymptomatic thrombophilia: antithrombin deficiency, homozygous mutations
of factor V Leiden, homozygous mutation of the combined prothrombin deficiency G202010A;
bLow risk asymptomatic thrombophilia: heterozygous mutation of factor V Leiden, heterozygous
mutation of prothrombin G202010A, protein C deficiency, protein S deficiency.
Venous filters may be used as a temporary measure in patients with contraindication
to anticoagulation.[4] Inferior vena cava (IVC) filters have been used safely and effectively to prevent
PTE in pregnant patients with confirmation of DVT in the lower limbs, as well as for
prophylactic use in patients with proximal DVT prior to delivery.[10]
[13] However, there is insufficient evidence to suggest that IVC filters should be used
routinely during pregnancy in patients with DVT and, until further studies are performed,
their use should be considered following the same absolute indications for the non-pregnant
population, or in individuals in whom there are concerns about childbirth. The rates
of complications in pregnant patients are comparable to those of the non-pregnant
population, and there is no significant fetal morbidity or mortality. Both suprarenal
and infrarenal positioning can be used, although there are more theoretical benefits
with the suprarenal placement.[31]
For women undergoing cesarean delivery without additional risk factors for VTE, the
American College of Chest Physicians (ACCP) recommendations suggest no prophylaxis.
For women with one major or two minor risk factors ([Table 2]), pharmacologic prophylaxis is recommended. For patients at very high risk, combined
mechanical and pharmacologic prophylaxis is recommended. The ACCP also supports post-partum
pharmacologic prophylaxis for all women with a prior VTE event, and recommends against
antepartum pharmacologic prophylaxis for women with a single, provoked, and non-estrogen
related event; however, prophylaxis is recommended for all other women with a history
of VTE ([Table 3]).[32]
Table 2
American College of Chest Physicians risk factors for venous thromboembolism
|
Major risk factors
|
|
Immobility (strict bed rest for > 1 week in the antepartum period)
|
|
Post-partum hemorrhage > 1 L with surgery
|
|
Previous venous thromboembolism event
|
|
Pre-eclampsia with fetal growth restriction
|
|
Thrombophilia
|
|
Antithrombin
|
|
Factor V Leiden (homozygous or heterozygous)
|
|
Prothrombin G20210A (homozygous or heterozygous)
|
|
Medical conditions
|
|
Systemic lupus erythematosus
|
|
Heart disease
|
|
Sickle cell disease
|
|
Blood transfusion
|
|
Post-partum infection
|
|
Minor risk factors
|
|
Body mass index > 30 kg/m2
|
|
Multiple gestation
|
|
Post-partum hemorrhage > 1 L
|
|
Smoking > 10 cigarettes/day
|
|
Fetal growth restriction
|
|
Thrombophilia
|
|
Protein C deficiency
|
|
Protein S deficiency
|
|
Pre-eclampsia
|
Table 3
The American College of Chest Physicians (ACCP) recommendations for antenatal and
post-partum pharmacologic prophylaxis
|
Antepartum
|
Postpartum
|
|
Low-risk thrombophilia without personal or family history of VTEa
|
Vigilance recommended
|
Vigilance recommended
|
|
Low-risk thrombophilia without personal history of VTE; family history positive for
VTE
|
Vigilance recommended
|
Prophylaxis recommended
|
|
Low-risk thrombophilia with single prior VTE event
|
Prophylaxis recommended
|
Prophylaxis recommended
|
|
High-risk thrombophilia without personal or family history of VTE
|
Vigilance recommended
|
Prophylaxis recommended
|
|
High-risk thrombophilia with single prior VTE event or family history of VTE
|
Prophylaxis recommended
|
Prophylaxis recommended
|
|
Single prior VTE, no thrombophilia, idiopathic event, or provoked by pregnancy or
estrogen
|
Prophylaxis recommended
|
Prophylaxis recommended
|
|
Single prior VTE, no thrombophilia, event provoked by non-estrogen-related transient
risk factor
|
Vigilance recommended
|
Prophylaxis recommended
|
|
Multiple prior VTE events
|
Prophylaxis recommended
|
Prophylaxis recommended
|
Abbreviation: VTE, venous thromboembolism.
Note: aThe ACCP defines high-risk thrombophilias as homozygosity for factor V Leiden or prothrombin
20210A mutation; other thrombophilias are considered low-risk.
Therapeutic Measures
Once the diagnosis of VTE is established, the treatment should begin as soon as possible.
After initiating the basic care of support and monitoring, anticoagulant therapy is
initiated.[6]
According to the ACCP guidelines published in 2016, patients with lower limb DVT or
PTE due to surgical procedures should receive anticoagulant therapy for 3 months,
with the drugs of choice being dabigatran, rivaroxaban, apixaban or edoxaban.[33] Since pregnant and lactating women were excluded from studies with such drugs, these
recommendations do not apply to them. Thus, in these groups, the use of LMWH is recommended
for at least 6 weeks postpartum, with the minimum duration of the anticoagulant therapy
being 3 months.[32]
Regarding the management of massive PTE cases in pregnant women with hemodynamic impairment,
the treatment strategy remains controversial. More aggressive approaches, such as
pulmonary thromboaspiration and thrombolysis, are warranted to save the mother's life.[6]
Thrombolysis is generally contraindicated during gestation and the puerperium due
to the high risk of bleeding. However, over the past decade, advances in minimally
invasive technologies have stimulated aggressive treatment of DVT using percutaneous
techniques. Endovascular treatment using mechanical thromboaspiration alone or in
combination with pharmacological thrombolytic agents has received much attention in
the literature as a safe and effective means of treating acute postpartum DVT.[34]
Discussion
Venous thromboembolism is the leading cause of maternal death during pregnancy and
the postpartum period in developed countries. According to the World Health Organization
(WHO), 2% of all maternal deaths in the world are caused by VTE, and 14.9% of maternal
deaths in developed countries are related to thromboembolic events, including, among
these countries, mainly the United States, due to the higher prevalence of risk factors
and lower incidence of maternal death due to causes such as hemorrhage and sepsis.[1]
Approximately 80% of venous thromboembolic events during pregnancy correspond to DVT,
and 20% correspond to PTE. Two thirds of the cases of DVT occur during gestation,
and are distributed with relative homogeneity in the three trimesters. In contrast,
43% to 60% of pregnancy-related episodes of pulmonary embolism occur in the puerperium.[6]
There are several risk factors for the development of VTE in pregnant women, with
thrombophilia and the previous history of VTE being the main ones. Age > 35 years
is also an important factor, since pregnant women aged ≥ 35 years present a relative
increase of 70% in the incidence of VTE when compared with women aged between 25 and
34 years.[6]
[13]
It has been proven by several studies that the morbidity and incidence of VTE is higher
in women who undergo cesarean delivery compared with those who opt for vaginal delivery.
A study in Canada, which included women who delivered between April 1991 and March
2005, showed differences between the group of women undergoing planned cesareans and
the group of women undergoing planned vaginal delivery, with overall rates of severe
morbidity for the entire period of 14 years of 27.3 and 9.0 per 1,000 births respectively.
The cesarean group presented a higher risk of developing VTE (OR: 2.2, 95% confidence
interval [95% CI]: 1.5–3.2) than the vaginal delivery group.[14] In another study conducted in India between 2003 and 2006, cesarean section was
associated with a 3.01-fold increase in the risk of maternal mortality compared with
vaginal delivery.[17]
Despite the higher maternal risk of VTE after cesarean section and the numerous campaigns
that stimulate vaginal delivery, cesarean rates remain high, reaching 90% in the private
sector. The high rates do not correspond to the high number of cesareans performed
by medical indication, but by the cesarean sections performed at the request of the
mother. The CFM guarantees the patient's autonomy in choosing the type of delivery
that best suits her, and the reason most Brazilian women choose cesarean delivery
is the absence of pain.[3]
It is also worth noting that, in Brazil, childbirth care does not constitute an exclusively
medical act. The public health system admits the nursing professional's performance
in the process of childbirth, with legal regulations made by Ordinance no. 163, dated
09/22/1998, of the Health Care Secretariat of the Brazilian Ministry of Health, and
by Resolution 223/1999 of the Brazilian Federal Nursing Council.[35] Therefore, the adequate preparation of these professionals for the detection of
VTE is indispensable.
