Observed or estimated absolute riska
Antepartum anticoagulation
Postpartum anticoagulation
Factor V Leiden, heterozygote
No family history
1.2 (0.8–1.8)
No
No
Positive family history
3.1 (2.1–4.6)
No
Yes
Prothrombin 20210A gene mutation, heterozygote
No family history
1.0 (0.3–2.6)
No
No
Positive family history
2.6 (0.9–5.6)
No
Yes
Protein C or S deficiency
No family history
~0.7 (0.3–1.5)
No
No
Positive family history
1.7–6.6 (0.4–14.7)
No
Consider
Antithrombin deficiency
No family history
0.7 (0.2–2.4)
Yes
Yes
Positive family history
3.0 (0.08–15.8)
Yes
Yes
Factor V Leiden, homozygous
No family history
4.8 (1.4–16.8)
Consider
Yes
Positive family history
14.0 (6.3–25.8)
Yes
Yes
Prothrombin 20210A gene mutation, homozygous
No family history
3.7 (0.2–78.3)
Consider
Yes
Positive family history
n/a
Yes
Yes
A further consideration for the practicing physician is the eventuality of multiple risk factors coinciding in one patient rendering a cumulative, elevated risk of VTE during the postpartum period, for example, a woman with a weak thrombophilia in the postpartum period and one or more of the following: inflammatory bowel disease, age >35, prior superficial phlebitis, BMI > 25 kg/m2, immobilization, Cesarean section, postpartum complications such as hemorrhage and infection, and smoking (Jacobsen et al. 2008; [88]). Importantly, the literature indicates that a family history of VTE, which can be thought of as a phenotypic manifestation of thrombophilia, portends a further two- to fourfold increased risk for VTE [7]. Clinical guidelines therefore recommend that pregnant women with a weak, inherited thrombophilia, who do not have a personal history of prior VTE, but do have a positive family history for VTE, undergo clinical vigilance in the antenatal period and prophylactic- or intermediate-dose anticoagulation in the postpartum period [4]. Prior history of VTE, particularly in association with a temporary risk factor, is also considered to be a weak risk factor outside of an estrogen-associated event. Only 3 out of 125 women (2.4 %) with prior history of VTE, none with a history of provoked VTE, had antepartum recurrence of VTE in a prospective cohort of 125 pregnant women with a single prior VTE in whom antepartum heparin was withheld (Brill-Edwards et al. 2000). The combination of two or more of these independent risk factors, particularly in the setting of heterozygous FVL or prothrombin G20210A mutation, may confer a VTE risk high enough for consideration of antithrombotic therapy. It is generally recommended that women who suffered an unprovoked VTE or estrogen-associated VTE receive thromboprophylaxis both antepartum and postpartum.
Key Points
- 1.
The daily risk of VTE is significantly greater in the postpartum period than the antepartum period. Distinct anticoagulation recommendations are therefore made for the antepartum and postpartum periods based on the individual patient’s risk factors.
- 2.
The inherited thrombophilias present a varying range of risk for VTE rather than a uniformly elevated risk of VTE.
- 3.
Heterozygous Factor V Leiden or prothrombin G20210A mutation in isolation (without a personal history of VTE or a positive family history for VTE or other mitigating factors) can be managed without prophylactic anticoagulation.
- 4.
Potent thrombophilias (e.g., antithrombin deficiency or homozygous Factor V Leiden) in isolation are an indication for prophylactic- to intermediate-dose postpartum anticoagulation. Many experts consider the risk to be sufficiently high to warrant prophylaxis in the antepartum period in addition to the postpartum period.
- 5.
Potent thrombophilias combined with a positive family history of VTE are an indication for prophylactic- to intermediate-dose anticoagulation in the antepartum and postpartum periods.
- 6.
We recommend routine thromboprophylaxis for women with a history of idiopathic or estrogen-associated VTE throughout pregnancy and in the postpartum period.
Case 2
A 32-year-old woman G4P0 with a history of recurrent early pregnancy loss presents to her obstetrician reporting a positive home pregnancy test 4.5 weeks after her last menstrual period. The patient recounts having three spontaneous miscarriages at 6, 7, and 8 weeks of gestation, respectively. She reports being diagnosed with antiphospholipid antibody syndrome following her last miscarriage and recalls being instructed to present for medical attention promptly following a positive home pregnancy test. She has been taking a low-dose aspirin daily. She has no personal history of thromboembolic disease, venous or arterial. Review of her past records reveals persistently positive lupus anticoagulant. She is initiated enoxaparin on 40 mg daily at this visit in addition to the low-dose aspirin that she takes. The patient carries her pregnancy to term, when enoxaparin is switched to unfractionated heparin twice daily in preparation for labor and delivery. Patient undergoes a Cesarean delivery at 41 weeks due to non-progress of labor. Enoxaparin is resumed in the early postpartum period and continued for 6 weeks.
Clinical Impression
Obstetric antiphospholipid antibody syndrome
Discussion of Management
A substantial literature supports the association between antiphospholipid antibodies (APLA) and recurrent and late pregnancy loss [24, 34, 48, 70]. The definition for antiphospholipid antibody syndrome (APS) requires meeting one clinical criterion involving either a venous or arterial thromboembolic event or pregnancy complication/loss, in addition to persistently positive lupus anticoagulant or an antiphospholipid antibody (Table 2) [60]. Obstetric APS refers to APS that manifests with pregnancy complications or failure. The strongest association between an APLA and pregnancy loss has been found for lupus anticoagulant with an odds ratio of 3 for any miscarriage and greater than tenfold for late third trimester loss [63]. These risks are moderate for anticardiolipin antibodies, whereas risks are weak or inconsistent for anti-β2 glycoprotein 1 antibodies [1]. There has been considerable effort to improve pregnancy outcomes in obstetric APS. The most striking results were derived from a single-center study of 90 women with confirmed APLA and three or more consecutive miscarriages, without a personal history of thromboembolism, SLE, in whom hormonal, anatomic, and chromosomal abnormalities as a cause of recurrent pregnancy loss had been excluded. Low-dose aspirin was initiated at conception, and participants were randomized to continue aspirin alone or in combination with UFH 5000 units subcutaneously twice daily until 34-week gestation. A significant benefit on live birth rates was observed in women treated with unfractionated heparin (UFH) plus aspirin as compared to aspirin alone, 71 % versus 42 % [71]. A systematic review of randomized trials comparing UFH or LMWH in combination with aspirin or aspirin alone in patients with obstetric APS (five trials, n = 334) demonstrated that the frequency of live births was higher in the combination treatment group as compared to aspirin alone (74.3 % vs. 55.8 %), the number needed to treat being 5.6 [53]. Although compelling, these trials had small sample sizes with heterogeneous populations, such that the live birth rate with aspirin alone varied between 40 % and 80 %. In addition, the benefit of antithrombotic therapy in women with late pregnancy loss or pregnancy complications related to placental insufficiency remains unclear. Guidelines from the ACCP recommend UFH or LMWH plus aspirin for women with obstetric APS associated with recurrent early pregnancy losses and refrain on commenting on other subgroups of women [4].
Table 2
Revised classification criteria for APS
Clinical criteria | Laboratory criteria |
|---|---|
1. Vascular thrombosis One or more clinical episodes of venous, arterial, or small vessel thrombosis, in any tissue or organ Thrombosis must be confirmed by objective validated criteria 2. Pregnancy morbidity (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of (i) eclampsia or severe preeclampsia or (ii) recognized features of placental insufficiency (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded | 1. Lupus anticoagulant present in plasma, on two or more measurements obtained at least 12 weeks apart 2. Anticardiolipin antibody of IgM and/or IgG isotype measured in the serum or plasma at medium or high titer (>40 GPL or MPL, or > the 99th percentile), on two or more occasions, separated by at least 12 weeks 3. Anti-β2-glycoprotein1 antibody of IgG and/or IgM isotype measured in the serum or plasma (titer >99th percentile), on two or more occasions, separated by at least 12 week |
Key Points
- 1.
The revised classification criteria for APS require that one clinical and one laboratory criterion be fulfilled: (a) evidence of thromboembolic disease, venous or arterial or pregnancy morbidity, and (b) persistent laboratory evidence of antiphospholipid antibodies, lupus anticoagulant and/or anticardiolipin antibody and/or β2-glycoprotein1 antibody.
- 2.
In women with obstetric APS as manifested by recurrent early pregnancy loss, there is evidence that combined therapy with heparin and aspirin leads to improved live birth rates; based on this data, we recommend combination therapy during pregnancy for this subset of women with APS.
- 3.
The value, if any, of antithrombotic therapy in women with obstetric APS associated with late pregnancy loss or placental insufficiency remains unknown.
Case 3
A 29-year-old woman is referred by her reproductive endocrinologist for the management of recurrent pregnancy loss. She has a history of four consecutive first trimester miscarriages. She has celiac disease well controlled on a gluten-free diet. The last two pregnancies were achieved with assisted reproductive technology, and she is anxious to undergo a trial of prophylactic anticoagulation should she become pregnant again. This has been suggested by her reproductive endocrinologist, and she has read on the Internet that this could improve her chances of a successful pregnancy. She would like to coordinate this with the start of her next clomiphene cycle. An extensive workup for recurrent pregnancy loss has been negative so far, including negative testing for antiphospholipid antibody. Pathologic analysis of the previous products of conception is not available. She does not have a personal or family history of VTE. She is counseled during the visit that the available literature does not demonstrate a benefit from prophylactic anticoagulation in the setting of unexplained recurrent pregnancy losses and that while prophylactic anticoagulation with LMWH is fairly safe, the risks do include major maternal bleeding. She elects a trial of prophylactic LMWH in the event of pregnancy. She undergoes another cycle of IVF and does achieve pregnancy at which time she starts LMWH. At 7-week developmental age, a spontaneous abortion is diagnosed based on the absence of a fetal heartbeat.
Clinical Impression
Utility of low-molecular-weight heparin to improve pregnancy outcomes
Discussion of Management
Hypercoagulability with ensuing thrombosis of placental vasculature is one mechanism that has been put forth to explain placenta-mediated pregnancy complications and pregnancy failure. This hypothetical mechanism raises the possibility of a therapeutic intervention with anticoagulants, a prospect that is understandably tempting to both patients and their physicians. While basic science research on genetic mouse models of thrombophilia has provided evidence of a link between fetal demise and activated coagulation in the placenta [39], epidemiologic studies in humans have not convincingly demonstrated an association between thrombophilia and pregnancy failure or complications outside of obstetric APS [1, 21, 42, 81]. Two recent randomized trials, the SPIN and ALIFE studies, sought to address the efficacy of antithrombotic therapy for women with recurrent pregnancy loss [22, 41]. Women with two or more unexplained pregnancy losses were randomized to low-dose aspirin plus LMWH (enoxaparin 40 mg daily in SPIN and nadroparin 2,850 IU daily in ALIFE) to aspirin 80 mg alone in SPIN or to placebo in ALIFE trial. The pregnancy outcomes did not differ between the treatment and control groups in either study. A Cochrane database systematic review on aspirin or anticoagulants for treating recurrent miscarriage in women without APS subsequently reinforced the findings of the SPIN and ALIFE studies (de Jong et al. 2014). Therefore, the current guidelines recommend against the use of antithrombotic therapy in women with unexplained recurrent pregnancy losses ([4]; Royal College of Obstetricians and Gynaecologists 2011).
Key Points
- 1.
Recurrent, unexplained pregnancy loss is defined as the absence of APLA, maternal hormonal abnormalities, maternal anatomic abnormalities, and parental/fetal chromosomal abnormalities.
- 2.
The association between inherited thrombophilia and pregnancy complications/loss is controversial, and the current guidelines do not recommend screening women with recurrent pregnancy losses for inherited thrombophilia.
- 3.
Antithrombotic therapy with LMWH and/or low-dose aspirin does not affect the live birth rate in women with recurrent, unexplained pregnancy loss.
Thrombocytopenia in Pregnancy
Case 1
A 32-year-old primigravida is noted to have a platelet count of 54,000 per μl during her first prenatal visit at 8 weeks of gestation. She is asymptomatic and denies any bleeding symptoms. Her past medical history and family history are unremarkable; in particular, there is no history of thrombocytopenia. Her physical exam is normal with no evidence of bleeding gums or a petechial rash. A white blood cell count is 9,000 per μl and hemoglobin 14 g per dl. Other routine antenatal labs are normal, including viral studies for HIV, HBV, and HCV. Serologic testing for Helicobacter pylori is negative. Her serum immunoglobulins are normal (IgG 850 mg per dl (normal 650–1,400), IgM 45 mg per dl (normal 30–60), and IgA 120 mg per dl (normal 50–200)), and an antinuclear antibody (ANA) screening test is negative. In the absence of symptoms, she is monitored conservatively with monthly platelet counts. She remains stable until gestation week 32 when her platelet count drops to 38,000 per μl. Weekly monitoring is initiated at this time. At week 37, with a platelet count of 22,000 per μl, she is administered a total of 2 g per kg of intravenous immunoglobulin (IVIG) over 2 days and simultaneously started on 10 mg of prednisone a day. A rapid recovery ensues with the platelet count increasing to 130,000 per μl after 2 days of IVIG therapy and remaining stable. Epidural anesthesia is safely administered at the onset of labor at week 39 resulting in the uncomplicated birth of a female neonate with a cord platelet count of 225,000 per μl. Prednisone is tapered over the next 2 weeks. Her platelet count is noted to be 180,000 per μl on routine follow-up at 4 weeks postpartum.
Clinical Impression
Immune thrombocytopenia (ITP) in pregnancy
Discussion of Management
Thrombocytopenia (platelet count < 150,000 per μl) affects about 8–10 % of all pregnancies [13]. A more stringent International Working Group definition of thrombocytopenia (platelet count < 100,000 per μl) limits this occurrence to about 1 % [78]. Table 4 enumerates causes of thrombocytopenia in pregnancy and their basic clinical characteristics.
Table 3
Association between thrombophilia and pregnancy complications
Type of thrombophilia | Recurrent first trimester miscarriage | Single second trimester miscarriage | Stillbirth (third trimester loss) | Preeclampsia (mild or severe) |
|---|---|---|---|---|
Anticardiolipin antibodies | 5.1 (1.3–8.7) | ? | 9.26 (0.86–99.8) | 2.7 (1.65–4.51) |
Anti-β2-glycoprotein1 antibodies | 2.12 (0.69–6.53) | ? | 23.5 (1.2–455) | 19.14 (6.34–57.77) |
Lupus anticoagulant | NA | 14.3 (4.7–43.2) | 54.2 (2.4, 1198) | 1.45 (0.76–2.75) |
Factor V Leiden mutation (heterozygote) | a | 4.1a (1.9–8.8) | 2.0 (0.4–9.7) | a |
Factor V Leiden mutation (homozygote) | 1.9a (1.0–3.6) | 8.6 (2.2–34.0) | 2.1 (1.1–3.9) | 1.23a (0.89–1.70) |
Prothrombin G20210A mutation (heterozygote) | 2.7 (1.4–5.3) | ? | 2.7 (1.3–5.5) | 1.25 (0.79–1.99) |
Gestational Thrombocytopenia and Immune Thrombocytopenia
Gestational thrombocytopenia accounts for about 80 % of thrombocytopenia in pregnancy [12]. With a typical onset in the second to third trimester of pregnancy, most cases are mild (platelet count > 80,000 per μl), rarely < 50,000 per μl. Frequency increases as pregnancy progresses and so does severity of thrombocytopenia. Although gestational thrombocytopenia is thought to be secondary to increased clearance and hemodilution, similar to gestational anemia, it is not an expected occurrence in a pregnancy unlike anemia. This does not impact neonatal platelet count and resolves in the early postpartum period with a tendency to recur in subsequent pregnancies.
Thrombocytopenia occurring in the first trimester, especially with a history of thrombocytopenia outside of pregnancy or neonatal thrombocytopenia, is more consistent with immune thrombocytopenia (ITP) [31]. ITP is the second most common cause of isolated thrombocytopenia in pregnancy accounting for approximately 3 % of cases (Sainio et al. 2000). Both gestational thrombocytopenia and ITP are diagnoses of exclusion, but a platelet count of <50,000 per μl is more consistent with the latter or with other rarer causes of thrombocytopenia. A laboratory evaluation of moderate to severe thrombocytopenia (platelet count < 50,000 per μl) is carried out to rule out systemic disorders, both pregnancy specific and general, and diagnose secondary causes of ITP. This workup includes complete blood counts, evaluation of the peripheral blood smear, basic coagulation tests (prothrombin time, partial thromboplastin time, and fibrinogen), complete metabolic profile, viral studies (HIV, HBV, HCV), antiphospholipid antibody syndrome screen (lupus anticoagulant, anticardiolipin antibodies, and β2-glycoprotein-1 antibodies), and, if indicated based on history of hemorrhage, a von Willebrand disease (vWD) panel to rule out type IIB vWD. A discussion of management of ITP in pregnancy follows, with other disorders discussed at the end of this section.
In the absence of randomized trials in this field, guidelines on monitoring and management of thrombocytopenia in pregnancy are based on lower levels of evidence and clinical reasoning [61]. The threshold to monitor platelet counts more frequently than routine prenatal visits is moderate thrombocytopenia (platelet count < 80,000/ μl). Initially counts are obtained every 2–4 weeks. If the platelet count is >30,000 per μl, monthly monitoring until gestation week 34 is appropriate, at which time the frequency is increased to weekly assessments. Table 5 summarizes the American Society of Hematology guidelines for the management of ITP in pregnancy [61]. Treatment is deemed necessary in the first two trimesters for platelet counts of <10,000 per μl or symptomatic thrombocytopenia or for any procedures (a platelet count of ≥50,000 per μl is considered adequate for procedures). From gestation weeks 34–36, treatment is indicated to keep platelet counts over 50,000 per μl in preparation for labor and delivery [69].
Table 4
Typical characteristics of thrombocytopenic disorders of pregnancy
Cause | Prevalence | Clinical characteristics | ||
|---|---|---|---|---|
Onset | Severity (platelet count per μl) | Characteristics | ||
Isolated thrombocytopenia | ||||
Gestational thrombocytopenia | ~80 % | Second to third trimester | >80,000 | No bleeding No fetal thrombocytopenia Spontaneous resolution |
Immune thrombocytopenia (ITP) | ~3 % | Anytime (typically predates pregnancy) | <100,000 | Bleeding and fetal thrombocytopenia possible Treatment for severe cases |
Drug-induced thrombocytopenia | <1 % | Anytime | <100,000 | Resolution upon discontinuation of the offending drug |
Congenital thrombocytopenia | <1 % | Predates pregnancy | <100,000 | Bleeding and fetal thrombocytopenia possible |
Type IIb vWD | <1 % | Thrombocytopenia often worsens with pregnancy | <100,000 | Bleeding possible |
Systemic disorders | ||||
Preeclampsia | 15–20 % | Mid-second to third trimester | >50,000 | No bleeding No fetal thrombocytopenia |
HELLP syndrome | <1 % | Mid-second to third trimester | >50,000 | Bleeding rare No fetal thrombocytopenia |
Acute fatty liver of pregnancy | <1 % | Late third trimester | <100,000 | Often associated with DIC No fetal thrombocytopenia |
TTP/HUS | <1 % | Anytime | <50,000 | Thrombosis and bleeding possible No fetal thrombocytopenia |
Antiphospholipid antibody syndrome | <1 % | Anytime | <100,000 | Thrombosis and pregnancy loss possible |
Viral syndromes (EBV, CMV, HIV, HCV, HBV) | <1 % | Anytime | <100,000 | Spontaneous resolution (can also be associated with ITP) |
Corticosteroids and IVIG are first-line agents for the treatment of ITP in pregnancy as listed in Table 5 [61, 69]. There are no randomized trials or large prospective cohorts of treatment of pregnancy-associated ITP to back evidence-based management. Prednisone is considered safe in pregnancy, although its use in first trimester may be associated with increased risk of cleft lip and palate [66]. Additionally, its use is associated with increased maternal weight gain, hyperglycemia, and worsening hypertension [48]. Thus, the lowest dose that achieves a hemostatically effective platelet count can be considered, such as prednisone 10–20 mg orally daily. Intravenous immunoglobulin (IVIG) 2 g per kg administered over 2 days, with or without prednisone, is an alternative particularly when a more rapid recovery in platelet count is desired such as close to term or for a procedure or when there is a less than adequate response to prednisone. IVIG has the same potential adverse effects here as in the nonpregnant population which includes thrombosis and severe headache.
Table 5
Summary of American Society of Hematology guidelines for medical management of ITP in pregnancy
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