Medical Problems During Pregnancy

Thrombophilia and Thrombocytopenia in the Pregnant Woman

Lourdes M. Mendez¹, Anish V. Sharda¹ and Jeffrey I. Zwicker¹

(1)

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Jeffrey I. Zwicker

Email: jzwicker@bidmc.harvard.edu

Keywords

ThrombocytopeniaVenous thromboembolismPregnancy associated thrombosisGestational thrombocytopeniaIdiopathic thrombocytopenia purpura

Pregnancy and Venous Thromboembolism

Introduction

A number of factors contribute to an increased risk of vascular thromboembolism (VTE) during pregnancy including augmented venous stasis secondary to anatomic changes and a heightened activation of the coagulation cascade. Compression of the left iliac vein by the left iliac artery impedes venous return accounting for the preponderance of left lower extremity deep vein thrombosis (DVT) during pregnancy [73]. Evidence of heightened activation of the coagulation cascade comes from measurements of decreased anticoagulant activity such as of protein S, increased procoagulant activity, and decreased fibrinolysis [19, 83]. The “hypercoagulability” of pregnancy peaks in the early postpartum period and is posited to occur in preparation for the hemostatic challenge of delivery [45]. As in the general population, there is significant interest in risk stratifying pregnant women to identify those at high risk that would benefit from anticoagulation.

Two-thirds of all pregnancy-associated DVT occur antepartum distributed evenly throughout the three trimesters, the remaining one-third occurring postpartum [73]. Taking into account that the antepartum period is approximately sevenfold greater in duration than the postpartum period, it becomes clear that the absolute daily risk of venous thromboembolism (VTE) is considerably higher during the postpartum period. In a recent study that assessed more than one million pregnancies in California, the odds of experiencing a thrombotic event was tenfold higher in the first 6 weeks postpartum, and the increased risk persisted up to 12 weeks [43]. The wide range in the absolute risk of VTE that exists during pregnancy is exemplified by comparing a woman without a personal or family history of VTE during the antepartum period who has a risk of <0.1 % over 40 weeks and a woman with a personal history of VTE and thrombophilia in the postpartum period, who has a risk 5 % over 6 weeks ([87]; Pabinger et al. 2005). Thus, the risk of VTE in the antepartum and postpartum period is considered separately prior to making recommendations regarding antithrombotic therapy in a given case.

The risk of harm to the patient from antithrombotic therapy forms a crucial part of the equation when estimating the net clinical benefit or lack thereof. Beyond major hemorrhage, the patient may also encounter minor bleeding, allergic reactions, heparin-induced thrombocytopenia (though rare), limited obstetrical anesthesia options, and wound complications following delivery. VTE-related deaths represent a leading cause of maternal mortality in the developed world and yet, fortunately, remain uncommon accounting for 0.8–4.7 deaths per 100,000 pregnancies (Berg et al. 2010; [15]). Major bleeding rates from low-molecular-weight heparin (LMWH) in the antepartum period are extremely low (0 %, 95 % CI, 0–0.6 %) and appear to be increased in the postpartum period (0.3 %, 95 % CI, 0–1 %) [11, 23, 26, 29, 33, 35, 36, 41, 56, 76, 80]. The proportion of major bleeding events that are fatal is about 3.5–4 %, whereas the proportion of VTE that are fatal (as extrapolated from other populations) is about 1.4–2 % [49, 62], that is, approximately a half of that of the fatal bleeding risk. This implies that VTE risk must exceed the major bleeding risk by two- to threefold to achieve a mortality benefit. Generally speaking, a conservative estimate is that an absolute VTE risk of >3 % either in the antepartum or postpartum period would be needed for the antithrombotic therapy to provide a net clinical benefit to the patient [79]. Such estimates naturally raise the question – which populations have a calculated risk high enough to meet such a threshold?

Case 1

A 28-year-old primigravida, heterozygous for factor V Leiden, is seen in the hematology clinic at 12 weeks of gestation. She has no other significant past medical history. In particular she does not have a personal history VTE nor of any bleeding problems. Her family history is notable for idiopathic DVT in a brother, who is the proband. Thereafter, she was found to be heterozygous for this trait upon screening. The patient is currently asymptomatic with an unremarkable first trimester. Based on her heterozygous factor V Leiden status and positive family history for VTE, she is recommended postpartum prophylaxis with LMWH. The patient has a normal pregnancy and delivers a healthy male neonate at 41 weeks of gestation. She is initiated on enoxaparin 40 mg subcutaneously daily on the first postpartum day for a total of 6 weeks.

The Clinical Impression

Pregnancy with factor V Leiden

Discussion of Management

Pregnancy is a transient, independent risk factor for venous thromboembolism. The incidence of VTE increases tenfold from 1 in 10,000 to 1 in 1,000 during pregnancy [3, 56, 57] and a further tenfold in the postpartum period [43, 73]. This risk is further modified by acquired and inherited risk factors.

The most common genetic determinant of thrombophilia is factor V Leiden, which is present in approximately 5 % of Caucasians (including European, Arab, Jewish, and Indian populations) [74] and, interestingly, is not present in African Black, Chinese, or Japanese populations. The next most prevalent genetic determinant in Caucasians is the prothrombin 20210A mutation [67]. Factor V Leiden refers to a point mutation that converts arginine to glutamine at position 506 in factor V, rendering it resistant to activated protein C-mediated (APC) cleavage [16]. Factor V Leiden was therefore originally termed “APC resistance.” The Leiden thrombophilia study found that overall, the relative risk for VTE is increased sevenfold for factor V Leiden heterozygotes and 80-fold for homozygotes [46]. Nonetheless, only about 5 % of factor V Leiden heterozygotes will experience a VTE in their lifetime; the overwhelming majority will remain free of VTE. Prothrombin 20210A mutation results from a single nucleotide transition (guanine to adenine) at position 20210 of the 3′-untranslated region of the prothrombin gene resulting in elevated plasma prothrombin (factor II) levels. Heterozygous prothrombin 20210A mutation is associated with about twofold increase in risk of VTE, whereas the homozygous state is associated with a much higher risk (De Stefano et al. 2001). The deficiencies of natural occurring anticoagulant proteins c and s and antithrombin are rare, but associated with a 10–20-fold increased risk of VTE.

The differences in the VTE risk in the antepartum and postpartum periods and its interaction with an individual patient’s risk factors, inherited and acquired, are taken into account to formulate recommendations for antithrombotic therapy. Large prospective cohort studies of patients with heterozygous FVL or prothrombin mutation [20, 37, 50, 51, 84, 86] and randomized control trials [23, 36, 41, 56, 80] have demonstrated a low risk of venous thromboembolism (VTE) in the antepartum period in the absence of prophylactic anticoagulation. For asymptomatic (no personal or family history of VTE), homozygous FVL and prothrombin mutation, antenatal prophylaxis is not recommended per the American College of Chest Physician (ACCP) guidelines [4]; however, the risk of antenatal VTE [40, 55] is deemed to be high enough by many experts to justify antenatal prophylactic anticoagulation. The data on pregnant women with antithrombin deficiency is limited, but given the high risk of VTE in the nonpregnant antithrombin-deficient population, this is regarded as a particularly potent thrombophilia during pregnancy and treated with antenatal antithrombotic therapy (Conard et al. 1990; [9]). Asymptomatic antithrombin-deficient patients are treated with weight-adjusted LMWH, whereas those with a personal history of VTE are treated with therapeutic doses of LMWH; moreover, pooled human antithrombin concentrate is administered around the time of delivery. Previous history of estrogen-associated VTE has been shown to have a high antepartum recurrence in the absence of anticoagulant prophylaxis, as high as 10 % in some retrospective studies (Pabinger et al. 2005; De Stefano et al. 2006), and, hence, warrants antithrombotic therapy. The risk of VTE in the postpartum period is high in potent thrombophilias warranting antithrombotic therapy [4, 82]. In addition, compound heterozygosity for FVL and prothrombin G20210A mutation also confers a high risk of VTE in the postpartum period, and therefore postpartum antithrombotic therapy is recommended for this group. This is not the case for the weak thrombophilias, where, like during the pregnancy, only clinical vigilance is recommended (see Table 1).

Table 1

Inherited thrombophilias and prophylactic anticoagulation

	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

^aObserved or estimated absolute risk of VTE, antepartum and postpartum combined, % pregnancies (95 % CI)

• Data based on Table 7 in Bates et al. [4]

• Recommendation for antepartum and postpartum anticoagulation (AC) based on ACCP 9th Edition Guidelines

• Antithrombin deficiency recommendations are based on Bramham et al. [9]

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. 1.

2. 2.

3. 3.

4. 4.

5. 5.

6. 6.

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

The diagnosis of APS requires that at least one clinical criterion and one laboratory criterion should be met. Adapted from [60]

Key Points

1. 1.

2. 2.

3. 3.

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. 1.

2. 2.

3. 3.

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)

Adapted from Middeldorp et al. [59]

^aThe distinction between heterozygosity and homozygosity cannot be discerned

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)

Modified from Gernsheimer et al. [31]

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

Treatment indications	Platelet count < 10,000 per μl Platelet count < 30,000 per μl in second and third trimester Symptomatic ITP
First-line agents	Prednisone 10–30 mg per day IVIG 2 g per kg over 2 days
IVIG indications	Steroid failure Initial treatment: platelet count < 10,000 per μl third trimester Initial treatment: platelet count < 30,000 per μl and bleeding
Safe platelet count for delivery	>50,000 per μl
Mode of delivery	Based on obstetric indications

Adapted from Gernsheimer et al. [31]

The options for refractory ITP during pregnancy are limited. Splenectomy can be safely performed in the second trimester but is rarely necessary. Anecdotal reports of successful use of anti-D immunoglobulin in non-splenectomized Rh-positive patients [58] and azathioprine [2] are also available, although these agents have potential fetal toxicities. Intravenous anti-D immunoglobulin may cause hemolytic anemia in both mother and fetus and must be used cautiously. There is ample evidence of safe use of azathioprine in pregnancy in transplant and lupus [68], but a concern for preterm labor and intrauterine growth restriction has been raised. Cyclosporine also appears to be safe in pregnancy when used in inflammatory bowel disease and transplant settings [75], but its use in ITP in pregnancy has not been reported. Delayed onset of azathioprine and cyclosporine limits their usefulness as steroid-sparing agents. Successful rituximab use has also been reported [28], but it is not recommended for use in pregnancy as it crosses the placenta and may cause neonatal immunodeficiency. One retrospective series of 153 pregnancies associated with maternal rituximab exposure was associated with 90 live births, of which 22 were premature, one associated with neonatal death, 11 hematological abnormalities, and two congenital deformities [17]. As the maternal conditions were serious, it is difficult to generalize this literature. Thrombopoietin receptor agonists are contraindicated in pregnancy, as animal studies were associated with postimplantation losses and increased mortality with romiplostim.

Serious maternal hemorrhage remains uncommon in vaginal deliveries even with severe thrombocytopenia, and unusual with platelet counts > 50,000 per μl. Two large cohorts of ITP in pregnancy [27, 90] showed that only about 31–33 % of pregnant patients with ITP required treatment, and 74–82 % of pregnancies resulted in normal deliveries. A total of 37.5 % of patients in the cohort of Webert et al. received epidural anesthesia, most with platelet counts >75,000 per μl. Thus, the mode of delivery is based on obstetric indications. When platelet counts remain <50,000 per μl despite treatment, platelet transfusions can be considered but generally result in minimal to no platelet increase due to antibody-mediated consumption of transfused platelets. Epidural anesthesia and analgesia are generally considered safe for a platelet count greater than 75,000 per μl, but local practices vary [5].

Fetal thrombocytopenia (platelet count < 100,000 per μl) complicates 22–28 % of the cases of ITP in pregnancy [27, 90]. There is no clear correlation between the severity of maternal thrombocytopenia and development of neonatal thrombocytopenia, but moderate to severe neonatal thrombocytopenia (platelet count < 50,000 per μl) occurs in about 10 % of the cases [90]. The best predictor of the severity of neonatal thrombocytopenia is its occurrence in an earlier pregnancy [13]. The risk of major hemorrhage, particularly intracranial hemorrhage, is rare. A small, randomized clinical trial revealed that antenatal steroids do not impact neonatal platelet count or outcomes and, hence, should not be used for this purpose [18]. Neonatal platelet count is tested at the time of birth, preferably via peripheral or cord blood sampling, and further monitoring depends on the severity of thrombocytopenia. Typically, the platelet count reaches a nadir 2–5 days after birth and normalizes in a week.

The risk of ITP is higher in subsequent pregnancies but mothers with a prior history of ITP are less likely to require treatment for ITP in subsequent pregnancies when compared to those with a new diagnosis [90].

Other Causes of Thrombocytopenia in Pregnancy

Preeclampsia is the second most common cause of thrombocytopenia in pregnancy defined as hypertension (systolic > 140 mmHg or diastolic > 90 mmHg) that develops after gestation week 20 associated with proteinuria (>0.3 g per 24 h) [10]. Thrombocytopenia complicates about 50 % of cases of preeclampsia, but platelet count < 50,000 per μl occurs only in <5 % of cases [57]. HELLP syndrome defined as Hemolysis (peripheral smear schistocytosis, LDH > 600 U per L, or total bilirubin > 1.2 mg per dL) Elevated Liver enzymes (aspartate transaminase > 70 U per L), and Low Platelet count (<100,000 per μl) occurs in <1 % of pregnancies, complicating 10–20 % of cases of severe preeclampsia [44]. Acute fatty liver of pregnancy (AFLP) is a rare life-threatening condition occurring in late third trimester with many overlapping features of severe preeclampsia and HELLP syndrome. In addition to severe abnormalities in liver function (total bilirubin > 5 mg per dL), there is evidence of moderate to severe normocytic anemia, thrombocytopenia, hypoglycemia, metabolic acidosis, and acute kidney injury. Severe thrombocytopenia with platelet counts < 20,000 per μl is uncommon in severe preeclampsia/eclampsia, HELLP syndrome, and AFLP. The specific management of these conditions is discussed in chapters dedicated to these conditions, but delivery of fetus is the mainstay of treatment. The use of steroids in HELLP syndrome remains controversial except for fetal lung maturity [92]. Plasma exchange has been shown to improve outcomes in severe HELLP syndrome and AFLP, but the evidence is limited [25, 54]. Disseminated intravascular coagulopathy (DIC) can often complicate these conditions, and its management does not differ from DIC in non-pregnancy patients.

Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, neurologic abnormalities, and acute kidney injury. Although not specific to pregnancy, TTP is more common in women of reproductive age, with increased frequency in pregnancy [85]. Up to 25 % of cases of TTP have been described in association with pregnancy. The pathophysiology of TTP involves deficiency of von Willebrand factor (vWF) cleaving enzyme ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif, member 13). Both congenital deficiency (Upshaw-Schulman syndrome) and acquired cases secondary to neutralizing autoantibodies can manifest for the first time during pregnancy. Atypical hemolytic uremic syndrome (HUS), associated with congenital defects in the alternative complement pathways, can also complicate pregnancy. As compared to TTP, renal dysfunction is more common in HUS. The management of these disorders in pregnancy is similar to that of nonpregnant patients [30]. Thus, plasma exchange is the mainstay of the treatment with frequency of exchanges guided by serum LDH and platelet counts. Eculizumab has not been used for pregnancy-associated atypical HUS. The risk of relapse in subsequent pregnancies is 100 % in congenital cases and as high as 20 % in acquired cases of TTP/HUS [72]. Hence, subsequent pregnancies require careful monitoring from early pregnancy.

Antiphospholipid syndrome is described elsewhere in this chapter. SLE can be associated with secondary ITP, the management of which is similar to primary ITP. Viral syndromes and drug-induced thrombocytopenia are self-limiting conditions. Type 2b vWD is a rare inherited bleeding disorder associated with mild thrombocytopenia. Increased affinity of platelet glycoprotein Ib to vWF in this condition causes accelerated clearance of vWF and platelets. Women with this disorder may first be recognized during pregnancy when thrombocytopenia becomes more pronounced with gestation [47] as the production of vWF increases. Occasionally, platelet counts can decrease < 20,000 per μl, usually close to term, with rapid recovery after delivery [38]. vWF panel which shows a normal vWF antigen levels, decreased vWF activity, decreased high-molecular-weight vWF multimers, and an abnormally increased low-dose ristocetin-induced platelet aggregation aids in the diagnosis. Levels of vWF and factor VIII should be increased to > 50 IU per dL to cover delivery and any surgical procedures and can be achieved with administration of purified vWF/factor VIII concentrate. Platelet transfusions may be required at the time of the delivery for platelet counts < 50,000 per μl.

Key Points

· Thrombocytopenia occurs in approximately 10 % of all pregnancies; most cases are mild and secondary to self-limiting gestational thrombocytopenia.

· Immune thrombocytopenia occurs in approximately 3 % of all pregnancies; the management of ITP in pregnancy is similar to nonpregnant cases with low-dose corticosteroids and IVIG being the backbone of therapy.

· The mode of delivery in ITP is driven by obstetric indications; the goal platelet is >50,000 per μl for delivery.

· A self-limiting fetal thrombocytopenia can complicate ITP in pregnancy; the risk of intracranial hemorrhage is low and typically occurs after delivery.

· Preeclampsia, HELLP syndrome, and AFLP are pregnancy-specific systemic syndromes that can result in mild to moderate thrombocytopenia and occasional DIC.

· TTP and atypical HUS are thrombotic microangiopathies that can complicate pregnancies with a high risk of recurrence in subsequent pregnancies.

Case 2

A 30-year-old G5P0 with a history of recurrent pregnancy losses is seen in hematology clinic at 10 weeks of gestation. Her first pregnancy resulted in a spontaneous abortion of a twin pregnancy at 6 weeks; second, an intrauterine fetal demise at 24 weeks, fetal necropsy associated with liquefaction of intracranial and other body cavities; third, a spontaneous abortion at 13 weeks; fourth and last, an intrauterine fetal demise at 31 weeks associated with fetal intracranial hemorrhage, erythroblastosis, and hydrops. Patient does not have any significant past medical history, and a complete workup of recurrent pregnancy loss is found to be normal except for platelet antigen incompatibility. She is identified as human platelet antigen-1a (HPA-1a) negative with father being HPA1a positive, homozygously. In addition, anti-HPA-1a antibodies are detected in maternal serum. Patient is initiated on IVIG 2 g per kg per week, and prednisone 60 mg daily added at 20 weeks. An elective Cesarean section is performed at 34 weeks after the administration of betamethasone for fetal lung maturity. A female fetus is delivered with cord blood platelet count 14,000 per μl. The neonate is treated with HPA-1a negative platelets to keep platelet count > 30,000 per μl. A head ultrasound is normal and thrombocytopenia resolves in a week after delivery.

Clinical Impression

Fetal and neonatal alloimmune thrombocytopenia (FNAIT)

Discussion of Management

FNAIT is a devastating disease with an incidence of ~1 in 1,000 to 2,000 pregnancies [8]. It results from alloimmune destruction of fetal platelets by maternal antibodies directed against platelet cell membrane antigens inherited from the father, similar to hemolytic disease of the newborn. In contrast to hemolytic disease of newborn, platelet alloimmunization can occur even in the first pregnancy in FNAIT, and, hence, it is common for the firstborns to be affected. FNAIT is suspected when either neonatal thrombocytopenia occurs within the first 24–48 h after birth or fetal demise resulting from intracranial hemorrhage. Intracranial hemorrhage occurs in about 20 % of cases with 80 % of these occur before 30 weeks of gestation, documented as early as 20 weeks [89].

The laboratory diagnosis of FNAIT is based on the identification of the offending antigen by typing of maternal and paternal platelet antigens and serological detection of maternal anti-platelet alloantibodies. The prevalence of HPA-1a phenotype in Caucasians is about 2.5 %, accounting for 75 % of the cases of FNAIT, followed by HPA-5b and HPA-3a [91]. In Asians, HPA-4b is involved more often. HLA-DR antigen B3*0101 positivity increases the risk of FNAIT in HPA-1a negative mothers.

The management of an infant with neonatal thrombocytopenia depends on its severity. Compatible platelets are transfused for severe thrombocytopenia (<30,000 per μl) with or without IVIG. Screening head ultrasound is obtained to rule out intracranial hemorrhage. Thrombocytopenia usually resolves within 1–2 weeks of birth [6]. Due to recurrence of FNAIT with increasing severity in subsequent pregnancies with incompatible fetus, the management of subsequent pregnancies is imperative. If father is homozygous for the implicated HPA, then the fetus will have a 100 % chance of possessing the antigen, whereas those with heterozygous fathers will have a 50 % chance. Chorionic villous sampling at 8–10-week gestation or amniotic fluid sampling at 18–20 weeks can help identify the fetus at risk in case of paternal heterozygosity, but these procedures carry their own risk of adverse events, particularly if the fetus is thrombocytopenic.

Management is based on risk stratification with IVIG and steroids forming the basis of the treatment. Table 6 summarizes the risk groups and recommended management [64]. Randomized trials are lacking in this field and most data come from prospective and retrospective cohorts. A small, randomized trial compared low-dose IVIG (0.5 g per kg per week) to standard-dose IVIG (1 g per kg per week) in pregnant females with a history of FNAIT without intracranial hemorrhage and found no difference in outcomes [65]. Pregnancies with very high risk of FNAIT, as our patient, are commonly managed with IVIG 2 g per kg per week starting at 12 weeks of gestation, supplemented by prednisone 1 mg per kg daily at 20 weeks. An elective Cesarean delivery is carried out at 34–36 weeks. In a prospective cohort, no intracranial hemorrhage recurred in seven cases treated with this regimen [14].

Table 6

Risk stratification and management of fetal and neonatal alloimmune thrombocytopenia

Risk group	Definition	Risk	Management
			IVIG	Prednisone	Cesarean delivery
1	Previous fetal or neonatal thrombocytopenia or ICH of unknown etiology	Unknown	–	–	–
2	Previous FNAIT but no ICH	Standard	2 g/kg at 20 weeksa	0.5 mg/kg at 32 weeks	37–38 weeks
3	Previous FNAIT with ICH at or after 28 weeks gestation	High	1 g/kg at 12 weeks; 2 g/kg at 20 weeksa	0.5 mg/kg at 28 weeks	35–36 weeks
4	Previous FNAIT with ICH before 28 weeks gestation	Very high	2 g/kg at 12 weeks	1 mg/kg at 20 weeks	35–36 weeks

Modified from Pacheco et al. [64]

IVIG intravenous immunoglobulin, FNAIT fetal and neonatal alloimmune thrombocytopenia, ICH intracranial hemorrhages

^aAlternatively 1 g/kg IVIG plus prednisone 0.5 mg/kg

Key Points

· FNAIT results from alloimmune destruction of fetal platelets by maternal antibodies directed against incompatible paternal antigens.

· The most commonly implicated platelet antigen is HPA-1a accounting for over 75 % of all cases in Caucasians.

· The most devastating consequence of FNAIT is fetal intracranial hemorrhage occurring in approximately 20 % of all cases, as early as 20 weeks of gestation.

· Management is risk stratified with IVIG and steroids being the backbone of therapy.

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