Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum : Obstetrics & Gynecology

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Reviews: Clinical Expert Series

Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum

Lim, Ming Y. MBBChir, MSCR; Abou-Ismail, Mouhamed Yazan MD; Branch, D. Ware MD

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Obstetrics & Gynecology 141(1):p 85-108, January 2023. | DOI: 10.1097/AOG.0000000000005024
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Thrombotic microangiopathies (TMAs) are a spectrum of distinct disorders characterized clinically by microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction secondary to endothelial cell injury and microvascular thrombi formation.1 The most common pregnancy-related TMA is the syndrome of preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Though not unique to pregnancy, other rare TMAs, mainly thrombotic thrombocytopenic purpura (TTP), complement-mediated hemolytic-uremic syndrome (CM-HUS, also known as atypical hemolytic uremic syndrome), and catastrophic antiphospholipid syndrome (CAPS) may occur during pregnancy or the postpartum period, perhaps due to pregnancy acting as a trigger.2 Without prompt recognition and treatment, these infrequently encountered TMAs are associated with high rates of serious maternal morbidity with long-term sequelae or maternal-fetal lethality. Yet differentiating preeclampsia or HELLP syndrome from these rare TMAs during pregnancy can be diagnostically challenging as there are significant clinical overlap in their presentation. Timely, accurate diagnosis of TTP, CM-HUS, or CAPS is critical because management for these TMAs varies significantly.

With regard to the diagnosis and management of HELLP syndrome, readers are referred to the American College of Obstetricians and Gynecologists’ (ACOG) Practice Bulletin No. 222.3 Also, a previous review of rare conditions that share some clinical and laboratory features with HELLP syndrome included acute fatty liver of pregnancy.4 This condition is the subject of a recent Clinical Expert Series in obstetrics and gynecology.5 Our review will focus on the several non–pregnancy-specific TMAs that may occur during pregnancy or postpartum: TTP, CM-HUS, and CAPS.


Pathophysiology and Epidemiology

Thrombotic thrombocytopenic purpura results from a severe deficiency of the enzyme ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) that cleaves ultra-large multimers of von Willebrand factor released from vascular endothelial cells (Fig. 1).6–9 In the presence of turbulent blood flow (high shear stress), ultra-large von Willebrand factor multimers unfold and have a high binding affinity to the platelet glycoprotein Ib/IX/V receptors. This then results in the activation of the platelet glycoprotein IIb/IIIa complexes, which stimulates spontaneous platelet aggregation.10–12 In severe ADAMTS13 deficiency, there is a persistence of these ultra-large von Willebrand factor multimers in the circulation. This leads to microvascular thrombi formation in organs with high shear blood flow (most commonly heart, brain and kidneys) and microangiopathic hemolytic anemia with thrombocytopenia.

Fig. 1.:
Pathophysiology of thrombotic thrombocytopenic purpura (TTP). ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13; VWF, von Willebrand factor. Created with BioRender.com.

Severe ADAMTS13 deficiency (defined as activity less than 10%)13,14 can be congenital (Upshaw-Schulman syndrome) due to a homozygous or compound heterozygous mutation in the ADAMTS13 gene, located on chromosome 9q3415 or acquired due to anti-ADAMTS13 immunoglobulin (Ig)G autoantibodies (immune-mediated TTP).16 Based on national registries, the prevalence of TTP is estimated at 6–13 cases per million people with the majority of cases being acquired (only approximately 5% congenital).17,18

Pregnancy is a known trigger for TTP and accounts for approximately 5–10% of all TTP cases.17,18 There is a higher proportion of congenital TTP presenting during pregnancy (up to one quarter to one third)2 as compared with general-onset TTP (approximately 5%). During normal pregnancy, von Willebrand factor and factor VIII levels rise two- to fourfold19 to reduce the risk of bleeding at time of delivery. There is also an associated physiologic reduction in ADAMTS13 activity throughout pregnancy due to consumption by higher von Willebrand factor levels and hormonal changes, but typically does not reach less than 20%.20,21 These physiological changes can exacerbate the low ADAMTS13 levels in individuals with congenital TTP to a critical level resulting in overt presentation of TTP. Additionally, in the presence of ultra-large von Willebrand factor multimers (from either congenital TTP or pregnancy-induced immune-mediated TTP), turbulent blood flow with high shear stress in the maternal spiral arterioles that supply the placenta leads to spontaneous placental arteriolar thrombosis22 and, thus, exacerbation of TTP.

Clinical Presentation and Diagnosis

Traditionally, the clinical pentad of TTP consists of 1) thrombocytopenia (platelet count less than 100×109/L); 2) microangiopathic hemolytic anemia (defined as raised serum lactate dehydrogenase [LDH] more than 1.5 times the upper limit of normal, undetectable serum haptoglobin, and peripheral smear findings of fragmented red blood cells [schistocytes]); 3) neurologic abnormalities; 4) fever; and 5) renal dysfunction. However, it is well recognized that not all patients with TTP present with the clinical pentad, with only one third of patients presenting with neurologic abnormalities.23 Also, most patients do not present acutely with renal dysfunction until late in the disease process if left untreated. Thus, the presence of microangiopathic hemolytic anemia and thrombocytopenia alone without another apparent cause should raise the consideration of TTP as a possible diagnosis.

Obtaining an ADAMTS13 activity is time-critical, because an activity less than 10% can distinguish the diagnosis of TTP from other TMAs. Unavailability of this diagnostic test may result in delayed diagnosis and treatment24 and adverse outcomes.25 Hence, the initial diagnosis of TTP is often a clinical diagnosis. To aid in the diagnosis when the ADAMTS13 results are not yet available, clinical risk assessment models have been developed to predict ADAMTS13 deficiency. The two most common models that uses clinical and laboratory parameters are the PLASMIC score26 (Box 1) and the French score27 that was developed by the French TMA Reference Center (Box 2). The PLASMIC score classifies patients into low-risk (score 0–4), intermediate-risk (score 5), and high-risk (score 6–7) categories, with the risk of severe ADAMTS13 deficiency of 0–4%, 5–24%, and 62–82% in each risk category, respectively.26 The French score uses a much simpler three-criteria score looking at platelet count, serum creatinine levels, and presence of antinuclear antibodies.27 When at least one criterion was met, the positive predictive value of having severe ADAMTS13 deficiency was 85%. The positive predictive value increases to 98.7% when all three criteria are positive. However, neither of these scores has been validated in pregnancy.

Box 1.

PLASMIC Score26 to Predict ADAMTS13 Deficiency


Box 2.

French Score27 to Predict Acquired Severe ADAMTS13 Deficiency*

  • Laboratory criteria:
    • • Platelet count less than 30×109/L
    • • Serum creatinine level 2.26 mg/dL or less (200 micromoles/L)
    • • Detectable antinuclear antibodies
  • Interpretation:
    • • At least 1 positive criterion: PPV 85% (95% CI 82.6–87.7)
    • • All 3 criteria positive: PPV 98.7% (95% CI 96.4–100)

ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13; PPV, positive predictive value.

*Defined as ADAMTS13 activity level less than 20%.


Pathophysiology and Epidemiology

Complement-mediated hemolytic-uremic syndrome occurs as a result of abnormalities in the complement regulatory proteins, causing uncontrolled dysregulation and amplified activation of the complement alternative pathway (Fig. 2).28 This leads to release of anaphylatoxins, excess formation of the membrane attack complex through the terminal complement pathway, and subsequent microvascular endothelial activation and injury, platelet activation and aggregation, and systemic TMA.29 Abnormal complement regulatory proteins that may be involved include factor H, factor I, CD46 (membrane co-factor protein [MCP]), complement activators C3 and factor B, and thrombomodulin. Genetic variants in these relevant complement regulatory proteins have been identified (eg, loss-of-function variants of CFH, CFI, or CD46, or gain-of-function variants in CFB or C3, or heterozygous missense THBD variants) and account for approximately 40–60% of cases.30–33 In a small subset of cases, deletions of CFHR1 and CFHR3 have been associated with autoantibodies against factor H, resulting in complement dysregulation.34–36 These genetic defects alone may be insufficient to cause TMA, because there is incomplete penetrance among carriers of pathogenic variants of the relevant complement proteins. A “multiple-hit” hypothesis for triggering the clinical phenotype of CM-HUS has been proposed, with suggested environmental triggers including infection, autoimmune exacerbation, and pregnancy.37

Fig. 2.:
Pathophysiology of complement-mediated hemolytic uremic syndrome. *Deletions of CRHR1 and CFHR3 have been associated with autoantibodies against factor H, resulting in complement dysregulation. MAC, membrane attack complex. Created with BioRender.com.

Complement-mediated hemolytic-uremic syndrome is estimated to affect 0.5–2 people per million.38,39 It is a rare disorder representing less than 3% of all TMAs.40 Pregnancy is a well-established trigger for CM-HUS, accounting for 16% of cases occurring in individuals of child-bearing age in the largest published series from three national registries.41 CM-HUS can occur during any trimester and postpartum. The risk of pregnancy-associated CM-HUS is highest in primigravid patients.41,42 However, when it presents during subsequent pregnancies, most patients have no history of it.43 Also, because 75% of cases occur in the postpartum period (up to 3 months after delivery),41,43 CM-HUS should be considered in the differential diagnosis of postpartum preeclampsia.

Clinical Presentation and Diagnosis

Complement-mediated hemolytic-uremic syndrome can present with microangiopathic hemolytic anemia and thrombocytopenia alone without another apparent cause. What distinguishes CM-HUS from TTP and CAPS in the early stages of the disease is the degree of renal involvement; many patients with CM-HUS present with acute and rapidly evolving kidney injury. Neurologic and cardiac involvement is less commonly seen in CM-HUS.28

There is currently no single diagnostic test for CM-HUS. The diagnosis is suspected based on the clinical and laboratory presentation, and the exclusion of pregnancy-specific TMAs, TTP and CAPS on clinical and laboratory grounds. Importantly, in CM-HUS, ADAMTS13 activity is typically greater than 20%. Testing for regulatory components of the alternative complement pathway (C3, C4, factor H, factor H autoantibody, factor I, factor B, and MCP/CD46 expression by flow cytometry) is recommended, yet testing is not available at most institutions. In addition, although abnormal quantitative levels of the complement regulatory proteins may support the diagnosis, they are neither sensitive nor specific for CM-HUS.32 Hence, CM-HUS remains a clinical diagnosis.

At the time of clinical diagnosis, especially if treatment of CM-HUS is initiated, a genetic susceptibility panel that detects the most common genetic causes of CM-HUS should also be performed. Identification of pathogenic variants confirms the diagnosis, although no identifiable variant is found in about one third of confirmed CM-HUS cases.32 Despite this and the long turnaround time, genetic testing remains useful because it not only informs the disease process but also may provide prognostic information regarding risk of progression, risk of relapse, and risk of recurrence in subsequent pregnancies.32


Pathophysiology and Epidemiology

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombotic or obstetric clinical features and the persistence of circulating antiphospholipid antibodies.44 One of the obstetric clinical criteria of APS includes premature birth of a morphologically normal neonate before the 34th week of gestation due to eclampsia and severe preeclampsia.44 CAPS represents a subgroup of APS, defined by multiple organ thromboses, often in the microvasculature, and with multi-organ compromise.45 Experts consider antiphospholipid antibodies to be central to the pathogenesis of APS, with numerous cellular and subcellular mechanisms proposed.46,47 One possible unifying antiphospholipid-mediated mechanism for APS morbidity and CAPS is complement-mediated inflammation.47–49 Complement activation was observed in the sera of more than 80% of individuals with CAPS in one study.50 The same group of investigators documented germline variants in complement genes in 6 of 10 patients with CAPS, a proportion similar to that of patients with CM-HUS.50 Another group has shown that the levels of the complement cleavage product C5a and soluble C5b-9 (terminal complement complex) in seven patients during the remission phase of CAPS were significantly higher than those in the thrombotic patients with APS and in healthy controls.51 Similar to CM-HUS, experts hypothesize that CAPS is triggered by secondary hits, including infections, surgery, malignancy, and withdrawal of anticoagulant medications.52

The estimated annual incidence of APS is 1–2 per 100,000 persons and the estimated prevalence is 40–50 cases per 100,000 persons.53 CAPS is less frequent—among APS cases, the Euro-Phospholipid Project Group reported an incidence of 1% in 10 years.54 The contribution of antiphospholipid antibodies resulting in CAPS to the overall problem of TMAs in pregnancy is unknown.

Clinical Presentation and Diagnosis

CAPS presents with evidence of thromboses, often in small vessels, in multiple organs over a period of hours or days. It is a life-threatening condition, with a mortality rate approaching 50%.54 The diagnosis requires laboratory confirmation of antiphospholipid antibody results meeting international criteria.44 The three clinical criteria for the diagnosis of “definite” CAPS are shown in Box 3.55 When only two of the three clinical criteria for definite CAPS are met, the patient is classified as having “probable” CAPS. Features typical of TMA, including thrombocytopenia and microangiopathic hemolytic anemia, commonly accompany CAPS. Among cases of CAPS in pregnancy, a wide variety of organs, including the heart, kidneys, skin, spleen, brain, adrenals, lungs, pancreas, and eyes, have been compromised.56 CAPS should be considered in the differential in individuals who are pregnant with severe organ involvement or multi-organ involvement. The presence of antiphospholipid antibodies establishes the diagnosis.

Box 3.

Classification Criteria for Catastrophic Antiphospholipid Syndrome

  • 1. Evidence of involvement of 3 or more organs, systems, tissues, or a combination
  • 2. Development of manifestations simultaneously or in less than 1 wk
  • 3. Confirmation by histopathology of small-vessel occlusion in at least 1 organ or tissue*
  • 4. Laboratory confirmation of the presence of aPL antibodies according to international criteria44
  • Definite CAPS
    • • All 4 criteria
  • Probable CAPS
    • • All 4 criteria, except only 2 organs, systems, tissues, or a combination involved, or
    • • All 4 criteria, except for the absence of laboratory confirmation of antiphospholipid antibodies by repeat testing, or
    • • Criteria 1, 2, and 4, or
    • • Criteria 1, 3, and 4, with the development of a 3rd event more than 1 wk but within 1 mo of presentation, despite anticoagulation

aPL, antiphospholipid; CAPS, catastrophic antiphospholipid syndrome.

*For histopathologic confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally.

Modified from Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. doi: 10.1191/0961203303lu394oa


Thrombotic thrombocytopenic purpura and CM- HUS have distinctly different pathophysiologies. Whether CAPS, like CM-HUS, is primarily a complementopathy appears likely, but has yet to be firmly established. Differentiating the diagnosis of TTP, CM-HUS, and CAPS from pregnancy-specific TMAs remains challenging given the significant overlap in their clinical presentation and common laboratory parameters. The typical features of TMAs occurring in pregnancy and postpartum are listed in Table 1. However, the clinician is reminded that no feature on its own is suffice to definitively confirm or exclude the diagnosis due to the possibility of atypical presentations of these TMAs. Clinical judgment with subspecialist input is imperative in making the final diagnosis.

Table 1.:
Overlapping and Distinguishing Clinical and Laboratory Features of Thrombotic Microangiopathies Occurring in Pregnancy and Postpartum

Preeclampsia and HELLP syndrome are a recognized clinical feature associated with antiphospholipid-related disease, including CAPS.44 Both preeclampsia and HELLP syndrome have also been reported to occur concurrently or as a result of TTP or CM-HUS, thus adding to the complexity in diagnosis and management.57–60 Indeed, hypertension, proteinuria, and renal impairment commonly occur in congenital TTP and CM-HUS presenting during pregnancy, which may result in misdiagnosis or delayed diagnosis.61,62 In a small cohort of seven pregnant patients with CM-HUS, three were considered to have preeclampsia or HELLP syndrome before the definitive diagnosis of CM-HUS was made.61

Infrequently, acute fatty liver of pregnancy may be confused with TTP or CM-HUS in that all three may present with elevated hepatocellular enzymes. However, progressively worsening liver dysfunction characteristic of acute fatty liver of pregnancy and leading to elevated serum ammonia levels, coagulopathy, and encephalopathy virtually excludes the diagnosis of TTP or CM-HUS.5,57,62

The degree of thrombocytopenia can be helpful in narrowing the differential diagnosis. Severe thrombocytopenia (platelet count less than 50×109/L), even in the presence of preeclampsia or HELLP syndrome, should raise the suspicion of TTP or CM-HUS. However, the absence of severe thrombocytopenia does not rule out TTP or CM-HUS. Similarly, severe renal impairment (eg, serum creatinine level 1.9 mg/dL or greater) is more suggestive of CM-HUS, may occur in CAPS, and is less likely in preeclampsia, HELLP syndrome, or TTP.63

The timing of presentation in pregnancy or postpartum may help differentiate the diagnosis of TTP, CM-HUS, or CAPS from the pregnancy-specific TMAs, with the latter being far less likely in the first trimester or before 20 weeks of gestation. After 20 weeks of gestation, the timing is less helpful in differentiating the diagnosis. Additionally, TMA presenting during the postpartum period is more suggestive of CM-HUS compared with TTP,41 and CAPS has been reported to occur postpartum.56

Given the diagnostic challenges, the International Working Group on Pregnancy-Related Thrombotic Microangiopathies proposed a step-by-step approach to rule in or out all possible causes of pregnancy-associated TMAs.64 Besides the common laboratory evaluation of a complete blood count, comprehensive metabolic panel and hemolysis markers (LDH, haptoglobin, reticulocytes), the list of additional tests suggested in the initial workup by the working group and the possible diagnoses are shown in Table 2.64 The majority of the suggested additional tests are readily available at most institutions with rapid turnaround time to aid clinical decision-making. The exceptions are testing for ADAMTS13 activity, soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor (PlGF) and quantitative levels of the regulatory components of the alternative complement pathway and genetic sequencing.

Table 2.:
List of Suggested Additional Tests for the Initial Workup in Pregnant or Postpartum Women Presenting With Thrombotic Microangiopathy, and Possible Diagnoses

As discussed above, ADAMTS13 testing is crucial to help distinguish the diagnosis of TTP from other TMAs. In the United States, because many hospitals do not perform the ADAMTS13 assay in-house, testing can be sent out to large reference laboratories, which have a turnaround time of 1–3 days. While awaiting the results, the PLASMIC or French scores, despite not being validated in pregnancy, may be helpful (Boxes 1 and 2). Consultation with a hematologist is recommended in this situation to determine whether treatment for TTP should be initiated empirically.

When the result of ADAMTS13 activity is available, severe ADAMTS13 deficiency (less than 10%) confirms the diagnosis of TTP in patients with high clinical suspicion or an intermediate-to-high–risk score.14 In those with low clinical suspicion or a low-risk score, severe ADAMTS13 deficiency strongly suggests the diagnosis but other clinical diagnoses should also be considered. An ADAMTS13 activity of greater than 20% often rules out the diagnoses of TTP. If the ADAMTS13 activity is between 10 and 20% (an equivocal result), clinical judgment with hematologist input is required to guide diagnosis and treatment.

Immunoassay biomarker testing for sFLT1 and PlGF are recommended by the working group to rule in or rule out preeclampsia or HELLP syndrome based on the sFLT1/PlGF ratio as a prediction tool when measured at the time of pregnancy-associated TMA.64 PlGF is decreased in preeclampsia,65,66 whereas sFLT1, which causes vasoconstriction and endothelial dysfunction, is increased in preeclampsia.67,68 When measured between 24 0/7 and 36 6/7 weeks of gestation, an sFLT1/PlGF ratio of 38 or lower had a negative predictive value of 99.3% (95% CI 97.9–99.9), whereas a ratio above 38 had a positive predictive value of 36.7% (95% CI 28.4–45.7) for a diagnosis of preeclampsia within 4 weeks.69 The use of the sFLT1/PlGF ratio in clinical practice has been shown to be cost effective70,71 and is recommended by the National Institute for Health and Care Excellence to help rule out preeclampsia in individuals presenting with suspected preeclampsia.72 However, whether testing remains cost effective when used as part of the evaluation for pregnancy-associated TMAs is unknown. Additionally, besides the lack of availability of testing in the United States, ACOG currently does not recommend the use of these immunoassay biomarkers as a screening tool to diagnosis preeclampsia.3

If all other possible diagnoses listed in Table 2 have been ruled out with reasonable clinical probability, CM-HUS is the most likely clinical diagnosis by exclusion. Results of regulatory components of the alternative complement pathway and CM-HUS genetic susceptibility panel have slow turnaround times and are not helpful in differentiating or confirming the diagnosis.32 Consultation with both nephrologist and hematologist is strongly encouraged, and treatment should be initiated accordingly. Although there is no reliable diagnostic test for CM-HUS, a recent study found that serum creatinine level 1.9 mg/dL or greater, LDH 1,832 units/L or greater, or serum creatinine level 1.9 mg/dL or greater in combination with LDH 600 units/L or greater may be used to effectively differentiate CM-HUS from HELLP syndrome in the postpartum period.63

In almost all cases of pregnancy-specific TMAs (preeclampsia with severe features, HELLP syndrome, and acute fatty liver of pregnancy), the definitive management is delivery as soon as feasible. However, the diagnosis of TTP, CM-HUS, and CAPS should be reconsidered in these patients who do not show clinical and laboratory improvement within 48–72 hours of delivery or in patients whose clinical situation decompensates after delivery.


If there is a high clinical suspicion for TTP based on clinical judgment or risk-assessment models (eg, PLASMIC intermediate- to high-risk score or at least one criterion met using the French score), daily therapeutic plasma exchange (TPE) should be initiated preemptively while awaiting confirmation of severe ADAMTS13 deficiency (Fig. 3). The most common replacement fluid used for TPE is fresh frozen plasma at 1.0–1.5 times the patient's plasma volume (ie, 40–60 mL/kg), but cryo-poor plasma (cryosupernatant) or solvent detergent-treated plasma are also acceptable options.73 If TPE is not available, transfer to a specialist center with TPE capabilities and specialist input is recommended. Although TPE is now the standard of care after the 1991 landmark trial demonstrating the superiority of TPE over plasma infusion for mortality and disease remission,74 plasma infusion should be considered while awaiting transfer to a specialist center. Expert consensus recommends that additional workup including troponin I and electrocardiogram should be performed to identify subclinical cardiac involvement.73 If there are signs of neurologic abnormalities, computed tomography or magnetic resonance imaging of the brain should also be considered.73

Fig. 3.:
Algorithm for the management of immune-mediated thrombotic thrombocytopenic purpura (iTTP) and congenital TTP (cTTP) during pregnancy. *Transfer to specialist center if therapeutic plasma exchange (TPE) not available locally. Consider platelet transfusion if there is severe bleeding or before invasive procedure with a high risk of bleeding. Defined as sustained platelet count 150×109/L or greater and lactate dehydrogenase less than 1.5 times the upper limit of normal and no clinical evidence of new or progressive ischemic organ injury. §Consider resuming TPE if there is concern for fluid overload. ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13; LDA, low-dose aspirin; LMWH, low-molecular-weight heparin.

Once the diagnosis is confirmed, expectant management with close obstetric monitoring and serial ultrasonography to evaluate fetal growth is generally acceptable. Emergent delivery is recommended only if there is a lack of response to TTP treatment or if there is clinical deterioration or fetal distress.64,75 If the pregnancy is at early-term (37 0/7 through 38 6/7 weeks of gestation),76 planned delivery should be considered.75

Although severe thrombocytopenia (platelet count less than 50×109/L) may be present, prophylactic platelet transfusion is generally not recommended due to the increased risk of arterial thrombosis and mortality.73,77,78 Platelet transfusions may be considered if there is severe bleeding or before invasive procedures with a high risk of bleeding.73

For pregnant individuals presenting with their first episode of TTP with no family history of congenital TTP, distinguishing between congenital TTP and immune-mediated TTP may not be possible initially. Hence, immunosuppressive therapy with steroids (oral prednisone 1 mg/kg daily or methylprednisolone 125 mg intravenously two to four times daily) is initiated at the same time as TPE.79 The presence of anti-ADAMTS13 IgG autoantibodies confirms the diagnosis of immune-mediated TTP but its absence does not rule it out. In the latter situation, DNA sequencing of the ADAMTS13 gene is required to make the diagnosis of congenital TTP.

Management of Immune-Mediated Thrombotic Thrombocytopenic Purpura

For the management of immune-mediated TTP, daily TPE and corticosteroids will likely be required for the remainder of pregnancy until delivery and into the postpartum period. Once a clinical response is achieved (sustained platelet count 150×109/L or greater, LDH less than 1.5 times upper limit of normal and no clinical evidence of new or progressive ischemic organ injury),13 the frequency of daily TPE may be reduced depending on the ADAMTS13 activity (Fig. 3). In the event that clinical remission is achieved during pregnancy, which is defined as a clinical response with no TPE for 30 days or more or with partial (20% or greater) or complete normalization of ADAMTS13 activity,13 TPE may be discontinued, with corticosteroids being continued to suppress further autoantibody production. Serial monitoring of ADAMTS13 activity at least monthly is performed to monitor for relapse (ADAMTS13 level decreases to less than 20%),13 at which time, TPE with or without additional immunosuppressive therapy is resumed.

In the general immune-mediated TTP population, the additional use of rituximab (an anti-CD20 monoclonal antibody, off label-indication) is recommended for refractory TTP79 (defined as persistent thrombocytopenia, lack of a sustained platelet count increment or platelet counts of less than 50×109/L and a persistently raised LDH level [greater than 1.5 times the upper limit of normal] despite five TPE and corticosteroids)80 and to reduce the risk of future relapse. Rituximab use during pregnancy is limited to case reports in the management of immune-mediated TTP and other autoimmune rheumatologic conditions such as systemic lupus erythematosus; none reported maternal or neonatal toxicity.81,82 However, the rituximab global drug safety database identified a few congenital malformations in individuals who were exposed to rituximab during pregnancy.83 As such, the use of rituximab during pregnancy as an adjunct in the management of immune-mediated TTP should be reserved for when the disease is refractory to TPE and steroids, with input from both a hematologist and a maternal-fetal medicine specialist. Although other immunosuppressive agents such as azathioprine and cyclosporine have been considered in the general immune-mediated TTP population with refractory disease,73 there are scarce anecdotal data on its use in pregnancy for the management of immune-mediated TTP.84 Reassuringly, these agents have been used for the management of autoimmune rheumatologic conditions in pregnancy.85 Generally, in refractory disease unresponsive to standard treatments with maternal or fetal compromise, delivery should be considered, which would then allow the use of immunosuppressive therapy such as rituximab as well as caplacizumab.

Caplacizumab is a humanized bivalent variable-domain–only Ig fragment (nanobody) that targets the A1 domain of von Willebrand factor, thus inhibiting the binding of von Willebrand factor multimers and platelets.86 The pivotal phase III clinical trial that led to its approval found that the addition of caplacizumab to standard of care was associated with faster normalization of platelet count and a lower incidence of a composite of immune-mediated TTP-related death, recurrence of disease, or thromboembolic event as compared with standard of care alone.87 Despite real world evidence showing favorable outcomes,88,89 it is important to note that caplacizumab does not eradicate anti-ADAMTS13 IgG autoantibodies or increase ADAMTS13 activity. It is not approved for use in congenital TTP or in pregnancy.

The first reported use of caplacizumab in pregnancy was published in 2022 in a 36-year-old pregnant woman with a history of immune-mediated TTP and persistently detectable anti-ADAMTS13 IgG autoantibodies.84 At 17 weeks of gestation, she developed microangiopathic hemolytic anemia and thrombocytopenia. Therapeutic plasma exchange, corticosteroids, and azathioprine were initiated. Despite an initial clinical response, she had refractory disease. Cyclosporine, rituximab, and caplacizumab were initiated 10 days after initial presentation, with normalization of platelet count within 3 days. Despite laboratory improvement, there was fetal compromise with severe early-onset intrauterine growth restriction (IUGR), oligohydramnios, and placental hydrops, resulting in termination of pregnancy at 21 weeks of gestation. Using liquid chromatography high resolution mass spectrometry, the authors also documented the transplacental transfer of caplacizumab, with its presence in amniotic fluid and fetal blood above the assay's limit of detection.84 Although the authors of the study advocate for administration of caplacizumab in pregnant patients with immune-mediated TTP early in the disease process due to the risk of adverse maternal and fetal outcomes, we would caution such an approach until more data are available.

Management of Congenital Thrombotic Thrombocytopenic Purpura

If the results of the ADAMTS13 gene sequencing are available during pregnancy and the diagnosis of congenital TTP is confirmed, daily TPE and corticosteroids can be discontinued (Fig. 3). Instead, fresh frozen plasma infusions (10–15 mL/kg) every 1–2 weeks is initiated to restore ADAMTS13 activity and to achieve a clinical response. Regular maintenance plasma infusions (ranging from every 2 weeks to twice weekly) are then continued to sustain a clinical response until delivery and through the postpartum period. Other ADAMTS13-rich plasma products may also be used including cryosupernatant and intermediate purity plasma-derived factor VIII concentrate (BPL 8Y; available in the United Kingdom); the latter allows for self-administration by patients and has a reduced risk of fluid overload.90,91

In some patients, the frequency and volume of plasma infusions may result in adverse transfusion reactions including transfusion-associated circulatory overload, transfusion-related acute lung injury, and allergic or anaphylactic reactions.92 The risk of fluid overload can be mitigated by resuming TPE at the same schedule as plasma infusions. For the other two reactions that result in intolerance to fresh frozen plasma, the use of plasma-derived factor VIII concentrates with high ADAMTS13 content may be considered instead (eg, BPL 8Y, Koate-DVI, Alphanate).93 In the near future, the availability of recombinant human ADAMTS13 (TAK-755) may eliminate the risk of adverse plasma transfusion reactions. Recombinant ADAMTS13 was found to have comparable pharmacokinetic profile to plasma infusions and importantly, was nonimmunogenic.94 Phase 3 clinical studies on the safety and efficacy of recombinant ADAMTS13 in patients with congenital TTP are ongoing (NCT03393975 and NCT04683003) with expected completion in 2026.

Supportive Care

In the general TTP population, international guidelines95,96 and expert opinions97 suggest starting low-dose aspirin when the platelet count has recovered to more than 50×109/L. The use of antiplatelet agents in the first 15 days of acute TTP was associated with a nonsignificant decreased mortality rate as compared with placebo (13.5% vs 2.8%).98 Pharmacologic deep vein thrombosis prophylaxis with low-molecular-weight heparin (LMWH) is also recommended when the platelet count is greater than 50×109/L due to the increased risk of venous thromboembolism (VTE) from acute illness and immobility.99 Based on data from the general TTP population, similar recommendations for low-dose aspirin and prophylactic LMWH have been suggested in the management of pregnant individuals with TTP to reduce the risk of placental microthrombi and VTE.75,100,101


Having a history of TTP is not a contraindication for future pregnancies. Although pregnancy is a known trigger for both immune-mediated TTP and congenital TTP, the risk of relapse is difficult to predict. Prepregnancy counseling from a maternal-fetal medicine specialist and hematology consultation with expertise in this rare disorder are critical. It is important to stress that even with proper treatment, there is a risk of maternal TTP recurrence during pregnancy and of obstetric complications including miscarriage, stillbirth, preeclampsia, and IUGR.102 Close obstetric monitoring throughout pregnancy with serial ultrasonographic assessment is required.

History of Immune-Mediated Thrombotic Thrombocytopenic Purpura

For individuals with a history of immune-mediated TTP, the risk of relapse is dependent on the ADAMTS13 activity at the onset of pregnancy; there is likely an increased risk of relapse if there is persistently low ADAMTS13 activity. Due to this increased risk, ADAMTS13 activity should be monitored before pregnancy, and if low (ADAMTS13 activity less than 20%), prophylactic administration of rituximab may be offered to eradicate anti-ADAMTS13 IgG autoantibodies and normalize plasma ADAMTS13 activity (Fig. 4). Expert consensus recommends waiting for 6–12 months after rituximab administration before attempting to become pregnant due to concerns for fetal malformations.73,83

Fig. 4.:
Algorithm for the management of women with a history of immune-mediated thrombotic thrombocytopenic purpura (iTTP) during pregnancy. *More frequent if ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) levels greater than 20% but not normal. Frequency of TPE varies depending on ADAMTS13 activity. CBC, complete blood count; TPE, therapeutic plasma exchange.

If the ADAMTS13 activity is normal in prepregnancy or at pregnancy onset, complete blood counts should be monitored during pregnancy at least monthly or if there are signs or symptoms of thrombocytopenia (eg, gum bleeding, epistaxis, petechial rash, easy bruising). ADAMTS13 activity levels are monitored every 2–3 months or more frequently if there is a drop in ADAMTS13 activity.

If the ADAMTS13 activity decreases to less than 20% during pregnancy with no evidence of TTP (no thrombocytopenia or microangiopathic hemolytic anemia), immunosuppressive therapy with low-dose corticosteroids (oral prednisone 0.5 mg/kg daily) is started to suppress anti-ADAMTS13 IgG autoantibody production. If the ADAMTS13 activity decreases further (less than 10%) despite low-dose corticosteroids, prophylactic TPE is initiated. The frequency of prophylactic TPE can range from twice weekly to every 2 weeks based on the ADAMTS13 activity with the goal of preventing a clinical relapse. If a clinical relapse occurs, the standard management of immune-mediated TTP in pregnancy is initiated (see Management of Thrombotic Thrombocytopenic Purpura in Pregnancy and Postpartum and Management of Immune-Mediated Thrombotic Thrombocytopenic Purpura).

History of Congenital Thrombotic Thrombocytopenic Purpura

For individuals with a history of congenital TTP who are currently not on prophylactic plasma infusions, this should be initiated once pregnancy is confirmed and continued until at least 4–6 weeks postpartum (Fig. 5). The risk of relapse during pregnancy is almost 100% without prophylactic treatment.75 Data from the United Kingdom Thrombotic Thrombocytopenic Purpura Registry showed a fetal survival rate of 58% in untreated pregnancies before congenital TTP was diagnosed, as compared with 100% in subsequent pregnancies after the diagnosis that were actively managed with prophylactic plasma infusions.62 Similarly, data from the Japanese congenital TTP registry showed a significantly lower birth rate in untreated pregnancies preceding the diagnosis, as compared with actively managed pregnancies after the diagnosis (50.0% vs 91.7%).102

Fig. 5.:
Algorithm for the management of women with a history of congenital thrombotic thrombocytopenic purpura (cTTP) during pregnancy. *Consider therapeutic plasma exchange if there is concern for fluid overload. CBC, complete blood count; ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13.

Typically, in the first trimester, plasma infusions (10–15 mL/kg) every 2 weeks is recommended.75,103 By the second trimester, the frequency is increased to weekly or even twice weekly depending on laboratory parameters (complete blood count, hemolysis markers) with the goal to maintain a normal platelet count and prevent hemolysis. However, if there are early signs of fetal compromise such as IUGR without apparent changes in laboratory parameters, this may warrant intensifying the infusion schedule.75,102

There is no consensus on the frequency of ADAMTS13 monitoring and the optimal ADAMTS13 activity with prophylactic plasma infusions. We suggest serial ADAMTS13 monitoring at least monthly during pregnancy. In addition to using clinical and laboratory parameters, the dosing schedule of plasma infusions should also be titrated to maintain a trough ADAMTS13 level of greater than 10–20% throughout pregnancy.64,102,104 It has been suggested that this approach may help to minimize the risk of early congenital TTP complications when laboratory changes are not yet apparent.104 If there are concerns for fluid overload due to the frequency and volume of plasma infusions, TPE may be used instead.

Planned delivery is recommended at early-term due to ongoing concerns for maternal and fetal complications.64,75,102,104

Because congenital TTP occurs due to a homozygous recessive or compound heterozygous mutation in the ADAMTS13 gene, the child of the affected mother is unlikely to be affected except in cases of consanguinity.

Supportive Care

There are no guidelines recommending the use of low-dose aspirin in individuals with a history of TTP. However, national guidelines from both ACOG105 and the U.S. Preventive Services Task Force106 on the use of low-dose aspirin to prevent preeclampsia list personal history factors (eg, low birth weight, small for gestational age, previous adverse pregnancy outcomes) as a moderate risk for preeclampsia. Based on previous pregnancy outcomes, low-dose aspirin (initiated after 12 weeks of gestation) could be considered on an individualized basis. This approach is recommended by some expert opinions103 but not by others.73

Pregnant individuals with a history of TTP and a history of VTE are usually offered prophylactic-dose LMWH throughout pregnancy to prevent recurrent VTE.73,107 In pregnant individuals with a history of TTP and no history of VTE, whether to offer prophylactic-dose LMWH is debatable among experts.73,75,103


Historically, the treatment of CM-HUS was TPE.4 However, the use of TPE was not as efficacious as for TTP. In the largest case series of 87 pregnant and postpartum patients with CM-HUS from three national registries—France, the United Kingdom, and Italy—the risk of end-stage kidney disease was similar in those treated with TPE and those who did not (51% vs 47%).41 Instead, eculizumab, a humanized hybrid IgG2/IgG4 kappa monoclonal antibody against the terminal pathway complement component C5, is now the standard of care for the treatment of CM-HUS.108

Typically, if TTP or CM-HUS is suspected during pregnancy or postpartum, TPE is initiated while awaiting ADAMTS13 activity levels. Once TTP is ruled out (ADAMTS13 activity greater than 20%), leaving CM-HUS the most likely clinical diagnosis by exclusion, eculizumab should be initiated immediately (Fig. 6). The dosing regimen for adults 18 years of age or older is 900 mg weekly for the first 4 weeks, followed by 1,200 mg for the fifth dose 1 week later, and then 1,200 mg every 2 weeks thereafter (Eculizumab package insert, Alexion Pharmaceuticals, 2019).

Fig. 6.:
Algorithm for the management of complement-mediated hemolytic uremic syndrome (CM-HUS) in women with a history of CM-HUS during pregnancy. *Vaccinate against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b. Consider continuing antibacterial drug prophylaxis for the duration while on eculizumab. Adjust dose based on degree of terminal complement blockage or serum eculizumab levels. §If on maintenance ravulizumab, switch to eculizumab for the duration of the pregnancy.

Although pregnant patients were excluded from prospective clinical trials, data from real-world patient studies have demonstrated its efficacy (improved renal outcomes and hematologic remission) and safety in pregnant patients with CM-HUS.64,109 Also, the use of eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria provides additional reassurance on its safety.110,111 Although eculizumab can be detected in cord blood, the effect of complement blockade on the fetus is unknown.110,112,113 A pooled analysis of more than 300 pregnant individuals with live births after exposure to eculizumab have not identified any concerns for adverse fetal developmental outcomes (Eculizumab package insert, Alexion Pharmaceuticals, 2019). As for breastfeeding, limited published data showed undetectable levels of eculizumab in breast milk.110

As pregnancy progresses with increased volume of distribution, the dose or frequency of eculizumab often needs to be increased.59,110 Monitoring the degree of terminal complement blockade is recommended during pregnancy using routine complement assays (ie, total complement activity, CH50; alternative pathway activity, AH50; C5 antigen and functional).114 An alternative is measuring serum eculizumab levels as a trough level of 50 micrograms/mL completely inhibits complement-mediated hemolysis in CM-HUS.108

Although eculizumab is efficacious in achieving hematologic and renal remission during pregnancy, data on pregnancy complications and fetal outcomes are difficult to ascertain and seem less favorable.64,109 In the Global aHUS Registry of 51 individuals with CM-HUS (28 during pregnancy; 23 postpartum), 54.9% had preeclampsia and 33.3% had HELLP syndrome, with no differences between those treated with eculizumab (n=27) and those not treated with eculizumab (n=24).109 This highlights the fact that preeclampsia or HELLP syndrome may occur as complications from CM-HUS even with appropriate treatment, and warrants close monitoring. Additionally, a systematic review of 12 published individual cases of pregnancy-associated CM-HUS treated with eculizumab reported the following outcomes: four healthy neonates delivered at early-term or full-term; three preterm births at 22, 31, and 32 weeks of gestation; three in utero fetal deaths, and two not documented.64 The three fetal deaths occurred at the time of CM-HUS diagnosis.64 Hence, even with appropriate treatment with eculizumab, close obstetric monitoring throughout pregnancy with serial ultrasonographic assessment is required. Emergent delivery is recommended if there are complications from CM-HUS (ie, preeclampsia or HELLP syndrome) or fetal distress.

Typically, eculizumab, if initiated antepartum, is continued throughout pregnancy and for at least 3 months postpartum due to the risk of relapse postpartum. Traditionally, indefinite therapy was recommended in the management of CM-HUS but this approach has been debated due to the high cost of treatment and the increased risk of meningococcal infections (see Supportive Care). Two recent studies and a systematic review of the literature demonstrated eculizumab discontinuation may be safe in those who achieved hematologic remission with stable kidney function for at least 3–6 months, based on using a monitoring protocol and absence of specific complement gene variants.115–117

In 2019, ravulizumab, a long-acting version of eculizumab, was approved for CM-HUS, which extended the maintenance dosing to every 8 weeks.118 In the pivotal trial that led to its approval, eight patients developed CM-HUS postpartum. All eight patients achieved hematologic remission.119 Five patients who were on dialysis at diagnosis discontinued dialysis within 21 days after treatment with ravulizumab.119 Although ravulizumab is effective with a favorable safety profile in patients presenting with CM-HUS postpartum, there are no data on its use during pregnancy, its effect on pregnancy outcomes and its presence in breast milk. At this time, we would advise against initiating ravulizumab during pregnancy until more data are available.

Supportive Care

Due to its mechanism of action as a complement C5 inhibitor in blocking terminal complement activation, both eculizumab and ravulizumab use increase the risk of meningococcal disease approximately 2,000-fold as compared with the general U.S. population.120 The risk of infection from Streptococcus pneumoniae and Haemophilus influenzae type b are also increased.120 All patients should receive vaccinations against Neisseria meningitidis, S pneumoniae, and H influenzae type b at least 2 weeks before the first dose of a complement C5 inhibitor in accordance with the Advisory Committee on Immunization Practices recommendations. However, due to the urgency of treatment in CM-HUS, vaccinations are typically administered immediately before complement C5 inhibitor administration, and 2 weeks of antibacterial drug prophylaxis with penicillin is initiated. Despite vaccinations, patients on complement C5 inhibitors remain at high-risk for meningococcal disease.120 As such, some have advocated for antimicrobial prophylaxis for the duration of complement C5 inhibitors treatment; the effectiveness of this approach has not been established.120 Complement C5 inhibitors should be discontinued if there are early signs of meningococcal infections as well as any systemic infection.


Having a history of CM-HUS is not a contraindication for future pregnancies. Prepregnancy counselling is critical to raise awareness on the unpredictable risk of relapse, as well as the high risk of obstetric and fetal complications if a relapse were to occur (Fig. 6). Using data from national cohort studies, the risk of relapse in subsequent pregnancies is estimated to be around 25%.61,121 On the other hand, a systematic review of published case reports of patients with known CM-HUS entering pregnancy reported a recurrence of 67% (8/12 pregnancies), albeit there is likely publication bias.122 Currently, there are no established factors that can predict the risk of relapse in a given pregnancy. Neither a prior uncomplicated pregnancy nor the absence of complement gene variants reduces the risk of relapse in subsequent pregnancies.41,61,121 Additionally, the presence of residual chronic kidney disease or a history of kidney transplant significantly increases the risk of adverse maternal and fetal outcomes during pregnancy.123

Expert consensus suggests an interval of at least 1 year from CM-HUS remission with stabilized kidney function before attempting to become pregnant.64 If pregnancy occurs while on maintenance eculizumab (particularly kidney transplant patients), this is generally continued throughout pregnancy and postpartum with dose or frequency escalation as needed. If pregnancy occurs while on maintenance ravulizumab, we recommend switching to eculizumab for the duration of the pregnancy. For patients who are no longer on treatment, prophylactic use of eculizumab during pregnancy is not currently recommended but could be considered on an individual basis.64,103

For all individuals with a history of CM-HUS, clinical and laboratory monitoring should occur at the start of pregnancy and continue for up to 3 months postpartum.64 The International Working Group on Pregnancy-Related Thrombotic Microangiopathies recommends monthly multidisciplinary clinic visits (obstetricians, hematologists, nephrologists) with close monitoring of blood pressure, proteinuria, hematologic parameters, renal function, hemolysis markers, and serial ultrasonographic assessments.64 For patients who are not on treatment, eculizumab should be initiated promptly at the first possible sign of CM-HUS relapse to optimize hematologic and renal recovery and maternal and fetal outcomes.

Supportive Care

For individuals whose index CM-HUS event occurred many years ago or who have unclear vaccination history, it may be advisable to revaccinate or receive boosters against N meningitidis, S pneumoniae, and H influenzae type b in the event of a relapse requiring eculizumab initiation.

There are no guidelines recommending the use of low-dose aspirin in individuals with a history of CM-HUS. Based on previous pregnancy outcomes, low-dose aspirin (initiated after 12 weeks of gestation) could be considered on an individualized basis.105,106


Recent American and European guidelines provide up-to-date information regarding the management of APS in pregnancy.124,125 The management of CAPS is based on expert opinion derived from case series.52,126 The life-threatening nature of the condition demands thoughtful consideration and early recognition of the condition, as is early involvement of relevant specialty consultants. A suggested algorithm for the management of CAPS is shown in Figure 7. High-quality treatment trials are lacking, but international guidelines suggest an initial approach using a combination of glucocorticoids, anticoagulation with a heparin agent, and plasma exchange or intravenous Ig125,127 Immediate treatment aims at controlling thrombosis. A recent meta-analysis suggested a lower mortality rate in those receiving this combination therapy.127 Case reports support the use of eculizumab128–130 and rituximab127 in selected cases of CAPS.

Fig. 7.:
Algorithm for the management of catastrophic antiphospholipid syndrome (CAPS) during pregnancy. *Expert opinion suggests eculizumab in cases with prominent thrombotic microangiopathic features and rituximab in cases with worsening thrombocytopenia without documented thrombosis as the most prominent clinical concern. Consultation with appropriate specialists is required.52 SLE, systemic lupus erythematosus.


Whether or not subsequent pregnancy triggers recurrent CAPS is unknown. The authors are aware of several patients with a history of CAPS who subsequently had successful pregnancies, and there is at least one favorable case report.131 Prepregnancy counselling is critical for informing the patient of the risks of adverse pregnancy outcome associated with APS, particularly among individuals who are persistently positive for lupus anticoagulant.

Supportive Care

Patients with a history of CAPS who choose to become pregnant should be managed according to guidelines.124,125


Thrombotic thrombocytopenic purpura, CM-HUS, and CAPS are rare TMAs that can occur in pregnancy. Differentiating these from pregnancy-specific TMAs is diagnostically challenging due to clinical overlap in their presentation. A prompt diagnosis is critical because there are specific treatments for these rare TMAs to optimize maternal and fetal outcomes. Even though pregnancy is a trigger for TTP and CM-HUS, and may be a trigger for CAPS, subsequent pregnancy is not absolutely contraindicated. Appropriate prepregnancy counseling with shared decision-making is a must. The care team should include appropriate specialists. Favorable maternal and fetal outcomes can be achieved with close monitoring during pregnancy and postpartum, with reintroduction of treatment, if indicated.132


Learning Objectives for “Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum”

After completing this continuing education activity, you will be able to:

  • Discuss the differences and similarities between preeclampsia and rare thrombotic microangiopathies of pregnancy;
  • Outline strategies for early recognition and treatment of these infrequently encountered conditions; and
  • Implement practical clinical approaches to diagnose and manage these rare thrombotic microangiopathies.

Instructions for Obtaining AMA PRA Category 1 Credits

Continuing Medical Education credit is provided through joint providership with The American College of Obstetricians and Gynecologists.

Obstetrics & Gynecology includes CME-certified content that is designed to meet the educational needs of its readers. This article is certified for 2AMA PRA Category 1 Credits.™ This activity is available for credit through January 31, 2026.

Accreditation Statement

ACCME Accreditation

The American College of Obstetricians and Gynecologists is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

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The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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The American College of Obstetricians and Gynecologists designates this journal-based CME activity for a maximum of 2 Category 1 College Cognate Credits. The College has a reciprocity agreement with the AMA that allows AMA PRA Category 1 Credits™ to be equivalent to College Cognate Credits.

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In accordance with the College policy, all faculty and planning committee members have signed a conflict of interest statement in which they have disclosed any financial interests or other relationships with industry relative to article topics. Such disclosures allow the participant to evaluate better the objectivity of the information presented in the articles.

How to Earn CME Credit

To earn CME credit, you must read the article in Obstetrics & Gynecology and complete the quiz, answering at least 70 percent of the questions correctly. For more information on this CME educational offering, visit the Lippincott CMEConnection portal at https://cme.lww.com/browse/sources/196 to register and to complete the CME activity online. ACOG Fellows will receive 50% off by using coupon code, ONG50.

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