Authors: Payal Bharatkumar Patel (1Department of Medicine, Legacy Medical Center, Portland, OR), Nidhi Patel (2Department of Medicine, Providence Medical Center, Portland, OR), Madeline A Hedges (3Department of Pediatrics, Division of Neonatology, Oregon Health & Science University, Portland, OR), Ashley E Benson (4Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Oregon Health & Science University, Portland, OR), Arjun Tomer (5Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR; 6Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR), Jamie O Lo (4Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Oregon Health & Science University, Portland, OR), Joseph J Shatzel (5Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR; 6Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR)
Categories: Article, iron deficiency anemia, thrombocytopenia, venous thromboembolism, pregnancy
Source: European journal of haematology
Doi: 10.1111/ejh.14372
Authors: Payal Bharatkumar Patel, Nidhi Patel, Madeline A Hedges, Ashley E Benson, Arjun Tomer, Jamie O Lo, Joseph J Shatzel
Hematologic complications are common in pregnancy and can significantly impact both maternal and fetal health. Recognizing and treating these complications can be challenging due to the limited evidence available to guide clinical consultants. Iron deficiency anemia is the most prevalent hematologic issue in pregnancy and often occurs due to increased maternal blood volume and the nutritional demands of the growing fetus. Thrombocytopenia is the second most commonly occurring hematologic issue in pregnancy and can be associated with increased blood loss and complications during childbirth. However, the most common type of thrombocytopenia in pregnancy is gestational thrombocytopenia, which does not typically require clinical management. Thus, it is important to distinguish gestational thrombocytopenia from other etiologies of thrombocytopenia in pregnancy that require immediate treatment, including immune thrombocytopenia, thrombotic thrombocytopenic purpura, preeclampsia, and HELLP (Hemolysis, Elevated Liver enzyme levels, and Low Platelet levels) syndrome. Other important hematologic conditions in pregnancy include noninherited anemias, such as autoimmune hemolytic anemia and aplastic anemia, as well as inherited anemias, such as sickle cell disease and thalassemia, which may require specialized management to optimize maternal and fetal outcomes. Additionally, bleeding disorders, such as von Willebrand disease and hemophilia, pose unique challenges in pregnancy, especially around the time of delivery, due to the risk of excessive bleeding. Lastly, thromboembolic disorders, such as venous thromboembolism (VTE), remain the leading cause of mortality in pregnancy in developed countries. Pregnancy related hormonal changes, venous stasis, and hypercoagulability contribute to an increased thromboembolic risk, further exacerbated by additional risk factors such as obesity or a prior personal or family history of VTE. This review aims to summarize current guidelines and management of the most common hematologic disorders in pregnancy.
The physiological state of pregnancy can result in both direct and indirect changes to hematologic indices. While many of these changes are normal and necessary, pregnancy can predispose women to certain hematologic disorders and exacerbate pre-existing conditions resulting in increased maternal and fetal morbidity and mortality. Conditions such as iron deficiency anemia, thrombocytopenia, and bleeding disorders can increase the risk of preterm birth, fetal growth restriction and postpartum hemorrhage. The estimated prevalence of anemia in pregnancy ranges from 17 to 31% in Europe and North America and up to 44 to 61% in South East Asia and Africa. [1] The most common hematologic complication in pregnancy is iron deficiency anemia, followed by thrombocytopenia, affecting 7 to 12% of all pregnancies. [2]
Although hematologic conditions are common in pregnancy and associated with adverse outcomes, there is limited data on evaluation, management and treatment. This is because pregnant individuals are often excluded from clinical trials, thus the evaluation and treatment of hematologic complications is often extrapolated from nonpregnant populations. The lack of well-designed randomized controlled trials in pregnant individuals limits the availability of evidence-based recommendations. Despite anemia being prevalent in pregnancy, the hematologic indices indicated for transfusion of blood products to prevent maternal and offspring outcomes in pregnancy are undefined. Also contributing to this gap in knowledge is the unknown etiology of gestational thrombocytopenia and the inability to identify pregnancies at risk for maternal mortality and fetal morbidity, such as intrauterine growth restriction in pregnant individuals with inherited anemias such as sickle cell disease.
This review will summarize current guidelines and recommendations for common hematologic complications of pregnancy including iron deficiency anemia, rare inherited and non-inherited anemias, thrombocytopenia, thrombotic microangiopathies, and bleeding disorders. The goal of this review is to clarify existing practices in screening, management, and treatments for each condition and identify areas with limited clinical guidance for future research. (Figure 1)
Complications arise due to physiological changes in the maternal hematologic system aimed at supporting the demands of pregnancy. The World Health Organization (WHO) estimates the global prevalence of anemia in pregnancy is 37%. [3, 4] Plasma volume in pregnancy expands by 10–15% at 6 to 12 weeks of gestation and by 40–50% at 30 to 34 weeks’ gestation before plateauing. Red blood cell production starts to increase at approximately 16 weeks of gestation and reaches a 25% increase by 34 weeks.[5] Physiological anemia of pregnancy occurs due to disproportionate expansion in plasma volume compared to the total increase in red blood cell volume resulting in a dilutional effect. This physiologic process serves to enhance placental perfusion by reducing maternal blood viscosity, ultimately allowing for oxygen and nutrient delivery to the fetus through expansion of erythrocyte mass.[6] Although this dilutional anemia does not typically warrant treatment, there is no consensus on recommended hematologic indices for further screening making it challenging for healthcare providers to determine when to consider additional workup. It is generally considered that a hemoglobin (Hb) concentration <11 g/dL in the late first trimester and <10.5 g/dL in the second and third trimester should prompt further work up to rule out a cause other than physiologic anemia of pregnancy.[7, 8](Figure 2)
The estimated prevalence of iron deficiency during pregnancy in North America is reported to be greater than 50%, with nearly 12% of pregnancies affected by iron deficiency anemia (IDA).[9] It is important to recognize IDA in pregnancy early as it is associated with increased morbidity and mortality for both mother and fetus if left untreated. A recent study showed that severe anemia, defined as Hb <7.0 g/L during pregnancy, is associated with a near two-fold increased risk of maternal death.[10, 11]
Maternal consequences of IDA includes thyroid dysfunction, premature delivery (before 37 weeks’ gestation), placental abruption, preeclampsia, eclampsia, cesarean section delivery, postpartum hemorrhage, need for blood transfusion, hysterectomy, and postpartum depression.[12–17] Maternal iron deficiency has also been associated with an increased risk of adverse offspring outcomes including low birth weight (less than 2,500g), small for gestational age, and infant death.[18] Additionally, emerging evidence suggests that offspring are also at an increased risk for impaired cognitive development in early childhood and neurological disorders such as autism spectrum disorder and attention deficit disorder.[19, 20] Interestingly, although prior systematic reviews suggest that the risk of neurodevelopment in offspring is linked to iron deficiency, maternal iron supplementation does not significantly mitigate this risk.[21, 22] In addition, offspring of iron deficient mothers carry an increased risk for iron deficiency through the first year of life with 14% of infants born with a serum ferritin concentration <30 μg/L at birth.[23]
Screening for maternal iron deficiency is generally performed at least once during the at the initial prenatal visit, the start of the third trimester, and on admission to labor and delivery.[8] This is recommended by the United States Preventive Services Task Force (USPSTF) and has been adopted by both the American College of Obstetricians and Gynecologists (ACOG) and the Centers for Disease Control and Prevention (CDC).[24–26] The USPSTF recommends screening based on symptoms such as pallor, shortness of breath, fatigue, dizziness, and palpitations. In contrast, the British Society for Haematology recommends screening based on maternal risk factors, including active human immunodeficiency virus (HIV) infection, prior history of uterine bleeding, and comorbidities such as diabetes and obesity.[27–29] (Table 1)
Both hemoglobin and ferritin concentrations are used to screen for iron deficiency with or without anemia. Most guidelines follow a hemoglobin threshold based on physiologic changes in pregnancy as mentioned above (Hgb 11 g/dL or 10.5 g/dL).[30] If hemoglobin indices fall below this threshold, a serum ferritin can be ordered. Serum ferritin is 90% sensitive and 95% specific in the diagnosis of iron deficiency in pregnant women.[31] Reduced ferritin levels can suggest iron deficiency frequently before overt anemia develops as it reflects iron reserves stored in the liver. However, because ferritin is an acute phase reactant, it can be falsely elevated in patients with active inflammation or infection and transferrin saturation should be used instead.[32, 33]
At this time, ferritin is not universally used as an additional screening tool. Some guidelines favor the addition of ferritin to a full blood count while others reserve it for screening high-risk populations only; the International Federation of Gynaecology and Obstetrics (FIGO) advises against it.[34–37] This is further complicated by the different ferritin thresholds used, creating inconsistency and confusion among providers. The optimal threshold to identify iron deficiency is challenging, most guidelines use a serum ferritin <30 μg/L to define iron deficiency while others recommend <15 μg/L.[37, 38] Future research is needed to establish the most clinically and cost-effective universal screening approach to detect iron deficiency.
Once diagnosed, IDA should be treated with oral iron in the first trimester. The recommended dose is 30–60 mg elemental iron daily to offset the increased daily demand for enteral iron from 0.8 mg daily to 7.5 mg.[39, 40] A repeat hemoglobin is often measured 2 to 4 weeks after treatment and an adequate response within that timeframe is an increase in hemoglobin by 10 or 20 g/L.[41–43] Once hemoglobin levels normalize, some guidelines suggest continuing oral iron treatment for at least 3 months or through 6 weeks postpartum to ensure adequate iron repletion given the ongoing pregnancy demands.[44] Intravenous (IV) iron should be considered when oral iron is ineffective, gastrointestinal side effects are intolerable, or iron deficiency is diagnosed close to time of delivery. It is more efficient at treating iron deficiency and with fewer side effects. A recent meta-analysis comparing oral versus IV iron found that IV iron reduced maternal complications by 21% compared to oral iron and treated anemia more efficiently, but had no effect on neonatal complications.[45] Despite its benefits compared to oral iron, at this time IV iron is not recommended during the first trimester because of a lack of safety data. [44]
Although the current literature is conflicting, it is important to review the potential concerns regarding routine iron supplementation in pregnant individuals without iron deficiency. It has been suggested that an elevated hemoglobin concentration from iron supplementation increases blood viscosity and results in decreased placental perfusion leading to complications such as low birth weight.[46–48] A recent systematic review and meta-analysis also demonstrated a positive association between iron supplementation and risk of gestational diabetes, however these studies excluded randomized controlled trials (RCTs).[49–51] Interestingly, all of these RCTs have demonstrated no association between pregnancy and gestational diabetes risk. At this time, because these adverse findings are not consistent, routine iron supplementation in pregnancy regardless of iron deficiency status is still recommended.
Thrombocytopenia is defined as having a platelet count less than 150 × 10/L and is the second most common hematologic complication of pregnancy, developing in 5–12% patients.[52, 53] It is categorized by mild (> 100 × 10/L), moderate (50 – 100 × 10/L), and severe (< 50 × 10/L). The etiology for thrombocytopenia is broad and ranges from milder forms, such as gestational thrombocytopenia secondary to physiologic changes of pregnancy that often does not require treatment, to more severe forms like preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome that can be life-threatening and require urgent diagnosis and management.[54] An initial workup for newly discovered thrombocytopenia includes obtaining a complete blood count, reticulocyte count, peripheral blood smear, liver function tests, and screening for Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus (HIV). It is also important to obtain a detailed patient history (e.g., medication use, prior bleeding episodes, and family history) and perform a thorough physical exam (e.g., vitals, skin findings, lymph node examination) to aid in narrowing the differential and guide further workup.[55] (Table 2)
Gestational thrombocytopenia accounts for approximately 75% of all cases of thrombocytopenia in pregnancy.[56] In general, platelet counts are decreased in all pregnant individuals when compared to non-pregnant individuals, with the nadir occurring at the time of delivery.[57] Gestational thrombocytopenia remains a diagnosis of exclusion and typically occurs in the second trimester, defined as a platelet level between 70–100 × 10/L.[56] A further workup is indicated if low platelets are noted prior to the second trimester and if platelet counts are less than 70–100 × 10/L. If platelet counts are between 70–100 × 10/L, patients may not be eligible for neuraxial anesthesia given the increased risk for an epidural hematoma. If platelets remain greater than 70–100 × 10/L with no further complications, then routine blood counts should be checked monthly during the pregnancy through 6 weeks postpartum.[56] Patients with asymptomatic gestational thrombocytopenia will typically return to their baseline platelet counts in approximately 6 to 8 weeks, so a complete blood count should be checked after 6 weeks postpartum.[57]
Immune thrombocytopenia (ITP) comprises approximately 3% of all thrombocytopenia cases during pregnancy and is characterized as autoantibodies developing against platelet antigens leading to platelet destruction and preventing platelet production.[58] It is the most common cause of platelet levels below 50 × 10/L in pregnancy and is a diagnosis of exclusion.[58] Although challenging to distinguish between ITP and gestational thrombocytopenia, gestational thrombocytopenia is commonly associated with platelet counts greater than 100 × 10/L whereas ITP is associated with platelet counts below 70–80 ×10/L.[56] In addition, ITP often presents in the first trimester or early second trimester whereas gestational thrombocytopenia will typically present in the mid-to-late second trimester.[59] The laboratory workup for ITP includes obtaining a complete blood count, peripheral smear, liver function tests, urinalysis, and testing for HIV and Hepatitis C.[59] Testing for Helicobacter pylori infection may also be indicated based on the geographical region.[60]
Management includes frequent monitoring with urinalysis, complete blood count, blood pressure, and weight; this should be performed monthly during the first and second trimester, followed by every two weeks after 28 weeks and weekly after 38 weeks.[61] Although platelet counts between 20 – 30 × 10/L are considered stable, it is recommended that pregnant individuals have a platelet count of greater than 50 × 10/L by the time of delivery or before a major procedure.[62, 63] Oral corticosteroids or intravenous immunoglobulin (IVIG), or both, is considered first-line treatment for maternal ITP. Although both have shown similar efficacy, treatment should be individualized and take into account the occurrence and severity of symptoms (e.g., bleeding), potential adverse effects, and the timeline for desired platelet count increase. Oral prednisone at a dosage of 10 to 20 mg/day for at least 21 days is generally recommended as the initial treatment with titration to the minimum dose that maintains a platelet count that prevents major bleeding.[64, 65] Although dexamethasone can be considered, prednisone is preferred as it does not cross the placenta to the fetus.[66] An initial response following prednisone treatment is expected within 4 to 14 days following prednisone initiation with a peak response within 1 to 4 weeks.[67] Because of the high cost and limited availability, IVIG is usually reserved for cases of ITP refractory to oral corticosteroids, presence of severe adverse effects from corticosteroids, or when a rapid platelet increase is needed (e.g., delivery).[61] IVIG is often administered as a one-time dose of 1 g/kg that can be repeated if necessary with an initial response usually occurring within 1 to 3 days and achieving a peak response within 2 to 7 days.[65] If an adequate increase in platelet count is not achieved using oral corticosteroids or IVIG alone, then the next step would be to combine the two treatments. Second line treatments have variable efficacy. Azathioprine and cyclosporine can be considered, but can have a delayed response time to increasing platelet levels, and Rituximab can cross the placenta and result in fetal exposure.[66] Splenectomy is considered when patients with ITP fail first-line treatments and can be accomplished safely in pregnancy, ideally in the second trimester between 16 to 20 weeks due to increased fetal risks and technical challenges later in gestation.[60] There are newer treatment options emerging for ITP in pregnancy, including the use of thrombopoietin receptor agonists (TPO-RAs). A recent study of 45 reported pregnancies noted that 86.7% had a platelet response with TPO-RA and no significant adverse maternal or newborn outcomes, such as VTE.[68] However, because two of the TPO-RA agents, Romiplostim and Eltrombopag, have been detected in breast milk, it should be used with caution when breastfeeding.[68]
TTP is a rare acquired or congenital disorder that occurs in 1 of 25,000 pregnancies due to a deficiency of ADAMTS13, a metalloprotease enzyme that cleaves secreted von Willebrand factor.[69, 70] Two-thirds of cases of TTP present during the third trimester and a third are diagnosed in the first or second trimester.[71] Patients with TTP may present with symptoms of tissue ischemic injury involving the central nervous, gastrointestinal, and cardiovascular systems, as well as fatigue, pallor, headache, and vomiting.[69] Diagnosis of TTP is made when an ADAMTS13 assay detects less than 10% activity. In addition, acquired TTP is diagnosed if anti-ADAMTS13 autoantibodies are present, but if no autoantibodies are present, congenital TTP should be considered and genetic analysis obtained for further workup.[72]
The diagnosis of TTP is challenging because features of TTP overlap with other thrombotic microangiopathy (TMA) syndromes such as preeclampsia, HELLP syndrome, disseminated intravascular coagulation, and antiphospholipid syndrome. Unlike other TMA syndromes, TTP is not usually associated with peripheral edema or hypertension.[73] In the absence of an available assay, the PLASMIC score, which considers platelet count, hemolysis labs, INR (international normalized ratio), and creatinine, can be utilized to identify TTP from other TMAs. A PLASMIC score of 6 or higher suggests severe ADAMTS13 deficiency.[74]
Although the ADAMST13 assay is the gold standard for diagnosis, a high clinical suspicion should prompt timely management because untreated TTP has a high mortality rate of up to 90%.[73] Pregnancy management entails ultrasound evaluation of fetal and placental status. First line therapy is plasma exchange and corticosteroids. Immunosuppressive therapy is essential for acquired TTP but not for congenital TTP, and plasma therapy must be regularly performed for subsequent pregnancies complicated by congenital ITP.[72] Once management has been initiated, further management will be guided by trending ADAMTS13 levels. For both congenital and acquired TTP, patients can deliver vaginally if their ADAMTS13 levels are greater than 20 to 25%.[73] Following delivery, frequent complete blood counts every other day are recommended for the first 3 to 5 days postpartum, and ADAMTS13 levels should be checked within three weeks postpartum.[73] Patients that are symptomatic or have overt TTP should be managed with plasma exchange for at least two days after remission, defined as normal platelet count, and rising LDH and hemoglobin levels.[75] If a patient is asymptomatic and has ADAMTS13 levels between 10 to 20%, then low dose corticosteroids (0.5 mg/kg/daily of prednisone) should be initiated. If < 10%, then prophylactic plasma exchange every 1 to 2 weeks should be initiated.[73]
Hemolytic uremic syndrome (HUS) is a form of TMA that predominantly involves the renal, cardiovascular and neurological systems. At least 90% of HUS cases are related to production of Shiga toxin-producing bacteria, E. coli bacteria, and Shigella infections.[76] The remainder of cases, including pregnancy-related HUS, are complement-mediated atypical HUS, where an inherited or acquired defect leads to excessive activation of complement.[76] Presentation of pregnancy-related HUS can occur at any time, but commonly occurs within three months postpartum.[77] The symptoms associated with pregnancy-related HUS are similar to HELLP syndrome, including hypertension, proteinuria, and acute kidney injury, but a key distinguishing factor is normal serum liver enzymes. Lab findings include anemia with hemoglobin < 10 g/dL, platelet levels between 50 to 100 × 10/L, and evidence of acute kidney injury.[78, 79] The patient’s workup should include ruling out TTP, testing for Shiga toxin stool pathogen to rule out infection-induced HUS because the management will differ, and genetic testing to determine defects in complement activation. The mainstay treatment for atypical HUS is Eculizumab, a monoclonal anti-C5 antibody, which has demonstrated improved kidney function and glomerular filtration rate within a week of initiating therapy and reduced rates of disease relapse.[80] Plasma exchange and plasma infusions are considered for supportive management of HUS as they do not address the underlying complement dysfunction and are associated with adverse reactions.[79] Renal transplantation is not recommended prior to conception or during pregnancy because of poor outcomes from disease recurrence.[80] Ravalizumab, a long acting C5 inhibitor, is approved for treatment of atypical HUS and has been shown to be effective postpartum, but is not recommended for use in pregnancy because of limited safety data.[81]
Preeclampsia is the most common form of thrombocytopenia under the umbrella of TMA.[82] It is the development of persistently elevated blood pressures in pregnancy after twenty weeks of gestation or within 6 weeks postpartum with at least one other manifestation including thrombocytopenia, impaired liver function or injury, new-onset renal insufficiency, pulmonary edema, and cerebral or visual disturbances. Persistent hypertension is defined as having systolic blood pressures greater than 160 mmHg or diastolic blood pressures above 110 mmHg.[83] Thrombocytopenia is present in half of the patients with preeclampsia, and signs of low platelets and elevated liver enzymes can occur prior to symptoms of headache, proteinuria and elevated blood pressures, leading to delays in diagnosis and management.[82] Patients with preeclampsia are categorized into those with or without severe features. The presence of proteinuria (300 mg/24 hr urine collection) defines preeclampsia without severe features. Severe features are defined as new onset thrombocytopenia (<100 × 10^9^/L), impaired liver function (two times the upper limit of normal), renal insufficiency (serum creatinine >1.1 mg/dL or doubling of the serum creatinine concentration) and evidence of pulmonary edema or new onset headache unresponsive to medication.[84] Women with any of these high-risk features should receive aspirin (81 mg/day), initiated between 12–28 weeks’ gestation and continued until delivery.[85] Delivery rather than expectant management is recommended at or beyond 37 weeks’ gestation. If delivery is indicated less than 34 weeks’ gestation, administration of corticosteroids for fetal lung maturation is recommended.[86] Management is directed at prevention of seizures and control of hypertension. Magnesium sulfate is the mainstay of treatment to prevent seizures in women with preeclampsia with severe features.[87, 88] However, there is no consensus regarding the prophylactic use of magnesium sulfate for the prevention of seizures.[89, 90] The goal of treating severe hypertension is to prevent congestive heart failure, renal injury or failure, and ischemic or hemorrhagic stroke. It is recommended to administer antihypertensive therapy, including IV hydralazine, labetalol, and oral nifedipine, as soon as reasonably possibly, ideally within 30–60 minutes of diagnosis.[91] For gestational hypertension or preeclampsia without severe features, vaginal delivery is preferred.[92, 93] For preeclampsia with severe features, vaginal delivery is possible, but is less likely with decreasing gestational age at diagnosis.[94]
HELLP syndrome occurs in 10% of patients with preeclampsia and affects 0.5% to 0.9% of all pregnancies.[95] It also occurs after 20 weeks’ gestation and risk factors include multiparity, multiple gestation, a personal or family history of preeclampsia or HELLP syndrome, elevated body mass index, and advanced maternal age.[96]
When a pregnant individual produces antibodies against the father’s platelet antigens fetomaternal alloimmune thrombocytopenia (FMAIT) can occur, also known as fetal and neonatal alloimmune thrombocytopenia (FNAIT).[97] This will lead to both a reduction in number of platelets in addition to platelet dysfunction due to alloantibodies, and increased fetal and neonatal morbidity and mortality.[98] Complications of FNAIT range from growth restriction and systemic bleeding in the fetus to petechiae and intracranial hemorrhage in the neonate.[99] On occasion, neonatal thrombocytopenia is discovered incidentally in the immediate postnatal period and additional work up, including a neonatal and maternal complete blood count, platelet immunological tests, and a neonatal cranial ultrasound should be performed.[97] There is no clear screening test utilized for FMAIT, but if a patient has previously had FMAIT, then management in a subsequent pregnancy includes maternal IVIG with or without corticosteroids.[100] The dose and timing of IVIG initiation in pregnancy is determined based on the potential severity of the FNAIT. Serial intrauterine platelet transfusions to prevent severe fetal thrombocytopenia is not generally recommended due to a high risk for complications like fetal hemorrhage or intrauterine death.[101]
Non-inherited anemias, more commonly related to nutritional deficiencies but less commonly associated with immune-related etiologies, can lead to an increased risk of infection or bleeding.[102] These disorders include aplastic anemia and autoimmune hemolytic anemias.
Aplastic anemia (AA) is a rare blood disorder that can be life-threatening during pregnancy for both mother and child and occurs in two per million cases per year.[103] Immune mediated bone marrow failure is the hallmark of the disease, leading to anemia, thrombocytopenia, bleeding, and increased risk of infection due to an immunocompromised state.[104] AA can be classified by etiology and severity (Table 3), 80% of cases are idiopathic with the remaining 20% of cases resulting from medications, infections (e.g., hepatitis), and hereditary forms of marrow failure that are later reclassified. Hemorrhage and sepsis are the two most common causes of death in AA.[105] Treatment is guided by early recognition of the underlying cause of cytopenia given the risk of pancytopenia is too great to wait for spontaneous resolution.[106] If a causative drug reaction or infection is identified and the medication cannot be discontinued or the infection cannot be treated, depending on the gestational age at diagnosis, early delivery or termination of pregnancy can be considered. The initial approach to a non-pregnant patient with AA involves a comprehensive review of neutrophil counts, comorbidities, and age to determine if they can be observed or should be treated with colony-stimulating factors (CSF), cyclosporine, methylprednisolone, thrombopoietin memetics and antithymocyte globulin (ATG).[107] Supportive management with serial blood transfusions to a goal of a Hb >8 g/dL and platelet count >20 × 10^9^/L is recommended. Several case reports have noted the successful use of CSF, cyclosporine, and methylprednisolone in pregnancy.[108, 109] There is still limited experience in using ATG in pregnancy as the risks and benefits are not understood.[110] AA remains a complex disorder that that requires a multidisciplinary team approach, conservative transfusion strategies to minimize risk of alloimmunization and continuous monitoring of fetal well-being and growth.[103]
Autoimmune hemolytic anemia (AIHA), occurring in three per one hundred thousand patients per year, is characterized by the destruction of red blood cells due to autoantibodies produced by the immune system, leading to anemia.[111] AIHA can be classified into warm antibody, cold agglutinin disease, and mixed-type AIHA based on the temperature at which the antibodies react with the red blood cells. Both maternal and fetal complications have been reported. Maternal complications include premature rupture of membranes, placental detachment and preeclampsia. Fetal complications include respiratory distress, fetal growth restriction preterm birth, and perinatal death.[111] Treatment may include corticosteroids as first-line therapy to suppress autoantibody production and if refractory, rituximab may be considered. Transfusions should be carefully managed to avoid exacerbating hemolysis and alloimmunization.[112] Overall, close monitoring and timely intervention are key to mitigating complications associated with this challenging condition.
Inherited anemias, although rare, can cause significant defects in red blood cell (RBC) integrity that can be harmful in pregnancy.[113] These disorders include sickle cell disease (SCD), select thalassemias, enzyme deficiencies, red cell membrane disorders and Diamond-Blackfan anemia (DBA). (Table 4)
SCD is a collective term for a group of autosomal recessive diseases which have a point mutation in the beta-globin chain gene. It is one of the most common inherited anemias affecting pregnancies, especially individuals of African, Mediterranean, Middle Eastern, and Indian descent. The main mechanism of sickling is secondary to impaired microcirculation, which is compounded by the physiological changes in pregnancy resulting in increased maternal and fetal mortality and morbidity including preeclampsia and preterm delivery.[114–116] Pregnancy induced hypercoagulability, increased blood viscosity, and metabolic demand combined with the fragility of sickled cells can increase the risk of vaso-occlusive crises, acute chest syndrome, venous thromboembolic events, and infections.
Because SCD has a wide range of presentations, it is hard to monitor and predict the progression of disease. It is important to check for the presence of alloantibodies, ideally prior to conception, followed by a thorough assessment for associated chronic disease processes such as iron overload, hypertension, preeclampsia, hepatic dysfunction, VTE, proteinuria, or frank nephropathy. Risk stratification is typically determined by the frequency of recurrent transfusions. This is in part due to these patients having an increased risk of alloimmunization and hemolytic disease in the fetus.[117–119]
Treatment is guided by managing associated chronic disease processes and frequent patient follow-up every 2 to 3 weeks starting at 32 weeks’ gestation.[120] Given the increased risk of fetal growth restriction, serial assessments of fetal growth via ultrasonography is recommended every four weeks beginning in the 28^th^ week of gestation.[121] For acute pain in the setting of vasoocclusive crises, a tailored opioid plan along with IV hydration is preferred as the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the first trimester of pregnancy can be associated with miscarriage and in the third trimester with pulmonary hypertension.[122, 123] Additionally, antenatal corticosteroids are not recommended for pain management.[124] The role of prophylactic transfusions to augment oral or IV pain medications is currently only indicated in high risk patients, such as those with a history of severe SCD related complications or to reduce recurrent pain episodes.[125] There is limited and low-quality data regarding continued use of hydroxyurea in pregnancy. A recent retrospective study showed increased risks of miscarriage and low birthweight in pregnant patients who were continued on hydroxyurea.[126] However, given the paucity of evidence, it is recommended to involve a sickle cell disease specialist and a maternal-fetal medicine provider to engage in a shared decision with the patient in order to determine the timing of use. Patients with SCD also have an increased risk of VTE.[127] Prophylactic anticoagulation should be considered in pregnant patients with SCD if they meet high risk criteria, such as anticipated decreased mobility.[128] Furthermore, as SCD is associated with an increased risk of preeclampsia, the Society for Maternal-Fetal Medicine recommends initiating low-dose aspirin at 12 weeks’ gestation for risk reduction.[125]
Historically, thalassemias are more common in certain endemic countries including regions of the Middle East and Southeast Asia, but with increased migration, the prevalence is increasing in Northern Europe and North America.[129] In pregnancy, thalassemias are divided into transfusion dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT). It is important to note that although conception is possible in patients with TDT, most patients age 25 and greater are infertile due to hypogonadotropic hypogonadism from hemosiderosis and endocrinopathies.[130] Those with TDT who successfully conceive should be closely monitored for cardiac complications. Pregnancy leads to a 25 to 30% increase in cardiac load, which in the setting of iron overload can result in cardiac failure and death.[131] An extensive cardiac workup including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging (MRI) is recommended. If significant iron overload is seen on cardiac MRI, TDT patient should be discouraged from trying to conceive until this is optimized.[132] Other complications of TDT patients are liver dysfunction, which can be monitored via MRI, and an increased risk of gallstones which can be surgically managed prior to conception.[133] The goal of TDT management is to reduce iron overload, but because the use of iron chelators in pregnancy is contraindicated due to the lack of safety data.[134] Treatment is limited to deferoxamine and only in the third trimester in cases of severe iron overload.[135]
In patients with NTDT, pregnancy is not contraindicated, but patients have a greater than 30% increased risk of VTE This reflects a hypercoagulable state driven by endothelial damage and iron-mediated free radical formation.[136] Given the increased risk of VTE, a prophylactic dose of low-molecular-weight heparin should be given peripartum. [137] Transfusions should also be limited to those with a Hb <10 g/dL given a high risk of alloimmunization.
Enzyme deficiencies and red cell membrane disorders are both inherited conditions that cause anemia and the most common is pyruvate kinase deficiency (PKD), an enzyme abnormality resulting in disruption to the glycolytic pathway, and hereditary spherocytosis, an erythrocyte disorder resulting in altered membrane transport function.[138] Clinical manifestations of both diseases include chronic hemolysis, jaundice, splenomegaly, and iron overload. Pregnancy specific complications are limited and largely based on published case reports but include an increased risk of anemia, preterm birth and miscarriage.[113] Given pregnancy is regarded as a hemolytic trigger, management largely consists of blood transfusions, and in some cases, splenectomy may be considered to reduce red blood cell destruction.[139–141] For hereditary spherocytosis, 800–1000ug of folic acid is also necessary if there are signs of chronic hemolytic anemia.[142]
Diamond Blackfan Anemia (DBA) is a rare form of congenital pure red cell aplasia related to ribosome synthesis resulting in pro-apoptotic hematopoiesis and ultimately bone marrow failure that occurs in seven cases per million live births.[143] Studies have demonstrated that patients with DBA have an increased risk of low birth weight infants, preterm delivery, worsened anemia, increased transfusion requirement, iron overload, and resistance to corticosteroids.[144–146] Advancements in treatment, including stem cell transplants for DBA have improved and now individuals with DBA are able to reach childbearing age.[147] Given the rarity of this disease, guidelines for management, including the use of iron chelation therapy during pregnancy, remain limited. Instead, management recommendations are derived from treatment of thalassemia and thus recommend against the use of iron chelators. In cases of severe iron overload, deferoxamine in the third trimester can be considered. [148] Additionally, maternal anemia should also be managed to optimize fetal oxygenation. Although there is no consensus on transfusion thresholds based on hemoglobin levels, a recommendation of Hb < 10 g/dL based on physiological changes has been widely adopted with management ultimately guided by the clinical presentation. [146]
Alloimmunization occurs when antibodies against red blood cell antigens form, with a reported incidence in the general population of 0.46% to 2.4 %.[149] The most common cause of alloimmunization in pregnancy is Rh(D) incompatibility. Rh(D) incompatibility can occur from a prior blood transfusion or from fetomaternal hemorrhage, when a small amount of fetal blood crosses into the maternal bloodstream. Fetomaternal hemorrhage is often without consequence, however, in cases of trauma, invasive procedures, miscarriage, delivery, and maternal infection, a larger amount of fetal blood crosses into the maternal bloodstream increasing the risk of alloimmunization.[150] In pregnancy, these antibodies can significantly decrease RBC lifespan in the fetus leading to hemolytic disease of the fetus and newborn, or erythroblastosis fetalis.[151]
Screening typically occurs at the first prenatal visit with ABO and RhD typing. This test can be repeated in the second trimester if needed. Additionally, antibody screening with an indirect antiglobulin test can be used after blood typing and repeated every two to four weeks.[152] These tests, if positive, are followed by antibody titration testing as certain titers are associated with severe hemolytic disease of the fetus and newborn. An antibody titer higher than 8 or 32 confer a higher risk of developing disease and need closer monitoring for fetal anemia.[153] If a critical titer is reached, serial middle cerebral artery doppler assessments using ultrasonography is recommended after 16 weeks’ gestation to screen for fetal anemia. An elevated middle cerebral artery doppler peak systolic velocity greater than 1.5 multiples of the median is concerning for fetal anemia and periumbilical blood sampling is performed for confirmation.[154, 155] A fetal hemoglobin greater than 2 standard deviations below the mean for gestational age is diagnostic for fetal anemia and an intrauterine transfusion through the umbilical cord under ultrasound guidance is indicated. The overall procedure risk to the fetus is approximately 4–5%, secondary to hemodynamic complications including bradycardia and vasospasm.[156] Intrauterine transfusions are more technically challenging earlier in pregnancy when the umbilical cord is smaller in diameter, but the benefits of the procedure outweigh the risks given expectant management will ultimately result in fetal demise. A prior case series has demonstrated perinatal survival of 80% if intervention is performed by 22 weeks.[157]
Prevention of alloimmunization typically involves Rh immunoglobulin (RhIG) prophylaxis and is given to Rh-negative mothers at 30 weeks’ gestation and again within 48 hours after delivery or any invasive procedure during pregnancy.[158] Maternal therapies for pregnancies complicated by alloimmunization include intravenous immunoglobulin (IVIG), plasma exchange, and monoclonal antibodies although treatment is still a topic of ongoing research. IVIG has shown potential benefits in managing severe maternal alloimmunization. A meta-analysis showed an association with prolonged gestational age at the first intrauterine transfusion, reduced risk of fetal hydrops, and higher chances of live birth at 28 and 32 weeks.[159] Plasma exchange can also be considered, but has not been used as a standalone treatment. Most studies describe treatment with IVIG and plasma exchange, demonstrating improved maternal outcomes such as delaying the onset of fetal anemia. [160, 161] Because IVIG or plasma exchange are not targeted maternal therapies, monoclonal antibodies can used for direct immunomodulation. M281 (Nipocalimib) is a monoclonal antibody that binds to neonatal Fc receptors and inhibits transplacental IgG transfer, and has shown promise in early phase trials of reducing circulating IgG levels by 84%.[162, 163] As a result of its initial safety and tolerability profile, there is an on-going multicenter open-label study examining the administration of nipocalimib in pregnant individuals at high risk for early onset severe hemolytic disease of the fetus and newborn with the primary endpoint being a live birth after 32 weeks of gestation without need for an intrauterine transfusion.[164]
Individuals with inherited bleeding disorders can experience increased hemostatic challenges when pregnant, especially during delivery and postpartum, especially if their clotting factor levels remain subnormal despite the normal physiological changes in pregnancy shifting towards hypercoagulability. In pregnancy, the most common inherited bleeding disorders include von Willebrand Disease (vWD), hereditary hemorrhagic telangiectasia, and hemophilia.[165] The remaining bleeding disorders that manifest in pregnancy are rare and comprise 3–5% of all inherited disorders. These disorders include deficiencies in fibrinogen and vitamin K dependent factors. Most are transmitted in an autosomal recessive manner and the prevalence varies from 1 in 500,000 to 1 in 2 million. [166]
von Willebrand disease (vWD) is the most common inherited bleeding disorder and is caused by both quantitative and qualitative defects of von Willebrand factor (vWF), an adhesive protein that binds platelets to exposed endothelium. Additionally, a reduction in factor VIII is seen in vWD as vWF carries factor VIII in circulation. There are three types of VWD: type 1 is the most frequent type and is associated with quantitative defects in vWF, type 2 is associated with qualitative defects in vWF, and type 3 is complete absence of vWF (Table 5). Despite levels of vWF and factor VIII rising during normal pregnancy, in patients with vWD, median levels of vWF remain low and can decrease during delivery; this translates to a 2 to 10-fold increased risk of antepartum and postpartum bleeding.[167]
Hereditary hemorrhagic telangiectasia (HHT) is the second most common bleeding disorder, often associated with nasal, cutaneous, or GI telangiectasias.[168] The worldwide prevalence is approximately 1 in 5,000, and remains a major cause of maternal morbidity.[169] Pregnant patients with HHT are at a higher risk of bleeding in the second and third trimesters due to decreased peripheral vascular resistance and increased cardiac output.[168] Bleeding increases the risk of iron deficiency anemia, so screening and treatment for iron deficiency is vital.[170, 171] Although the majority of patients have uneventful pregnancies, severe complications including heart failure, intracranial hemorrhage, rupture of pulmonary arteriovenous malformations (AVMs), and stroke can occur. [171, 172] Furthermore, delivery can be complicated by severe epistaxis and gastrointestinal bleeding. It is recommended that patients are screened for pulmonary AVMs and treated during the second trimester given the ~1% chance of mortality if rupture occurs during delivery.[170] There are some theoretical concerns for spinal ventricular malformations, however, epidurals can be administered for patients with HHT and do not require a spinal MRI prior to administration.[170] In contrast to von Willebrand disease, postpartum hemorrhage is more common. This is attributed to endometrial telangiectasias, although the underlying mechanisms remain poorly understood. [173]
Hemophilia A and B are a result of either deficiency or absence of clotting factor VIII or IX, respectively. Both are X-linked recessive disorders; hence women are only affected as carriers. The prevalence of hemophilia carrier status is approximately 1 in 3000.[174] Both are associated with increased morbidity and mortality due to manifestations of deep muscle and joint bleeding, intracranial hemorrhage, and spontaneous and post-surgical bleeding.[167] The most accurate and noninvasive method to test if a male fetus is affected by hemophilia is through cell-free fetal DNA analysis in maternal plasma.[175] If noninvasive testing is inconclusive or not available, invasive methods such as chorionic villus sampling and amniocentesis can be used to obtain cells for direct genetic analysis.[176] Newborn males with hemophilia are at risk of intracranial hemorrhage particularly if delivered vaginally, which imparts a 4.4-fold increased risk of bleeding.[177] While cesarean delivery can reduce the risk of intracranial hemorrhage in neonates, it increases the risk of maternal bleeding.[178]
Management begins either prior to conception or early in pregnancy to discuss the increased risk of bleeding at time of delivery and strategies to optimize maternal and fetal outcomes. Studies have shown that factor VIII and IX levels less than 50% are associated with a greater risk of bleeding at time of delivery. Currently, management recommendations are based on observational studies and expert opinion because no randomized trials exist. There is a consensus that factor VIII and IX levels should be maintained above 0.50 IU/1mL for at least 3 days after a vaginal delivery and 5 days after a cesarean delivery.[179]
Medications such as Desmopressin, vWF concentrates, and antifibrinolytics (e.g., tranexamic acid) have been studied. Desmopressin can be administered intravenously or intranasally, and typically a Desmopressin trial is performed prior to pregnancy to assess for efficacy. To properly interpret the test, baseline vWF activity outside of pregnancy is necessary. Desmopressin is generally reserved for type I vWD and some patients with type 2 vWD, but is contraindicated in type 2B vWF as it may worsen thrombocytopenia. In approximately 1% of pregnancies, the use of Desmopressin is associated with life threatening hyponatremia, seizures and neurologic injury.[180, 181] This can often be avoided by limiting oral intake of water and avoidance of desmopressin in patients with inherited bleeding disorders and preeclampsia. Additionally, desmopressin is contraindicated in patients with underlying coronary artery disease and cerebrovascular disease given the increased risk of thrombosis.[165] If multiple doses of Desmopressin are needed or a Desmopressin trial was not performed prior to conception, use of vWF concentrates is recommended instead. Three plasma derivatives (Alphanate, Humate-P, Wilate) and one recombinant (Vonvendi) vWF concentrate are approved for use in the United States. The initial dose of plasma derivatives is usually 40–80 vWF: ristocetin cofactor assay activity units/1kg with maintenance doses between 20–40 vWF. This is typically given every 12 hours as needed.[179] Tranexamic acid is typically used in the setting of delayed-onset postpartum bleeding, the recommended dose is 1g every 8 hours for 10 to 14 days after delivery in all types of vWD.[165, 182]
Management and delivery of patients with inherited bleeding disorders requires attention to both maternal and fetal risks. While Factor IX levels do not increase significantly in pregnancy, Factor VIII levels increase physiologically in pregnancy, but not to the level of patients without hemophilia. This results in an increased risk of postpartum hemorrhage, with a reported range of 13–22%.[166] For management, the World Federation of Hemophilia strongly recommends virally inactivated plasma-derived or recombinant concentrated over use of cryoprecipitate of fresh frozen plasma (FFP). As stated above, these are given to maintain factor levels VIII and IX greater than 0.5 IU/1mL. Usual doses of factor concentrates are 20–50 IU/1kg.[179] Ultimately, managing bleeding disorders in pregnancy requires a tailored approach to optimize maternal and fetal outcomes.[183]
Venous thromboembolism (VTE) consists of deep vein thrombosis (DVT) and pulmonary embolism (PE) and it is a leading cause of maternal mortality, complicating approximately 1 in 1000 pregnancies.[184] Pregnant individuals are at a higher risk for VTE during the pregnancy and postpartum due to normal physiologic changes in pregnancy including increased hypercoagulability, venous stasis, and decreased venous outflow.[185] Certain factors increase the risk of VTE in pregnancy including inherited thrombophilia and acquired thrombophilia such as antiphospholipid syndrome, preeclampsia, prolonged immobility, and cesarean delivery.[186] Symptoms of VTE in pregnancy are often challenging to ascertain because they overlap with common symptoms in pregnancy including lower extremity swelling and pain, dyspnea, lightheadedness, fainting, and tachycardia.[187] 70 to 90% of DVTs seen in pregnant patients are left-sided and located in the proximal and iliac veins.[188] Due to the mortality associated with a missed VTE diagnosis, strong clinical suspicion should be followed by additional workup.
The workup for a suspected DVT includes a full leg ultrasound. If a PE is suspected, a full leg ultrasound is also often the first step to minimize radiation exposure, but if clinical suspicion is high then a ventilation-perfusion (VQ) scan, or Computed Tomography Pulmonary Angiography (CTPA) should be performed.[185] Laboratory testing used outside of pregnancy, such as a d-dimer test, is thought to have decreased specificity during pregnancy and thus there is conflicting recommendations for use. (Figure 3)
Although there is no clear consensus on management, overall patients with a history of a prior VTE or risk factors like thrombophilia should be started on VTE prophylaxis after the first trimester with unfractionated heparin or low molecular weight heparin (LMWH) antepartum through 6 weeks postpartum (Figure 4).[189] In the setting of acute VTE during pregnancy, it is recommended that patients be treated with LMWH or unfractionated heparin for at least three months in duration; LMWH being the preferred option due to cost and lack of routine laboratory monitoring.[190] Vitamin K antagonists like warfarin are contraindicated in pregnancy due to its teratogenic effects in the first trimester but can be resumed postpartum when lactating, and there is limited safety data regarding direct oral anticoagulants.[191, 192] Depending on the anticoagulation dose used antenatally, it should be held 12 to 24 hours prior to the scheduled delivery, with the plan to resume the medication within 6 to 12 hours after a vaginal delivery or 12 to 24 hours after a cesarean delivery.[193] Anticoagulation should be continued for a minimum of 6 weeks postpartum, the highest risk of VTE is during the initial 2 weeks postpartum.[194]
Hematologic complications during pregnancy are common and can pose significant risks to both maternal and fetal health. Normal physiologic changes in pregnancy can worsen existing hematologic disorders and also make diagnosis challenging. Understanding these complications and the best approach is crucial for timely diagnosis and management. Common hematologic conditions in pregnancy including iron deficiency anemia, thrombocytopenia, hypercoagulable states, and bleeding disorders. Management strategies often involve close monitoring, appropriate supplementation or therapies, and in severe cases, multidisciplinary care to optimize maternal and fetal outcomes. Early recognition and intervention are essential to mitigate potential complications. However, the absence of carefully conducted prospective studies complicates decision-making for consultants and future research is needed in many of the areas outlined in this review.