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Aplastic anemia during pregnancy: a review

of obstetric and anesthetic considerations
This article was published in the following Dove Press journal:
International Journal of Women’s Health

Efrain Riveros-Perez 1 Abstract: Aplastic anemia is a hematologic condition occasionally presenting during pregnancy.
Amy C Hermesch 2 This pathological process is associated with significant maternal and neonatal morbidity and
Linda A Barbour 3 mortality. Obstetric and anesthetic management is challenging, and treatment requires a
Joy L Hawkins 4 coordinated effort by an interdisciplinary team, in order to provide safe care to these patients.
In this review, we describe the current state of the literature as it applies to the complexity of
1
Department of Anesthesiology and
Perioperative Medicine, Medical aplastic anemia in pregnancy, focusing on pathophysiologic aspects of the disease in pregnancy,
College of Georgia, Augusta as well as relevant obstetric and anesthetic considerations necessary to treat this challenging
University, Augusta, GA, 2Maternal problem. A multidisciplinary-team approach to the management of aplastic anemia in pregnancy
Fetal Medicine, 3Obstetrics and
Gynecology, 4Department of is necessary to coordinate prenatal care, optimize maternofetal outcomes, and plan peripartum
Anesthesiology, University of interventions. Conservative transfusion management is critical to prevent alloimmunization.
Colorado School of Medicine,
Although a safe threshold-platelet count for neuraxial anesthesia has not been established,
Aurora, CO, USA
selection of anesthetic technique must be evaluated on a case-to-case basis.
Keywords: aplastic anemia, platelets, high-risk obstetrics, obstetric anesthesia, pregnancy

Background
Aplastic anemia (AA) is a life-threatening disorder1 that tends to worsen during
pregnancy. This disorder consists of pancytopenia as a result of hypocellular bone
marrow in the absence of an abnormal infiltrate or bone-marrow fibrosis.2,3 The
diagnosis of AA during pregnancy is associated with significant fetal, neonatal, and
maternal morbidity and mortality.4 Growth restriction affects the fetus, and neonatal
sepsis is more prevalent among babies from mothers with AA.5 A causal relationship
between pregnancy and AA has not been conclusively established;6 however, women
with AA can become pregnant, since there is no compromise of fertility. In these cases,
obstetric and neonatal complications range between 12% and 33%.7,8 Furthermore,
in the presence of thrombocytopenia, hemorrhagic complications during the peripartum
period requiring blood transfusions have been reported to have incidence as high as
75%.9 Anesthetic, hematologic, and obstetric care during pregnancy is discussed in
this paper from an interdisciplinary standpoint. Therapy during the peripartum period
is also approached in the context of a review of recent literature.

Review of literature
Correspondence: Efrain Riveros-Perez Acquired AA is an uncommon disorder characterized by progressive pancytopenia
Department of Anesthesiology and
Perioperative Medicine, Medical College caused by altered bone-marrow function. Incidence is estimated to be one to two cases
of Georgia, Augusta University, 1120 per million per year.10 Given the complexity of AA and the limited experience by
15th Street, Augusta, GA 30912, USA
Tel +1 706 721 7361
most providers, new guidelines by the British Society for Standards in Haematology
Email [email protected] on the diagnosis and management of adult AA were recently published.3 Pathogenic

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mechanisms underlying this disease are likely to be immuno- population of CD4+ T cells able to target hematopoietic cells
mediated, and include the overproduction of bone-marrow- positive for HLA-DRB1*0405, supporting the hypothesis
inhibiting cytokines elicited by abnormal T-cell response in that certain HLA alleles may play a role in activation of T-cell
a genetically predisposed individual.11 Pregnancy in associa- clones in AA.22 On the other hand, it has been postulated that
tion with AA is a rare but serious condition that poses serious certain HLA alleles might confer protection against autoreac-
maternal and fetal risks. Unfortunately, most of the current tive T-cell activation.23
literature has been limited to case reports, with few studies In addition to individual susceptibility, T-cell dysregula-
exploring risk factors and perinatal complications.12,13 tion is necessary for AA to develop. Transcriptional analysis
has shown altered regulation of CD4+ and CD8+ T  cells,
Pathophysiology of aplastic anemia whereas abnormal expansion of T-helper (TH)-1, TH2, and
Acquired AA is more common than the hereditary form. TH17 cell populations and underexpression of the Treg immu-
Typically, this disorder affects young adults who pres- nophenotype occur consistently in AA.24,25 Autoreactive
ent with peripheral pancytopenia in the absence of other T-cells produce proinflammatory cytokines, including
hematological diseases.14 Classification of AA determines TNFα and IFNγ.26,27 Both cytokines induce apoptosis, reduc-
indication for treatment, and depends on etiology and severity ing colony formation of hematopoietic progenitor cells.28
(Table 1).2 AA in the adult can be idiopathic (.80% of cases) Furthermore, intracellular expression of these cytokines
or induced by pharmacologic agents, infections (particularly predicts response to immunotherapy and is associated with
hepatitis), or hereditary forms with late-onset manifesta- poor clinical outcome.29,30 Aside from abnormal cellular
tions (eg, related to telomeropathies). Therapy is indicated immunity, other factors have been implicated in the patho-
in symptomatic disease, severe and very severe cases, and genesis of AA, including the role of innate immunity via
patients classified as nonsevere in whom severe cytopenia of depressed NK cells31 and mutations in telomerase-complex
at least one cell line requiring transfusions is present. genes that lead to decreased proliferation and survival of
Although the hematologic stem-cell (HSC) compartment hematopoietic progenitor cells.32–34
is affected in all types of AA, in the acquired form, the dam- Paroxysmal nocturnal hemoglobinuria (PNH) has been
age is extrinsic and involves direct and indirect mechanisms. considered a late clonal disease occurring in patients recover-
Direct injury can be caused by radiation therapy and cytotoxic ing from AA, and sometimes these two disorders overlap.35
agents, whereas indirect damage involves immunoeffector As is the case with AA, PNH is linked to HLA antigens, and
pathways, which are responsible for idiopathic cases and immunosuppressive therapy is useful to control the disease.
present in those preceded by a history of hepatitis.15,16 Cross- Complement inhibitors, such as the monoclonal antibody
reactive marrow antigen recognition by T cells is postulated eculizumab, have proven useful for treatment of PNH,
as the causative mechanism in most idiopathic cases of highlighting the underlying mechanism of red-blood-cell
the disease (Figure 1).17 Evidence supporting the role of destruction and bone-marrow suppression. This therapy has
the immune system in HSC injury includes serologic and been used with success in pregnancy.36
cytokine data and the dramatic clinical response to therapy
with immunomodulatory agents in animals.18–20 Pathophysiology in pregnancy
The HSC/progenitor cell is the target of immune attack The first report of AA was published by Ehrlich in 1888.
by activated T cells. The antigens responsible for autoimmu- Incidentally, his patient was pregnant and died 1 month after
nization remain elusive; however, autoantibodies have been delivery, due to postpartum hemorrhage.37 The causal rela-
identified in serum of patients with AA.21 The association tionship between pregnancy and AA is still unclear.38 Earlier
between human leukocyte antigens (HLAs) and susceptibility studies found no correlation between the conditions, and a
to develop AA has been widely studied. Nakao et al isolated a retrospective study comparing the frequency of pregnancy
in 35 newly diagnosed patients with the expected frequency
Table 1 Classification of aplastic anemia based on severity in the general population found no significant difference.38,39
Cells Nonsevere* Severe Very severe
Other reports endorse a direct association between pregnancy
Neutrophils ,1×109 cells/L ,0.5×109 cells/L ,0.2×109 cells/L
and AA,40 and pregnancy is even included as a cause of AA
Platelets ,50×109 cells/L ,20×109 cells/L ,20×109 cells/L in some reviews.41
Reticulocytes ,20×109 cells/L ,20×109 cells/L ,20×109 cells/L Hemorrhage and sepsis are the major reasons for death
Note: *In addition to ,25% bone marrow cellularity. in pregnant women with AA.9 When AA is present before

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Dovepress Aplastic anemia during pregnancy

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Figure 1 Pathophysiologic mechanisms of aplastic anemia.

Abbreviation: HLA, human leukocyte antigen.

conception, it usually worsens during pregnancy,42 and most and causes are still unclear.45,46 Animal models have provided
series have reported a significant decrease in platelet count some insight into mechanisms for altered maturation and
in almost all women with AA preceding pregnancy.9,43 Some proliferation of blood cells in pregnancy. In a murine model,
authors have reported remission of AA after delivery, and Zoller et al showed that injection of 17β-estradiol inhibits
others have suggested that termination of pregnancy should the development of developing thymocytes.47 Zhdanov et al
be considered for AA in pregnancy, especially in those demonstrated enhanced proliferative activity of erythroid
patients with severe disease.44 precursors in bone marrow that was increased by concomitant
Pathophysiological mechanisms underlying the asso- administration of iron.48 According to one theory, a popula-
ciation between AA and pregnancy have not been clearly tion of primitive CD34+ progenitors responsible for cellular
elucidated. It is known that estrogens increase plasma proliferation and regeneration is produced in maternal bone
volume in pregnancy more than red-blood-cell production, marrow in response to interaction with umbilical cord blood
resulting in anemia of pregnancy. It has been postulated that cells via immunologic signals.49 Pregnancy is also sometimes
hormonal influences may contribute to worsening of blood accompanied by gestational thrombocytopenia and rela-
counts in pregnant patients with AA, but the exact mechanism tive leukocytosis. The factors responsible for the observed

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thrombocytopenia in pregnant patients with AA are yet to the informed decision to recommend breastfeeding must be
be definitively elucidated.50 individualized.56 Additionally, reduced fertility is a common
clinical manifestation after HSCT, due to gonadal damage
Maternal and fetal considerations in secondary to myeloablative conditioning. Fertility prospects
aplastic anemia in pregnancy must be discussed with the patient before making the decision
Treatment of aplastic anemia in pregnancy to proceed with HSCT in the postpartum period.57
Principles of AA treatment during pregnancy include identi- The optimal treatment for AA depends on different fac-
fication of any underlying cause and treatment of cytopenias, tors, including patient age, neutrophil count, and presence
while minimizing maternal and fetal side effects of therapy. of comorbid conditions. In the nonobstetric population,
Termination should be considered if a triggering factor mild cases can be either observed or treated with specific
causing bone-marrow suppression, such as drug reaction or colony-stimulating factors, antithymocyte globulin (ATG),
infection, is detected, and the medication cannot be discon- cyclosporine, and methylprednisolone. 58 In pregnancy,
tinued or the microorganism cannot be adequately treated supportive management with transfusions to hemoglo-
if pregnancy continues. Waiting for spontaneous resolution bin .8 g/dL and platelet count .20×109/L is recommended.6
without further treatment is not recommended, as it places Additionally, there are reports of patients successfully treated
the patient at risk of complications related to pancytopenia.51 with prednisolone, cyclosporine, and GCSF.5,59 Regarding the
Pregnancy termination should also be considered for use of ATG in pregnancy, there is little published experience.
patients with severe pancytopenia, given the high likeli- A retrospective analysis of a group of 26 patients, including
hood of life-threatening maternal and fetal complications. two pregnant women, reported an overall response rate to
Furthermore, in a recent series of 61 women with AA, those treatment of 46% and 45% survival at 2 years, without special
with more severe thrombocytopenia had a sixfold-higher mention of outcome of pregnancy.60 Aitchison et al reported
complication rate related to one of the composite pregnancy a case series of five pregnant patients with AA treated with
outcomes – preeclampsia/eclampsia, preterm delivery, intra- ATG. In his series, four patients were treated during the
uterine growth restriction, and fetal and neonatal death – and postpartum period and only one before delivery, receiving the
an elevenfold increase in the composite outcomes, which medication at 23 weeks. The baby was delivered at 36 weeks,
included transfusion dependence after delivery, sepsis, weighing 1,700 g. The patient died 2 months postpartum as a
and bone-marrow transplant.9 result of an episode of pneumonia without recovery from her
The most common complications of AA in pregnancy, AA.54 ATG is a relatively safe medication, with side effects
in addition to postpartum hemorrhage, include premature mostly related to allergic reactions, vein irritation, nausea,
rupture of membranes, endometritis, growth restriction, sub- vomiting, and diarrhea. There are no reports of fetal adverse
chorionic hematoma, and placental abruption. Management effects attributable to ATG in humans, and low birth weight
of AA starts with accurate diagnosis, definition of severity, might be the result of comorbid conditions, rather than drug
and a comprehensive assessment, followed by supportive toxicity.61 Kutzler et al reported the successful use of ATG
treatment. Some therapies recommended for AA in the non- to treat kidney-transplant rejection in a pregnant patient.61 In
obstetric population include hematopoietic stem-cell trans- an animal study, antithymocyte therapy caused toxic effects,
plantation (HSCT) and use of immunosuppressive regimens.52 manifested as decreased placental development in a murine
HSCT, albeit associated with significant 5-year survival rates model.62 There is very limited experience using ATG in preg-
in nonpregnant patients,53 is contraindicated in pregnancy, nancy, and risks and benefits of this therapy are not clear.
due to teratogenicity associated with pretransplant immu- If corticosteroids are used, those unable to cross the
nosuppressant agents.54 Termination of pregnancy in order placenta, such as prednisone, prednisolone, and hydrocorti-
to perform HSCT is not usually recommended, because sone, are preferred, in order to minimize fetal brain exposure
of the relatively favorable prognosis for mother and fetus and the slight association of orofacial malformations.63 All
when medical therapy is optimally used.55 HSCT can be corticosteroids may increase the risk of glucose intolerance,
performed in the postpartum period. Immunosuppressant gestational diabetes, and premature rupture of membranes,
agents are excreted in breast milk, and some practitioners and their benefit is limited in AA compared to immunorelated
do not recommend breastfeeding while on those medica- causes of cytopenias that result from cell destruction (eg,
tions in the context of HSCT; however, reports of successful hemolytic anemia and idiopathic thrombocytopenic purpura).
immunosuppression in breastfed infants are encouraging, and Finally, cyclosporine, an immunosuppressant recommended

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Dovepress Aplastic anemia during pregnancy

for treatment of AA, seems to be associated with premature blood cell lines, with the goal of being conservative in terms
delivery and low-birth-weight infants, although it is dif- of transfusion practices. Fetal growth surveillance should
ficult to sort out whether this is due to the medication or an be performed by 28 weeks of gestation, and antenatal test-
underlying maternal condition. Because cyclosporine has not ing should also be offered by 30–32 weeks, due to the high
been shown to be consistently effective, it should be care- prevalence of growth restriction.
fully considered by the treating physician.64 Although some Mode of delivery should be carefully considered. 6
authors have reported an increase in neutrophil count during Vaginal delivery is preferred, because even with significant
pregnancy,65 in some instances severe thrombocytopenia can thrombocytopenia, hemostasis can typically be achieved with
occur. The use of GCSF was shown to be a safe and effective appropriate uterine contraction after delivery.73 A platelet
therapy in a retrospective analysis of 38 pregnant patients, count .20×109/L is deemed acceptable74 for vaginal delivery
and can be recommended when the disorder is accompanied and .50×109/L for cesarean delivery.75 Availability of
by significant neutropenia.66,67 cross-matched blood products can be difficult with a history
Transfusion of blood products is the mainstay of sup- of previous transfusions and alloimmunization. Multiple
portive treatment in AA associated with pregnancy; however, transfusions in patients with AA can lead to significant HLA
it may lead to complications, including hemochromatosis and alloimmunization, especially if nonleukocyte reduced blood
(most concerning) HLA alloimmunization.68 Alloantibodies products have been used. This presents significant problems,
against human platelets cause platelet-transfusion refracto- given the risk of maternal bleeding at the time of delivery
riness (PTR).69 There are two types of clinically relevant and the potential need for platelets to achieve hemostasis.
platelet alloantigens: type I antigens are shared with other HLA-matched platelets can be expensive and have limited
blood cells and tissue, which include glycoconjugates of availability.
the blood-group system and the polymorphic HLA class I Addressing permanent or long-acting reversible con-
molecule; and type II antigens are specific to platelets (human traception is of critical importance, given that AA does
platelet antigens [HPAs]). Alloantibodies to both types of not appear to decrease fertility, but is likely to progress or
antigens are responsible for PTR.70 If PTR is detected in relapse with subsequent pregnancies. Another relevant aspect
a pregnant patient who has received blood transfusions, to consider in the context of AA is the risk of neonatal
then HLA- and/or HPA-compatible platelet transfusions thrombocytopenia in mothers exposed to platelet transfu-
are indicated.71 sions. Neonatal alloimmune thrombocytopenia occurs when
When treating pregnant patients with AA, clinicians maternal antibodies directed against HPAs cross the placenta.
encounter significant ethical challenges. Therapy for maternal Clinically significant neonatal thrombocytopenia associ-
AA may put the fetus at risk secondary to exposure to medi- ated with HLA alloimmunization has been suggested;76,77
cations, whereas maternal complications occurring if AA however, one prospective study was unable to find this
is left untreated may also affect the developing fetus. The association.78
biomedical ethical principles of autonomy, beneficence,
nonmaleficence, and justice provide a guideline to make Anesthetic implications of aplastic
therapeutic decisions in these cases. In general, two rules anemia
apply to most ethical dilemmas: the maternal right to auton- The anesthetic management of a pregnant patient with diag-
omy must be granted, and risks, benefits, and alternatives nosis of AA requires coordinated interaction with other care
must be presented to the patient for her to make an informed teams, including the blood bank, hematology, obstetrics,
decision. From the legal point of view, it is clear that the interventional radiology, nursing staff, and neonatology.79
rights of the mother prevail over those of the fetus.72 A comprehensive anesthetic plan should incorporate differ-
ent aspects, including the presence and degree of cytopenias,
Perinatal implications of aplastic infectious and bleeding complications, systemic effects of
anemia anemia, and side effects of therapy.
Pregnancies complicated by AA require a multidisciplinary- The presence of severe thrombocytopenia, which per se
team approach. Collaboration between high-risk obstetricians, confers poor prognosis in the context of AA,9,80,81 puts the
hematologists, anesthesiologists, and transfusion-medicine patient at risk for surgical bleeding, and may contraindi-
specialists is necessary. Antepartum management includes cate the use of neuraxial techniques for labor and delivery.
frequent monitoring for clinically significant depletion of Platelet counts .50×109/L are generally considered safe by

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surgeons to perform a cesarean section;73 however, there is is currently no evidence from randomized trials to endorse
no absolute number for platelet count unanimously accepted this practice.
by anesthesiologists to perform a neuraxial block.82 The risk Other aspects related to anesthetic care of AA patients
of spinal hematoma following epidural and spinal anesthesia deserve mention, since neuraxial techniques may be contrain-
is estimated to be 1:168,000 and 1:200,000, respectively.83,84 dicated. The anesthesia-care provider must be ready to use
In a review of 61 case reports of spinal hematoma after general anesthesia if the patient is to undergo cesarean sec-
neuraxial anesthesia between 1906 and 1984, Vandermeulen tion. Postoperative pain relief with a multimodal approach is
et al found that 68% of the cases were receiving heparin, and reasonable to facilitate early ambulation and breastfeeding.90
only four cases had thrombocytopenia, with one also being on Adequate pain management also reduces systemic oxygen
heparin and another being a chronic alcoholic. This review consumption, which is critical in the context of anemia.
also suggests that the risks of placing and removing epidural Additionally, inadequate postpartum pain control has been
catheters are equivalent.85 A retrospective chart review of associated with chronic pain and depression.91,92 Infection is a
nonpreeclamptic thrombocytopenia (,100×109/L) reported risk in AA patients, especially when neutropenia is present.93
47 patients, of whom 91.9% received regional anesthesia Precautions must be taken when performing such procedures
with platelet counts of 80–99×109/L and 48.1% with counts as venous access, tracheal intubation, and neuraxial blocks.
of 50–79×109/L, with no neurologic complications.86 Another Antibiotic administration before surgical incision is also part
study retrospectively evaluated safety of lumbar puncture in of the anesthesiologist’s responsibilities.94
children with acute lymphoblastic leukemia and thrombo- Systemic analgesia can be obtained with inhaled nitrous
cytopenia. The authors found that 29 patients with platelet oxide and intravenous (IV) opioids. Nitrous oxide adminis-
counts ,100×109/L, 170 with counts of 11–20×109/L, and 742 tration requires special equipment and patient cooperation.
with counts of 21–50×109/L underwent the procedure with no Few good-quality studies have addressed labor analgesia
serious complications. The 95% CI for serious complications with nitrous oxide, and research on effectiveness, satisfac-
when platelet counts were 20×109/L or less was 0–1.75%, and tion, and adverse effects is still needed.95 Systemic opioid
was 0–0.37% when the count was 50×109/L or less.87 labor analgesia is widely used around the world; however,
Overall, in light of the heterogeneous etiology of the use of narcotics in the obstetric setting has been associ-
thrombocytopenia in retrospective studies and case reports ated with significant side effects and inferior efficacy when
published to date, and recognizing that some patients might compared with neuraxial techniques. Remifentanil has been
have low platelet counts, but normal or even enhanced used for labor analgesia based on its short context-sensitive
platelet function, no recommendation regarding a specific half-life. The use of IV patient-controlled analgesia (PCA)
threshold of platelet count can be made, and experience of with remifentanil has been associated with hypoxic episodes,
anesthesiologists as well as institutional protocols must be as well as cardiac and respiratory arrest during labor.96
considered to make the decision to perform a neuraxial block IV PCA remifentanil warrants one-to-one nursing and
in a patient with AA. continuous monitoring of oxygenation, capnography, and
The role of the anesthesiologist in management of anemic patient responsiveness. IV PCA with fentanyl is another
parturients with AA is critical, and encompasses preoperative alternative for labor analgesia. Miyakoshi et al compared
assessment, determining need for transfusion, and devising IV PCA fentanyl with no analgesia, showing longer labor in
strategies to optimize oxygen consumption:demand ratio. the fentanyl group with no difference in neonatal outcomes
The preoperative assessment must include evaluation of and patient satisfaction of 72%.97 Fentanyl is a safe and
the degree of anemia and determination of signs of cardio- clinically acceptable analgesic option in labor, especially in
vascular compensatory response and compromised organ nulliparous women.98
perfusion. The decision to transfuse should not be based on
a “trigger” hemoglobin level, but on evidence of poor organ Conclusion
perfusion, hemodynamic instability despite fluid resuscita- AA is a complex disorder that warrants a comprehensive
tion, coexisting diseases, presence of continuing blood loss, multidisciplinary-team approach, in order to devise an
and fetal well-being.88 Risks of blood transfusions must be obstetric, hematological, anesthetic, and neonatal plan and
balanced against benefits of increasing oxygen delivery anticipate complications during the peripartum period.
in the peripartum setting.89 Regarding the use of platelet Conservative transfusion strategies are necessary to avoid
transfusions prior to epidural analgesia/anesthesia, there complications related to alloimmunization. Close monitoring

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Dovepress Aplastic anemia during pregnancy

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