Abstract
Dear Editor,
Aplastic anemia is a rare disorder, both in the general population (2–6/million) and pregnancy. Immune destruction of the hematopoietic stem-cell compartment is the main feature of its pathogenesis, resulting in secondary decrease in the number of peripheral blood cell counts. Depending on the type of affected blood cells, it may present as a severe infection and other symptoms of altered immune status (white blood cells), tiredness and hypoxia (erythrocytes), hemorrhage, and petechiae (platelets). It necessitates an extensive diagnostic process, which in pregnancy should incorporate its severe complications, like pre-eclampsia, HELLP syndrome, acute fatty liver of pregnancy, and complications of viral infections. The diagnosis is usually established after bone marrow examination, which most commonly reveals hypocellular or “empty” marrow. Although not easily identifiable, the causative factors of aplastic anemia are thought to include exposure to chemicals, medical drugs, viral infections, and autoimmune disorders. It is assumed that pregnancy is one of the conditions of altered immune response that may potentially facilitate disease onset. Bone marrow transplant is an established first-line treatment in many cases, but is not feasible in pregnancy due to possible fetal complications. Immunosuppressive therapy and supportive blood and blood products transfusions are typically offered to pregnant women with diagnosed aplastic anemia.
Jehovah’s Witnesses, in support of their interpretation of the Bible, refuse to accept treatment with blood and blood products. Management of hematologic disorders in Jehovah’s Witnesses, especially those relying on supportive therapy with transfusions, presents an unusual medical and ethical challenge, as it is difficult to respect the patient’s will that is against all medical knowledge, established guidelines, and increases the risk of fatal complications.
A 37-year-old patient (gravida 2, para 0—the first pregnancy ended with spontaneous abortion at 6 weeks of gestation), presented with deteriorating platelet count, which was first noted at 14 weeks of gestation. At 21 weeks, the platelet count was 54 K/uL. Hematologic review at that point suggested corticosteroid therapy with prednisone (0.5 mg/kg), which was introduced and resulted in transient improvement in the platelet count (100 K/uL). At 25 weeks, the patient was admitted to hospital due to subsequent platelet drop to 54 K/uL. A Jehovah’s Witness, the patient runs an eco-farm in a rural area with her husband and denied any exposure to toxic chemicals, herbicides, and pesticides. She had no history of infection during her pregnancy and was not taking any medication. Her blood pressure was normal. On admission, the patient had no signs of purpura, and only solitary petechiae on the oral mucosa and lower leg bruises were noted throughout her hospital stay. Her blood group was A negative. Infectious origin of thrombocytopenia was excluded, as well as vitamin B6, B12, and folate deficiency. Liver function tests, electrolytes, and thyroid function tests were normal. Autoantibody screen was negative. Regular steroid therapy was implemented, at the initial dose of 0.5 mg of prednisone/kg and increased to 1.0 mg/kg as the observed increase in platelets to 90 K/uL was not sustained. A diabetic diet was introduced due to prolonged steroid administration to assure appropriate glycemic control. An additional course of steroids and tocolysis was implemented at 28 weeks due to symptoms of imminent preterm labor (2 doses of 12 mg of betametazone daily and nifedipine 10 mg every 6 h for 72 h), resulting in resolution of uterine contractions. In the days to come, herpetic lesions of the left upper eyelid occurred, which was the first and only episode during this pregnancy, for which the routine management with acyclovir was successfully implemented. Methyldopa at a dose of 1 g was started in order to control the blood pressure, as well as potassium supplements. At this time, vitamin B12 deficiency was noted and its supplementation was initiated (1000 I.U. i.m. daily for 10 days, followed by 1000 I.U. weekly). Blood film has shown an increased size of erythrocytes (MCV 116 fl) and elevated LDH (579 U/L). Since the platelet count was continuously low, the patient was referred to a tertiary hematologic center. There, the diagnostic process revealed no antiplatelet antibody, anti-HLA antibody, and no platelet-associated immunoglobulin (PAIg). Immature platelet fraction (IPF) was 2.5%. Fine-needle bone marrow biopsy and trephine biopsy were carried out. At 32 weeks, a significant toothache was reported, which was treated with analgesics (paracetamol) and antibiotic (clindamicin), as dental intervention was declined due to low platelets (47–65 K/uL). After a few days it resolved.
At 33 weeks, since the platelet count continued to decrease (22 K/uL), following hematologic suggestions, an intravenous immunoglobulin (IVIG) was started, with a total dose of 2 g/kg (0.4 g/kg daily for 5 days). Table 1 shows the dynamics of blood count changes.
The dynamics of blood count changes.
The result of trephine biopsy has shown a hypoplastic-aplastic marrow with 15% of occupied spaces, hypocellular erythroid and myeloid lines, and only solitary megakaryocytes. Aplastic anemia was diagnosed. According to the consultant hematologist, the patient had no chance of survival unless supportive therapy with multiple transfusions was implemented, which she repetitively declined in writing, which was witnessed by her husband and Jehovah’s Witnesses medical counselor.
Two days after hematologic review, the following signs of fetal distress were noted: abnormal tocography with minimal fetal heart rate (FHR) variability and occasional bradycardia and altered umbilical artery flow patterns with absent diastolic flow. Urgent Cesarean section was ordered. Thorough explanation of the magnitude of perioperative risk was given to the patient and her family, including the possibility of fatal complications that were likely to occur in the view of severe anemia, thrombocytopenia, and lack of consent for blood and blood products transfusion. Legal advice was sought and obtained, which confirmed patient’s right to decline a particular medical treatment, regardless of its effectiveness that had been proven beyond doubt. The surgery was started, with priority given to fetal wellbeing and little hope for good overall outcome.
A typical Cesarean section was performed and a female preterm neonate was delivered (2700 g/53 cm), in moderate condition (Apgar score 4/6/6). Monopolar cauterization was used to dissect skin and subcutaneous tissue, as well as the uterine muscle, to minimize the bleeding. An additional dose of oxytocin (5 I.U.), a dose of carbetocin (I.V.), prostaglandin E (I.V.), and misoprostol (p.r.) were administered due to inadequate uterine retraction. Tranexamic acid at the dose of 3.0 g and 2.0 g of cyclonamine were also given to reduce the risk of potential bleeding. The site of the uterine incision was sprinkled with hemostatic chemical chitosan (deacetylchitin). Typical surgical wound closure followed. Blood loss was estimated at approximately 700 mL.
Amniotic fluid suction from the upper airway of the neonate and distension of the lungs (NEoPuff device) were required after the delivery, with subsequent nCPAP support, FiO2 0.3–0.4. Umbilical cord blood has shown a pH of 7.08 and BE of 9.9. Lactate was 94 mg%. Surfactant was administered and after 20 h no breathing or hemodynamic support was required. The neonatal full blood count was: WBC, 15.9 K/uL; RBC, 4.24 M/uL; HGB, 15.3 g/dL; HCT, 47.3%; MCV, 112 fl; and PLT, 167.0 K/uL.
On postoperative day 1, tranexamic acid and prophylactic antibiotics were continued, along with supplemental oxygen via facemask. Iron and vitamin B12 were supplemented and epoetin beta was started. The antibiotic was changed and suction dressing was applied due to delayed wound healing. Additionally, antifungal therapy was initiated. On day 9, after another hematologic review, danazol was started at a dose of 800 mg. Minimal and delayed improvement in the platelet count was observed, with subsequent increase in red cell count. Steroids were stopped.
On day 23 after Cesarean section, the patient was discharged in a reasonable condition and referred to a hematologist center, which she declined. The neonate was also discharged in good condition, with the body weight at 3170 g and the following full blood count parameters: WBC, 15.1 K/uL; RBC, 5.66 M/uL; HGB, 18.4 g/dL; HCT, 52.5%; MCV, 97.6 fl; and PLT, 499 K/uL. At the subsequent follow-up visits, a gradual and spontaneous return to normal blood count parameters was observed (Table 1). Nine months after the delivery, both the mother and her baby are in good health. The patient returned to her normal level of daily functioning.
Discussion
In this case, we decided to present the discussion in the form of the diagnostics process that had been undertaken. Detailed information regarding the patient and her management is presented to make you familiar with dilemmas we were forced to face on every step of the management process, when each decision results in the outcome that creates new challenges.
In this case, as of the beginning of the second trimester, some thrombocytopenia was noted, which was first recorded at 14 weeks. Observational studies have shown that the platelet count in approximately 12% of pregnancies may reduce to less than 150 K/uL in the third trimester, but not less than 110 K/uL, which is enough to assure adequate hemostasis. 1 Only 1% of pregnant women would develop thrombocytopenia necessitating further observation and diagnosis, which is less than 100 K/uL. 2 Thrombocytopenia may present as an isolated abnormality or accompany other pregnancy-related disorders. It might be caused by inefficient platelet formation, which in the vast majority of cases is the result of drug use, toxins, vitamin deficiency, other hematologic disorders, bone marrow fibrosis, or aplastic anemia. It might also stem from increased platelet destruction (such as in autoimmune disorders) or both inefficient production and accelerated wasting. Thrombocytopenia in pregnancy, which is usually diagnosed towards the end of gestation, resolves spontaneously after the delivery and results from reduction in platelet half-life and plasma dilution. The diagnosis is based on exclusion of other likely causes of low platelet count. The core of the management is to administer oral steroids, most commonly prednisone at a dose of 0.5–1.0 mg/kg, which usually results in moderate increase in the platelet count. If ineffective, IVIG is recommended, 0.4–2.0 g/kg for 1–5 days. Second-line options include anti-D immunoglobulin, azathioprine, and cyclosporin A, although the safety of the last two medications in pregnancy is not certain. Other available treatments, like mycophenolate mofetil, cytostatics, and androgens are contraindicated.2–4 There are limited data on the use of thrombopoietin receptor agonists, which enhance production of platelets and monoclonal antibodies. 5 A few cases of splenectomy were reported, performed in the second trimester only, as the risk is then lower. 6
In the case of our patient, steroids and supplements of microelements were introduced, while thorough diagnostic process excluded the most likely causes of thrombocytopenia. Due to poor therapeutic effect and significant anemia, the IVIG treatment was commenced while the results of bone marrow trephine biopsy were pending. Once reported, it revealed features consistent with aplastic anemia.
Various causes of secondary aplastic anemia are indicated, e.g. multiple medications, radiation, viruses, and pregnancy. In pregnancy, the link between this condition and aplastic anemia was suggested more on the basis that the blood counts tend to improve after delivery than the actual pathophysiologic studies. 7 Its prevalence is estimated at two cases per million in Europe and 2–3 times more in Asia, but there are no data on its prevalence in pregnancy. It may occur in pregnancy for the first time or relapse after previously successful treatment. 8 The pathomechanism of aplastic anemia is not well described, as well as the link between spontaneous improvements in blood counts after the delivery. The fact that it is thought to be related to autoimmune hepatitis, pregnancy, and the use of some drugs, supports its immunologic background. Nevertheless, it is worth mentioning that the first case of aplastic anemia was described in pregnancy. 9 Clinical findings are typical for anemia, which is accompanied by easy bruising and prolonged bleeding. Laboratory findings are typical for pancytopenia, although the lymphocyte count may be normal. Usual management of aplastic anemia in pregnancy relies on packed red cells and platelets transfusions.10–12 It follows the guidelines that suggest keeping the hemoglobin concentration within the reference range and platelet count above 20 K/uL, which should assure a great chance for normal development of the pregnancy and good neonatal outcome. 10 Cyclosporine is an option and monitoring of its blood concentration should assure no negative fetal consequences. 13 As the therapeutic effect of cyclosporine is seen after 6–12 weeks, it was not feasible to implement it the case of our patient. According to a hematologic opinion, the patient would not survive without blood products transfusions, but it was not possible to transfuse due to lack of patient consent. No hematologic suggestions as to other treatment options were available.
Fetal monitoring was then set as the priority, since no other options of established effectiveness were available for the mother. The obstetric team was instructed to deliver the baby should fetal wellbeing become jeopardized. A few days later, after ultrasound and cardiotocography showed signs of fetal distress, Cesarean section was performed. All necessary measures were undertaken in order to be prepared for the likely hemorrhage. A senior obstetrician was appointed to perform the surgery as serious perioperative complications were anticipated.
No improvement was noted immediately postpartum, as blood counts were worse than results from before the Cesarean section. The hematologist that reviewed the case at that point once again strongly recommended blood transfusion as the treatment of choice, which, once again, was declined. As no other options were available, treatment with epoetin alfa and danazol was subsequently started.
Human recombinant erythropoietin (EPO, HuREPO, rhEPO) was first developed in order to treat anemia in patients with renal failure, also in pregnancy.14,15 The use of EPO in pregnant women does not increase the risk when compared to non-pregnant women. Sackmann Massa and Palovskt have successfully used EPO in a pregnant woman with myelodysplastic syndrome. 16 Although EPO does not cross the placental barrier, it is not possible to prove its safety for the developing fetus. Thus, blood and blood products transfusions remain the first-line treatment in pregnant women with diagnosed aplastic anemia. 17
Danazol is a synthetic anabolic, which acts through the inhibition of IL-1 and TNF-alpha and is successfully used in the management of immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), systemic lupus erythematosus (SLE)-related pancytopenia, as well as pure red cell aplasia (PRCA). Its effectiveness in aplastic anemia was confirmed in a number of case reports. Stadtmauer et al. reported an increase in the platelet count after treatment with danazol in patients with myelodysplasia. It was suggested that this result may be due to a decrease in monocyte Fc receptors expression, and thus its slower immune-mediated destruction. 18 In a study by Chuhjo et al., danazol was also indicated to have a positive effect on erythroid cell line in aplastic anemia, acting by enhanced erythropoiesis rather than improvement in red cell survival. 19
In our patient, after gradual improvement in blood counts was noted, the tendency towards normal values continued and she was discharged. After 9 months both the patient and the baby are in good health.
Aplastic anemia is a severe disorder that may also occur in pregnancy. The level of threat it presents to the pregnant woman and the developing fetus depends on the degree of bone marrow failure and, equally important, on treatment options that are at our disposal. The latter may be limited by lack of patient consent. And although the responsibility of medical professionals is to convince the patients to accept the treatment that is known to be effective, it is also ethically questionable to challenge their religious beliefs and rules they consciously decide to obey. To the best of our knowledge, our case has been the first to report a pregnancy where laboratory and pathology findings were indicative of severe and life-threatening aplastic anemia that ended with good neonatal outcome, without blood and blood products transfusions.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.