Management of aplastic anaemia in pregnancy in a resource poor centre

Aplastic anaemia occurring in pregnancy is a rare event with life threatening challenges for both mother and child. We present a successful fetomaternal outcome despite the challenges in the management of this rare condition in a tertiary but resource poor centre. This is case of a 37 year old Nigerian woman G6P0+5managed with repeated blood transfusions from 28 weeks of gestation for bone marrow biopsy confirmed aplastic anaemia following presentation with weakness and gingival bleeds. She had a cesarean section at 37 weeks for pre-eclampsia and oligohydraminous with good feto-maternal outcome. She was managed entirely with fresh whole blood and received 21 units. Aplastic Anaemia in Pregnancy is a rare event with poor feto maternal prognosis. Successful management is possible with good multi-disciplinary approach and availability of supportive comprehensive obstetric care.


Introduction
Aplastic anaemia (AA) is a rare bone marrow (BM) failure syndrome which occurs even more rarely in pregnancy. In AA, there is failure of production of haematopoietic stem cells and precursor cells associated with aplasia and fatty replacement of the marrow.
Subsequently, there is depression of all the cell lines with attendant anaemia, neutropoenia and thrombocytopoenia (pancytopoenia) [1].
Patients with AA are predisposed to recurrent infections and may have a bleeding diathesis [1][2][3]. Its' management poses a lot of challenges to the obstetrician due to the rarity and poor prognosis of fetal and maternal outcome. Good multidisciplinary collaboration is key for successful outcome. There exist little documented cases or study of aplastic anaemia in pregnancy in Nigeria. This is the first documented case of aplastic anaemia in pregnancy in University of Port Harcourt Teaching hospital, in South-South Nigeria. We present the case, our challenges and management carried out to achieve a successful feto-maternal outcome.

Patient and observation
Mrs KA was a 37 year old Gravida 6 Para 0 +5 / (G6P0 +5 / ), who presented to the University of Port Harcourt Teaching Hospital (UPTH) on the 28th October , 2015 at 28 weeks gestation with history of weakness and occasional gingival bleeding of 2 months duration. She had never had these complaints prior to pregnancy.
She had no history of jaundice, haematuria, bleeding from any other orifice or spontaneous bruising. There was no familial history of similar experience. She admitted taking some local oral herbal medications for secondary infertility of 3 years duration. She took this herbal medication for about 18 months and stopped one year before pregnancy was achieved spontaneously. The symptoms of weakness and gingival bleeding started at about 20 weeks of gestation. Prior to presentation at UPTH, she had received 5 units of whole blood transfusion in a private clinic over a period of four weeks. She was married to a 39 year old unemployed graduate and most of the financial aspect of her care was handled by her siblings.
She came on self referral following her elder sisters' insistence. On examination at presentation, she was markedly pale, afebrile, anicteric and had no pedal edema. Her blood pressure was 120/70mmHg and pulse rate was 90 beats per minute. Her abdomen was gravidly enlarged with a symphisio-fundal height of 29cm and a singleton active fetus. She was reviewed with the haematology team, admitted, investigations commenced and placed on double dose haematinics and antimalarials. Her investigations at presentation revealed: low Haemoglobin (Hb) of 7g/dl, normal White Blood Cell (WBC) Count and Absolute Neutrophil Count (ANC) of 5.1 X10 9 //L and 2.6 X10 9 //L respectively with low Platelet Count of 07 X10 9 //L and a low Absolute Reticulocyte Count (ARC) 21 X 10 9 //L. Significant peripheral blood film findings were a normochromic, normocytic anaemia with severe thrombocytopoenia.
There were no blasts neither was there dysplasia. Her blood group was B+, Hb genotype was HbAA and direct antiglobulin test was negative. Screening for HIV, hepatitis B and C were all negative. Her urinalysis was normal. Stool analysis showed no abnormality. gingival bleeding reduced and the petechial haemorrhages resolved.
She was discharged home on the 10 th / day postpartum following patient and relatives' complaints of financial and psychological issues with continuous admission. Her Hb was 14.7g/dl, WBC 4.0 X10 9 //L, ANC 1.9 X10 9 //L while platelet count was 8 X10 9 //L. A repeat bone marrow biopsy was not done. She was to continue with weekly outpatient appointment to the haematology clinic. She however defaulted for eight weeks. She was seen thereafter and is presently on cyclosporine and encouraged to continue follow-up.

Discussion
Aplastic anaemia is rare in pregnancy. It is caused by destruction of pluripotent stem cells in the bone marrow [1][2][3]. It has an annual incidence of 2-6/million, with the incidence higher in Asia about 2-3 fold than Europe [3]. Aplastic anaemia may be congenital or acquired. Acquired AA may be associated with paroxysmal nocturnal haemoglobinuria (PNH). Autoimmunity, viruses, drugs, chemicals, radiation or pregnancy, however acquired AA is most often idiopathic in up to 80% of cases [1,2,4]. The exact relationship between AA and pregnancy is unclear. In some patients, preexisting AA is exacerbated by pregnancy and marrow function improved on termination of pregnancy [4]. Pregnancy on itself has been said to be a trigger factor as termination of pregnancy [4].
Some cases develop AA during pregnancy and it reoccurs in subsequent pregnancies [4]. termination of pregnancy in some patients led to remission of the disease in an otherwise healthy women [5]. Our patient was otherwise healthy until she became pregnant. However she took some local oral herbal medications whose chemical component cannot be ascertained. Clinically, patients with aplastic anaemia present with weakness, easy fatigueability, recurrent infections, mucosal bleeds and skin haemorrhages such as petechiae purpura and ecchymoses [1,2,6,7].
Our patient had these symptoms of anaemia, bleeding gums, purpura and petechiae haemorrhages. Diagnosis of AA requires BM hypocellularity with at least 2 of thr following : HB < 10G/DL, ANC <1.5 X 10 9 //L, platelet count <50 x 10 9 //L and absolute reticulocyte count <60 x 10 9 //L [4]. In addition to this , there should be no abnormal cells, dysplasia or marrow fibrosis [6,8- [4]. Following delivery, cyclosporine was administered for this patient. Androgens were used before the advent of immunotherapy in AA but its use may cause the virilization of both the mother and female fetuses [10]. The efficacy of corticosteroids or granulocyte colony-stimulating factor is also equivocal [2,3,6,10]. The use of high dose corticosteroid or granulocyte colony stimulating factor is also equivocal while majority of cases do not respond to the use of growth factors [6,7,10,12] .Overall, current evidence does not favor the routine use of any drug therapy in the treatment of pregnancy-associated aplastic anemia [11]. However, when detected in early pregnancy (first trimester), most clinicians would offer a termination of pregnancy to enable definitive treatment to be initiated [3,[8][9][10].
Thus supportive therapy with serial red cell and platelet transfusions, with the use of prophylactic antimicrobials in neutropoenic patients is key [4]. The aim of supportive therapy is to carry pregnancy till term and delivery taken. Constraints in serial platelets transfusion for this patient were unavoidable due to the inability to provide platelet concentrate in this center. Blood donation and transfusion especially of blood components in this environment is less than optimal compared to developed countries.
An attempt to transfer her to the nearest center in another region where this was available was rejected by the patient due to availability of family and financial support. This is a norm observed in this environment. All units of blood were donated by relatives who had their platelet count assessed in addition to routine predonation screening. All donors with platelet counts < 280 x 10 9 /L were rejected. In resource poor setting where platelet concentrates are unavailable, the use of fresh whole blood which is blood that is not refrigerated after collection and is transfused within an hour of  [5,6,9,10] .While a few cases go into complete remission estimated at about 25-30%, [11] follow up of these patients is vital as some of them relapse, which in pregnancy has been estimated at about 33% [9,13]. Mrs KA is still on follow up and should remain on follow up in particularly in her subsequent pregnancies.

Conclusion
Aplastic anaemia in pregnancy is a rare entity. It poses a lot of challenges to the obstetrician, haematologist and family. Supportive therapy with serial blood transfusion is key to successful pregnancy.
Even in resource poor setting, fresh whole blood transfusions and joint management of AA in pregnancy is accompanied with satisfactory feto maternal outcomes.

Competing interests
The authors declare no competing interest.