Severe neonatal autoimmune thrombocytopenia secondary to maternal Evans syndrome

Abstract

Evans syndrome is a rare and chronic autoimmune disease seen in both paediatric and adult age groups. We present a case of severe thrombocytopenia in a neonate born to a mother with Evans syndrome who showed no response to intravenous immunoglobulin therapy initially and improved after treatment with methylprednisolone.

Background

Thrombocytopenia is present in 1%–5% of newborns at birth, and severe thrombocytopenia (platelets < 50 × 10⁹ /L) occurs in 0.1%–0.5% of newborns at birth.¹ Thrombocytopenia as an outcome for a neonate born to a mother with Evans syndrome is rare, and severe thrombocytopenia has never been described. There is also no published consensus on the optimal management of these babies. We present the first published case of severe thrombocytopenia in a neonate born to a mother with Evans syndrome. We also review the current literature on the follow-up and management of these babies.

Case presentation

We describe a baby girl, delivered late preterm (35+4 weeks), the second-born child to non-consanguineous parents. Her birth weight was 1.4 kg, less than the 10th centile for gestational age, and she did not require resuscitation at birth. The intrauterine growth restriction was attributed to the chronic maternal illness. The baby was not dysmorphic. Placental weight was 350 g and was normal on gross examination. Placental histopathology was not done.

Mother had regular antenatal check-ups at another hospital and was referred at 33 weeks to our hospital in view of rash, gum bleeding, haematuria and melena. On evaluation, the mother was found to have anaemia and thrombocytopenia.

Autoimmune workup of the mother showed low complements (C3, C4) with ANA, dsDNA and anti-SSA positivity and direct Coombs test (DCT) positivity (3+). She underwent bone marrow biopsy which showed peripheral destruction of platelets, consistent with findings of immune thrombocytopenia. A diagnosis of Evans syndrome (autoimmune haemolytic anaemia (AIHA) with immune thrombocytopenia (ITP) and a positive Coombs test) with systemic lupus erythematosus (SLE) was made (EULAR/ACR 2019 classification).

Prior to delivery, the mother had severe thrombocytopenia, with lowest platelet value prior to delivery of 4×10⁹ /L, and was admitted for the management of the same. She was treated with dexamethasone pulse therapy for 5 days and 2 g/kg of intravenous immunoglobulin (IVIG) over 5 days but did not show any improvement. Two days after the IVIG infusion, in view of variable deceleration seen on the cardiotocograph, an emergency caesarean section was done. During the surgery, the mother received multiple platelets, packed cell and cryoprecipitate transfusions.

At birth, the baby was active and was transferred to the nursery in view of being preterm and very low birth weight. She did not have any bleeding manifestations on initial examination and was started on intravenous fluids as per nursery protocol.

Investigations

At birth (within 2 hours), the baby was found to have severe thrombocytopenia (8×10⁹ /L) which was confirmed by a citrated sample and a manual platelet count. The baby was treated with IVIG (2 g/kg, given in two divided doses 24 hours apart). A platelet count sent after the first dose showed no improvement (6×10⁹ /L). On day 2, a left-sided grade 1 intraventricular haemorrhage (IVH) was detected on cranial ultrasound, and the baby received a platelet-rich concentrate transfusion. Following this, there was a transient, brief increase in platelet to 28×10⁹ /L. However, after the second dose of IVIG, serial platelet counts were <20×10⁹/L. The baby received an additional platelet-rich concentrate during this time in view of petechiae seen on the trunk. There was no progress in the IVH, and there were no other bleeding manifestations present. As there were no rise in platelet counts for 48 hours after completing the IVIG course, methylprednisolone was started at 1 mg/kg/day in two divided doses (from day 5 of life). Platelet counts rose from 13×10⁹ /L to 21×10⁹ /L after 48 hours of starting methylprednisolone. The dose of methylprednisolone was increased to 1.5 mg/kg/day in two divided doses. Further, platelet counts showed a rapid rise (figure 1).

Figure 1.

Trend in platelet counts, with interventions (timeline is not in linear scale).

Complete blood count done at birth showed haemoglobin of 13.4 g% with reticulocyte count of 3.26%. DCT was negative. The peripheral blood smear showed normal red cell structure, with few platelets without clumping. The haemoglobin values repeated did not show any further decrease. The liver function tests, electrolytes and thyroid profile were normal.

Treatment

The neonate required platelet transfusions on the first 3 days of life. IVIG was initiated on day 1 as two divided doses, given 24 hours apart. In view of the lack of expected response as evidenced by a lack of rise in platelet counts 48 hours after IVIG, methylprednisolone was initiated, following which platelets improved.

Neonatal outcome

Our neonate did not have evidence of mucosal haemorrhage or umbilical bleed at any time. The thrombocytopenia steadily improved from the third day of administration of methylprednisolone, and normalised (>150×10 ⁹ /L) on day 16 of life after two doses of IVIG and 5 days of methylprednisolone. The IVH did not show any sign of progression on repeat scans (done on day 3, 7 and 14), and the neurosonongram done at 4 weeks of life did not show signs of periventricular leucomalacia or hydrocephalus. The baby had adequate weight gain and was discharged after 32 days of hospital admission with last platelet count of 229×10⁹ /L and at 1.88 kg. The baby did not have any evidence of dermatologic, cardiac or hepatic abnormalities at birth or at review. The baby was reviewed 2 and 8 weeks after discharge and was growing well and gaining weight, with no evidence of thrombocytopenia or anaemia.

Maternal outcome

Postdelivery, the mother’s thrombocytopenia did not improve. She went on to require cyclosporine, intravenous methylprednisolone, repeat IVIG infusion, five doses of rituximab, multiple platelet transfusion, romiplostim and finally emergency splenectomy in view of refractory thrombocytopenia. Platelet counts continued to stay below 50×10⁹ /L. She had a cerebrovascular accident and deep vein thrombosis within a month after the delivery.

Discussion

Evans syndrome, first described in literature in 1951,² is rare and is characterised by simultaneous or sequential presence of a positive antiglobulin test, autoimmune haemolytic anaemia and immune thrombocytopenia. The true incidence is not well described. It is thought to represent up to 7% of AIHA and around 2% of ITP.³ Around half the cases of Evans syndrome are associated with another disorder, including lymphoproliferative disorders, common variable immunodeficiency and in this case, SLE.³

Neonatal auto immune thrombocytopenia occurs secondary to the transplacental passage of maternal antiplatelet IgG, leading to accelerated neonatal platelet destruction in an otherwise healthy newborn.⁴ The risk of severe thrombocytopenia (<20×10⁹ /L) ranges from 1% to 5%. The risk of severe bleeds leading to intracranial haemorrhages and death is typically less than 1%.⁵ Thrombocytopenia secondary to maternal SLE alone is well described and occurs secondary to the transplacental passage of anti-SSA/Ro antibodies. It is possible that the concomitant presence of antibodies secondary to SLE has contributed to the severity of the thrombocytopenia in the neonate.

Attempts have been made to correlate maternal presentation and history of Evans syndrome with neonatal outcomes. An antecedent history of splenectomy, or ITP refractory to splenectomy,^6–8 and a correlation between siblings regarding the occurrence and severity of thrombocytopenia⁸ and their nadir platelet counts have been found.⁹ While most studies did not show a significant association between maternal and platelet counts, a maternal platelet count less than 100×10⁹/L at delivery has shown a statistical trend for an association with the occurrence of autoimmune thrombocytopenia.⁸ Prior to delivery, the mother of the neonate we report had a platelet count of 4×10⁹ /L.

An incidence of Evans syndrome of 0.09 per 1000 births has been reported in a study done over a period of 5 years and 12 000 deliveries from a tertiary referral centre in south India.¹⁰ Out of the four cases of Evans syndrome in pregnancy, only one neonate had thrombocytopenia, which was asymptomatic and resolved without transfusions. A systematic review by Lefko et al¹¹ enumerates 14 pregnancies in women with Evans syndrome found in the literature until 2010. While the majority of the outcomes were normal, a neonate born to a mother on treatment for syphilis was a stillbirth at 35 weeks, diagnosed later to have a subdural haematoma. No details regarding platelet counts or presence of AIHA were available.¹² Letts et al¹³ described the outcomes of two pregnancies in a mother with Evans syndrome, one of which resulted in a stillbirth that showed evidence of erythroblastosis and autoimmune haemolysis and another that resulted in a normal healthy neonate with no complications. Another¹⁴ reported isoimmune haemolysis in a neonate at 2 months of age, which did not require treatment. There was no thrombocytopenia reported in this neonate at any time. Following this systematic review, a search for more recent reports revealed five other case reports, three of which described healthy babies with no complications.^15–17 The fourth reported the pregnancy ending with stillborn twins of 28 weeks gestation.¹⁸ The fifth reported a pregnancy complicated with severe pre-eclampsia and HELLP syndrome that resulted in a preterm small for gestational age neonate with persisting thrombocytopenia. No further details, however, were available regarding the degree of thrombocytopenia or the treatment that was required.¹⁹

Our neonate had a platelet count sent at birth with plans made to repeat it daily for the next 3–4 days, as platelet counts are usually expected to reach a nadir by day 2 to day 5 of life, coincident with the peak of reticulo-endothelial system activity.⁴ The severe thrombocytopenia at birth necessitated urgent intervention in our case with IVIG. IVIG at a dose of 1 g/kg/day on 2 consecutive days or 0.5 g/kg/day for 4 days⁴ is usually effective in raising the platelet count in 80% of cases. However, in the absence of response, or a delayed response, methylprednisolone at a dose of 1–2 mg/kg/day for 5 days is described to be successful in causing a twofold rise by the third day and a fourfold rise by the fifth day of treatment, similar to what was seen in our patient.²⁰

While the initial haemoglobin was 13.4 g%, there was no evidence of haemolysis during the initial nursery admission. At reviewat 2 and 8 weeks, there was no drop in platelets or haemoglobin.

Our new born had a grade 1 IVH at day 1 which persisted in the day 7 and day 14 scans and was asymptomatic and non-progressive for the same. An early neurosonogram to assess for the presence of an intracranial bleed is essential both to diagnose as well as to determine the possible management of the neonate and can guide transfusion practice.

This, to our knowledge, is the first case report of a neonate having severe thrombocytopenia secondary to maternal Evans syndrome. There are no specific recommendations for the management of these neonates. A platelet count at birth, with repeat platelet count over 3–4 days, monitoring for haemolysis and an early neurosonogram are vital. Repeat platelet counts at 2–3 weeks and a monitoring for evidence of haemolysis in the form of haemoglobin, reticulocyte count and peripheral smear are suggested at 8 weeks.

Learning points.

• Thrombocytopenia as an outcome for a neonate born to a mother with Evans syndrome is rare.

• A platelet count at birth, with repeat platelet count over 3–4 days, monitoring for haemolysis and an early neurosonogram are suggested.

• In the event of thrombocytopenia in the neonate, intravenous immunoglobulin therapy is usually effective in raising the platelet count. However, in the absence of response, or a delayed response, methylprednisolone is described to be successful. Discussion with a paediatric haematologist to optimise treatment is suggested.

• Repeat platelet counts at 2–3 weeks and a monitoring for evidence of haemolysis in the form of haemoglobin, reticulocyte count and peripheral smear suggested at 8 weeks.

Ethics statements

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Consent obtained from parent(s)/guardian(s).