Management of Evans’ Syndrome in Pregnancy: A Case Report and a Narrative Review

Abstract

Background/Objectives: Evans’ syndrome (ES) is a rare autoimmune disorder characterized by the simultaneous or sequential onset of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). Given its rarity, available data concerning the clinical course and optimal management in pregnancy are limited. Methods: We present the case of a 32-year-old woman who experienced ES during her first pregnancy. She had been previously diagnosed with childhood-onset SLE at the age of 14 but had been in treatment-free remission since the age of 24. The treatment of both AIHA and ITP included intravenous immunoglobulins, cyclosporine-A, high dosage oral corticosteroids, and, in the second trimester, rituximab. The delivery was planned at 34 + 6 weeks of gestation (GW); no immunological alterations or infectious complications were detected in the newborn. The post-delivery period was uncomplicated, and the mother was discharged with a normal blood count. A narrative review of available ES cases during pregnancy is also presented. Results: A total of 16 patients with ES in pregnancy were reported, including the one we described. None of them developed major bleedings during gestation, while a case of abruptio placentae with delayed postpartum hemorrhage occurred. ITP was difficult to treat in 4/16 women after delivery; 4/16 patients also developed gestational hypertensive disorders. Perinatal outcomes include 13/17 healthy newborns and 4/17 stillbirths (2 of them were twins), of which 1 was due to fetal AIHA. Gestational age at birth was before 37 GW in 8/17. In 15/16 women, ES resolved after delivery. Conclusions: The occurrence of ES during pregnancy has been rarely reported; it constitutes a clinical challenge due to the need for multiple treatments, including conventional immunosuppressants and/or biologic drugs as steroid-sparing agents. After delivery, ES appeared to be less resistant to treatment than it was during pregnancy.

1. Introduction

Evans’ syndrome (ES) is a rare autoimmune disorder characterized by the simultaneous or sequential occurrence of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) caused by co-existing, but serologically distinct, autoantibodies against platelets (PLT) and red blood cells (RBC) [1].

Due to the rarity of ES, little is known about its incidence in pregnancy [2,3,4,5,6,7,8,9,10,11,12,13,14,15]. The management depends on the severity of the cytopenia, but during pregnancy, it leads to significant challenges due to the lack of specific guidelines [16,17] and to concerns about potential adverse effects of medications [10]. Possible strategies include corticosteroids (GC), intravenous immunoglobulin (IVIG), azathioprine, and splenectomy or plasmapheresis in refractory cases. According to current guidelines, rituximab (RTX) may be considered in cases resistant to conventional treatment [18].

To the best of our knowledge, we present the first case of ES reactivation during pregnancy that, despite the treatment with IVIG, cyclosporine-A (CyA), and high-dose GC, also required RTX administration in the second trimester.

2. Case Report

In early February 2023, a 32-year-old woman was admitted to a local hospital because of severe anemia (Hb 7.9 g/dL) and moderate thrombocytopenia (PLT 56.000/mm³); she was pregnant at 6 + 5 weeks of gestation (GW). No significant bleeding events occurred, except for non-traumatic bleeding gums. Her medical history displayed a diagnosis of juvenile systemic lupus erythematosus (SLE) at 14 years of age that was made in another hospital, based on the findings of AIHA with a persistently positive direct antiglobulin test (DAT), mild leucopenia, antinuclear antibody (ANA), anti-double strand DNA antibody (anti-dsDNA), and mild complement consumption. Extractable nuclear antigen (anti-ENA) and antiphospholipid antibodies (aPL) were negative. No comorbidities or family history of autoimmune diseases were detected. She was treated with corticosteroids (GC), and then with hydroxychloroquine (HCQ), which was discontinued after 10 years due to the detection of a retinal defect. The patient was lost to follow-up because of treatment-free sustained remission. Since then, only occasional blood tests were performed. Six months before conception, a blood test was performed showing mild thrombocytopenia (PLT 98.000/mm³) and anemia (hemoglobin (Hb) 11.3 g/dL, MCV 104 fL, Ht 34.6%); no further investigations were performed. Her first spontaneous singleton pregnancy started in December 2022 without a preconception counselling regarding her previously diagnosed autoimmune disease.

During the hospitalization in February 2023, she was diagnosed with ES based on the association of ITP and AIHA (positive DAT, decrease in haptoglobin, and increase in lactate dehydrogenase) in the absence of other symptoms or signs of systemic autoimmune disease. During hospitalization, immunological tests (ANA, anti-ENA, anti-dsDNA, and rheumatoid factor) were negative, while decreased levels of complement components were detected (C3 60 mg/dL (normal values: 79–152 mg/dL) and C4 11 mg/dL (normal values: 16–38 mg/dL)). ADAMTS13 levels were normal. Anticardiolipin, anti-b2-glycoprotein I antibodies, and anti-prothrombin (IgG, IgA, and IgM) were all negative in ELISA tests. Due to persistent lupus anticoagulant (LA) positivity by silica clotting time and dilute Russell’s viper venom time, low-dose acetylsalicylic acid (LDA) and low-molecular-weight heparin (LMWH) at prophylactic dosage 4000 IU as primary prophylaxis of aPL-mediated fetal and maternal adverse outcomes were started at 11 GW once PLT values were above 50.000/mm³. Treatment with 1 mg/kg/day oral prednisone (PDN) (50 mg/day) was started, but because of a partial response, the patient required a blood transfusion with 2 RBC units, IVIG 2 g/kg in 2 days, and CyA 2 mg/kg/day (100 mg/day).

Due to persistent thrombocytopenia (PLT 37.000/mm³) and anemia (Hb 7.7 g/dL), at 10 + 6 GW she was transferred to our hospital, where a multidisciplinary team (rheumatologist, hematologist, obstetrician, and neonatologist) were involved in her management. Given the partial response of AIHA and ITP to treatment, and the need to reduce GC because of their potential side effects on maternal–fetal outcomes, CyA was increased up to 4 mg/kg/day. The patient was also treated with another three cycles of IVIG (2 g/kg in 5 days) and transfusions with 2 RBC units, 2 PLT units, and a PLT-rich plasma unit. Moreover, the PLT count showed no benefit after switching from oral PDN to endovenous dexamethasone (DEX) 40 mg for 4 days. Because of the lack of improvement despite this multitarget therapy, RTX was introduced following the ITP protocol (375 mg/m²/week for 4 weeks), combined with DEX 40 mg the day of each infusion. Prior to starting RTX, infectious and lymphoproliferative diseases were ruled out. Biosimilar RTX was started at 15 + 4 GW. Due to its slow onset of action, the patient required a fourth cycle of IVIG (30 g/day in 5 days) in association with 2 PLT units and a PLT-rich plasma unit after the second dose of RTX. Furthermore, after the third dose of RTX at 18 GW, a sepsis by granulicatella adiacens was identified and treated with daptomycin 8 mg/kg/day (as empirical therapy, later confirmed by the antibiogram) and a reduction in the CyA dosage (2 mg/kg/day). The patient also needed 2 RBC units and a fifth cycle of IVIG (2 g/kg in 3 days) due to persistent cytopenia (PLT 38.000/mm³ and Hb 8 g/dL). Following the resolution of sepsis, the patient received the fourth and last dose of RTX. Meanwhile, the patient underwent ophthalmologic investigations, which did not show any contraindication to HCQ; this medication was started at the dose of 200 mg every other day with 400 mg at 19 GW.

During hospitalization, the fetus was closely monitored. At 19 + 5 GW, the fetal anatomy appeared to be normal at ultrasound evaluation, and subsequent monthly fetal growth assessment was maintained within normal ranges. Doppler evaluation of the fetal middle cerebral artery, ductus venosus, and the umbilical artery, as well as the maternal uterine arteries, showed normal blood flow patterns. No signs of fetal intracranial hemorrhage were detected during the sonographic follow-up. Thanks to the improvement in the PLT count (97.000/mm³), the patient was discharged home at 21 + 3 GW after 15 weeks of hospitalization. At 31 GW, because of a new flare of ITP (PLT 60.000/mm³), she was readmitted to our hospital for the sixth cycle of IVIG (2 g/kg in 3 days) (Figure 1).

Due to the difficulty to control ITP and the risk of preterm labor, LDA was stopped, and antenatal GC for the induction of fetal lung maturity (DEX 40 mg/day for 4 days) was started. DEX dosage was primarily guided by the hematological condition. At 34 + 6 GW, the maternal PLT value dropped down again to 52,000/mm³, and a fetal ultrasound scan at 34 + 5 GW revealed intrauterine growth retardation (abdominal circumference at 4th percentile and estimated fetal weight at 7th percentile) without maternal and fetal Doppler abnormalities. As a consequence of the global medical status, the day after (34 + 6 GW), the patient underwent an elective caesarean section (CS) under inhalation general anesthesia after receiving a transfusion with 1 PLT unit. Her blood loss was estimated at 451 cc.

A healthy late-preterm baby girl was born, weighing 1800 g (6th percentile according to INTERGROWTH-21st tables [19]), 42 cm long (3rd percentile), and with a head circumference of 30 cm (10th percentile). Apgar scores were 6 and 8 at 1 and 5 min, respectively. Due to preterm delivery, low birth weight, and exposure to multiple immunosuppressants in utero, the newborn was admitted to the neonatal intensive care unit. The baby required non-invasive ventilation due to respiratory distress connected to prematurity, but it was discontinued after the first day because of rapid improvement in respiratory function. Her full blood count was normal, and her bilirubin levels were always below the treatment threshold. Minimal enteral feeding was started on her first day of life, and on day 5, she was on full enteral feeding, taking formula milk by bottle. Cranial ultrasound on the 1st and 8th day of life showed no signs of intracranial hemorrhage. Newborn metabolic screening, hearing screening, and red reflex examination were normal. Her lymphocyte immunophenotyping showed no abnormalities (

Table 1. Newborn lymphocyte immunophenotype detected on umbilical cord blood.

Lymphocyte	Value (/mm3)	Normal Values for Newborns (/mm3) [20]	Value (%)	Normal Values for Newborns (%) [19]
CD3+	1926	600–5000	74.8	28–76
CD4+	1333	400–3500	51.8	17–52
CD8+	574	200–1900	21.2	10–41
CD19+	342	40–1100	13.3	5–22
CD56+ CD16+	296	100–1900	11.5	6–58
HLA DR+			13.7%	1–6

Comment: All the lymphocyte subpopulations are normally distributed, compatible to the age of the patient; however, in fetal exposure to rituximab, the immunophenotype showed no alteration in the lymphocyte B subpopulation.

). She was discharged home in good clinical condition on day 10 at 36 weeks and 1 day gestational age, with a weight of 1960 g (3rd-10th percentile). She was followed-up in the Neonatology out-patient clinic, displaying regular growth. The infant received vaccinations against rotavirus, tetanus, whooping cough, poliomyelitis, hepatitis virus B, and haemophilus influenzae, according to national recommendations. The postpartum period was also uneventful for the mother, with an average PLT count of 110.000/mm³ and Hb 13 g/dL. She received 6 weeks of thromboprophylaxis with LMWH 4000 IU/day because of LA positivity, and she did not breastfeed due to her own choice. At the evaluation at 3 months after delivery, she was on HCQ 4 mg/kg/day and CyA 2.5 mg/kg/day. Her PLT count was 115.000/mm³ and Hb was 13.3 g/dL, while anti-dsDNA was negative and C3 and C4 were within normal levels.

3. Narrative Review

To the best of our knowledge, 15 case reports of women with ES during pregnancy were reported up to June 2024 [2,3,4,5,6,7,8,9,10,11,12,13,14,15]. Our retrospective research was performed across PubMed and Google Scholar databases using “Evans’ Syndrome” and “pregnancy” as keywords. One of the published reports is a systematic review of the available literature, including 10 case reports [10].

Table 2. Details of the 16 case reports of patients with occurrence of ES during pregnancy (either disease onset or disease flare).

Clinical Case	ES Onset (Age of the Patient, Years), Temporal Relationship with Pregnancy)	Obstetric History	Comorbidities	Clinical Manifestations in Pregnancy	Laboratory Test	Treatment During Pregnancy	GW at Delivery and Type	Pregnancy Complications	Fetal Outcome	Maternal Follow-Up
Silverstein (1966) [2]	18, flare at 20 in pregnancy (8 GW)	Primigravida	NA	Asymptomatic	Hb 12.7 g/dL PLT 59 × 109/mm3 DAT+	Prednisolone (15 mg/day), hydrocortisone 200 mg, and RBC unit before delivery	NA Vaginal spontaneous	Vaginal hematoma	Healthy newborn (2800 g)	No ES flare, prednisone 5–15 mg/day
Letts (1968) [3]	6, flare at 19 in pregnancy (28 GW)	Primigravida	NA	Jaundice	Hb 8 g/dL PLT normal value DAT+ Autoimmunity: -	NA	32 Vaginal induced	-	Erythroblastic stillbirth	No ES flare, prednisone 1 year later: 2nd pregnancy without complications
Passi (1997) [4]	19, in pregnancy (28 GW)	NA	NA	Epistaxis, hematuria	Hb 7.7 g/dL PLT 36 × 109/mm3 DAT+ (IgG–C3)	Prednisolone (60 mg/day), anti-D	37 NA	-	Healthy boy (2600 g), hemolytic anemia 2 months after delivery with spontaneous remission	No ES flare
Julius (1997) [5]	28, in pregnancy (28 GW)	3 previous pregnancies	NA	Epistaxis, petechiae	Hb 4.8 g/dL PLT 7 × 109/mm3 DAT+ (IgG–C3d) Anti-PLT-Ab + ANA 1:320	Prednisolone (80–100 mg IV), immunoabsorption	39 Vaginal spontaneous	-	Healthy newborn	No ES flare
Sherke (2001) [6]	22, in pregnancy (12 GW)	1 previous CS delivery with hemorrhage, 1 previous spontaneous abortion (2nd trimester)	NA	Epistaxis, bleeding gums, melena	Hb 6 g/dL PLT 17 × 109/mm3 DAT+ Autoimmunity: -	RBC units, PLT units, prednisolone (1 mg/kg/day), IVIG, splenectomy at 22 GW	36 CS	-	Healthy	No ES flare
Tuncer (2001) [7]	26, in pregnancy (20 GW)	Primigravida	Concomitant Glanzmann-like PLT disfunction	Asymptomatic	Hb 11.4g/dL PLT 49 × 109/mm3 DAT+ Autoimmunity: -	Metilprednisolone (1 mg/kg/day), PLT units	34 Vaginal spontaneous	Concomitant gonococcal infection treated with penicillin G and ceftriaxone. Abruptio placentae and delayed postpartum hemorrhage managed with tranexamic acid, transfusion of 3 RBC units, and methylergonovine	Premature boy (2300 g)	No ES flare
Phupong (2004) [8]	18, flare at 19 during pregnancy (13 GW)	Primigravida	NA	Asymptomatic	Hb 9.4 g/dL PLT 68 × 109/mm3 DAT+ (IgG) Autoimmunity: -	Prednisolone (60 mg/day)	35 + 4 Vaginal spontaneous	Concomitant Syphilis treated with penicillin G PE (31 GW)	Stillbirth with intracranial hematoma	No ES flare
Boren (2007) [9]	34, in pregnancy (38 GW)	Primigravida	NA	Asymptomatic	PLT 8 × 109/mm3 DAT+ Autoimmunity: -	RBC units, PLT units, prednisone, IVIG	NA Emergency CS	HELLP Difficult to treat ITP during postpartum requiring PLT and RBC units, solumedrol IVIG, splenectomy, RTX, and plasma exchange	Healthy boy
Lefkou (2008) [10]	29, during pregnancy (26 GW)	4 previous pregnancies	Sickle-cell trait	Asymptomatic	Hb 7.6 g/dL PLT 26 × 109/mm3 DAT+ (IgG) Anti-PLT-Ab+ aCL IgG, LA	Prednisolone (80 mg/day), IVIG	30 Emergency CS	PE (26 GW), then HELLP (30 GW)	Premature newborn	No ES flare
Lefkou (2008) [10]	28, during pregnancy (22 GW)	Primigravida	Previous MCTD diagnosis, then concomitant SLE diagnosis	Red nodules on the pulps of the fingers and toes	Hb 8.4 g/dL PLT 175 × 109/mm3 DAT+ ANA 1:640, SSA, SSB	Prednisolone RBC units, IVIG, AZA, HCQ, LDA	35 + 5 Emergency CS		Premature boy (2900 g)	No ES flare, HCQ
Nause (2015) [11]	31, during pregnancy (II trimester)	Previous vaginal delivery of healthy boy with severe postpartum hemorrhage	Concomitant SLE diagnosis	Asymptomatic	DAT+ Anti-PLT-Ab+ ANA 1:320	Prednisolone (20–100 mg/day)	36 + 4 Elective CS		Healthy girl (2510 g)	No ES flare
Parveen (2019) [12]	20, during pregnancy (22 GW)	Primigravida	NA	Melena	Hb 3.3 g/dL PLT 20 × 109/mm3 DAT+	Prednisolone (40 mg/day)	28 Vaginal induced	Eclampsia Difficult to treat ITP during postpartum requiring splenectomy	Stillbirth twin males	No ES flare
Suzuki (2018) [13]	35, AIHA during pregnancy (28 GW), then ITP 203 days after labor	1 previous pregnancy	NA	Asymptomatic	Hb 7.9 g/dL PLT 19 × 109/mm3 DAT+	NA	40 + 1 Vaginal spontaneous		Healthy newborn (3575 g)	No ES flare
Vadlamudi (2020) [14]	23, during pregnancy (38 GW)	1 previous pregnancy	Concomitant COVID-19	Epistaxis, ecchymosis	Hb 7.1 g/dL PLT < 10 × 109/mm3 DAT+	NA	38 Vaginal spontaneous	Difficult to treat ITP during postpartum requiring PLT and RBC units, dexamethasone, IVIG, RTX	Healthy boy	No ES flare
Santosa (2021) [15]	29, during pregnancy (39 GW)	1 previous spontaneous abortion	Concomitant COVID-19 (treated with remdesivir)	Hematuria	Hb 10 g/dL PLT 2 × 109/mm3 DAT+	Dexamethasone 6 mg/day, RBC units, PLT units	38 Emergency CS	Difficult to treat ITP during postpartum requiring frozen plasma transfusions, tranexamic acid, dexamethasone, HCQ + ICU admission for disseminated intravascular coagulation due to COVID-19	Healthy newborn (4280 g)	No ES flare
Our case	32 during pregnancy (6 GW)	Primigravida	SLE diagnosis at 14 years old	Bleeding gums	Hb 7.8 g/dL PLT 56 × 109/mm3 DAT+ C3 consumed	Corticosteroids RBC units, PLT units, IVIG, HCQ, CyA, RTX, LDA	34 + 6 Elective CS		Premature girl (1800 g)	No ES flare, HCQ and CyA

Abbreviations: ANA: antinuclear antibody; aCL: anti-cardiolipin antibodies; COVID-19: coronavirus disease 19; CS: caesarean section; CyA: cyclosporine-A; DAT: direct antiglobulin test; ES: Evans’ syndrome; GW: gestational week; ICU: intensive care unit; IVIG: intravenous immunoglobulin; Hb: hemoglobin; HCQ: hydroxychloroquine; HELLP: hemolysis with elevated liver enzymes and low platelet count syndrome; NA: not available PE: preeclampsia; PLT: platelets; RBC: red blood cells; RTX: rituximab; SLE: systemic lupus erythematosus.

summarizes 16 case reports, including the patient we have reported herein.

In 3/16 women, ES recurred in pregnancy [2,3,8]. Autoimmune screening was performed in 10/16 patients (see Table 2 for details). In 2/16 women with ANA positivity (one with a previous diagnosis of mixed connective tissue disease), the simultaneous onset of SLE and ES was recorded in pregnancy [10,11]. In 2/16 patients [14,15], ES occurred in association with COVID-19 infection, suggesting the potential role of SARS-CoV-2 or other viral infections as triggers for the ES onset; however, data are still unclear.

Concerning maternal complications, in the reported cases, 6/16 of women developed severe anemia, requiring RBC transfusions [2,6,9,10,15], while 5/16 required PLT transfusions [6,7,9,15], despite none of them developing major hemorrhages during pregnancy. Only one patient was treated with PDN 20 mg/day since the periconceptional period [8]. During gestation, all the patients were treated with GC, used successfully in monotherapy in 6/16 of them [2,7,8,11,12,15]; 5/16 patients also required IVIG [6,9,10], in one case, in association with azathioprine and HCQ [10]. Emergent splenectomy was performed in a patient because of refractory ES at 22 GW [6]. A case report described the use of Anti-D therapy in a patient resistant to GC and IVIG therapy, resulting in a poor response [4]. Finally, in a case complicated by severe cytopenia resistant to GC and IVIG, immunoadsorption was able to eliminate pathogenetic antibodies with consequent recovery of the blood count [5].

ES diagnosis did not influence the mode of delivery; the decision for a CS was made on obstetric indications. It is important to note that PLT values > 80.000/mm³ are required for regional analgesia due to the risk of spinal hematoma [14,21].

In the reported cases, delivery occurred between 32 and 40 GW, including 8/16 preterm births (of which 2 were before 34 GW). A total of 8/16 cases of vaginal deliveries without maternal complications have been described [2,3,5,7,8,12,13,14], while emergency CS was required in 4/16 patients (2 cases because of the onset of HELLP syndrome (hemolysis with elevated liver enzymes and low platelet count) [9,10] and 2 cases because of not reassuring cardiotocography) [10,15]. One patient presented vaginal hematoma after spontaneous vaginal delivery [2]; a case with concomitant Glanzmann-like PLT dysfunction presented abruptio placentae with a postpartum hemorrhage 20 days after delivery [7]. Another 4/16 patients developed difficult-to-treat ITP after delivery (see details in Table 2) [9,12,14,15]. Besides GC and IVIG, which represent the first-line treatments, rescue therapy such as RTX, plasma exchange, transfusions, tranexamic acid, and splenectomy were recorded in these cases.

Regarding obstetric complications, in 4/16 patients, gestational hypertensive disorders were reported [8,9,10,12], including a case of HELLP (in a patient with aCL IgG moderate triter and LA positivity) [10], a case of eclampsia (in a twin pregnancy) [12], and one case of preeclampsia (PE) at 31 GW in a patient with concomitant syphilis, resulting in fetal death with intracranial hematoma at 35 + 4 GW [8]. Due to the concomitant presence of risk factors different from ES (aPL, twin pregnancy, or infection) in 3/4 cases and the exposure to steroids, the association between ES and gestational hypertensive disorders is unclear.

Concerning perinatal outcomes, ES can affect the fetus or the newborn due to the transplacental passage of IgG antibodies, leading to fetal cytopenia [10]. Severe thrombocytopenia (PLT < 20 × 10⁹) is uncommon, but it may lead to fetal intracranial hemorrhage with death or neurological impairment [22]. AIHA can cause fetal growth restriction, preterm birth, or stillbirth [23]. In isolated maternal AIHA, hemolysis at birth is reported in 59% of the newborns [24]. Currently, there are no antenatal measures able to predict the occurrence of ES-related cytopenia in fetuses or newborns, since this is not related to maternal blood cell count or maternal response to therapy [25]. A close monitoring by means of a sonographic follow up is necessary to detect early signs of cytopenia. The risk of fetal thrombocytopenia should be taken into account when planning the mode of delivery, considering the use of instrumental vaginal delivery or fetal scalp electrodes for monitoring labor contraindicated [10]. The live birth rate in the available cases was 76% (13/17).

A case of erythroblastic stillbirth at 32 GW was reported; in such patient, warm agglutinin similar to those found in the maternal serum were detected [3]. Another case of stillbirth occurred at 35 + 4 GW due to subdural hematoma in a pregnancy complicated by syphilis; however, fetal thrombocytopenia was not proved [8]. Finally, a 2-month-old newborn developed DAT negative hemolytic anemia, which resolved in a couple of months without treatment [4].

In most cases of pregnancies complicated with ES, AIHA and ITP occurred simultaneously, except for the case of a women with AIHA in pregnancy, complicated with the onset of ITP 203 days after delivery [13].

After delivery, maintenance therapy was necessary in 4/16 patients (low-dose PDN in 2 patients, HCQ or HCQ in association with CyA in the others) [2,3,10]. In 15/16 patients, ES resolved after delivery, without flare during the follow-up period ranging from 4 weeks to 8 years. This pattern suggests a link between cytopenia and pregnancy. No cases of maternal death were reported.

4. Discussion

ES is a rare autoimmune disorder characterized by AIHA and ITP. AIHA diagnosis is based on the detection of regenerative hemolytic anemia associated with DAT positivity for IgG and/or complement component C3d [26]. For ITP diagnosis, routine anti-PLT antibodies detection is not recommended due to the lack of specificity and sensitivity of current assays [27]. Another rare ES manifestation includes autoimmune neutropenia [28], which is not recorded in pregnancy, probably because of the physiological pregnancy-associated neutrophilia [10]. ES may present as isolated or associated with autoimmune diseases (e.g., SLE or antiphospholipid syndrome), lymphoproliferative disorders, primary immunodeficiency, or drug assumption (cephalosporins, penicillin, or levodopa) [10,26]. The disorder may significantly complicate the gestational course, affecting both the mother and her fetus; however, its incidence in pregnancy is unknown. Considering that ES incidence in the general population is estimated at about 1.8 per million person-years [29], it probably represents only a minority of cases of gestational autoimmune cytopenia. ES may develop for the first time in pregnancy or recur in patients with a previous diagnosis because of its typical remission–relapse course. It is still unclear if pregnancy itself is an independent risk factor for ES onset, or if it can coincidentally occur during gestation [10], being more frequent during childbearing age [10,29].

In our patient, the diagnosis of SLE occurred when she was 14 years old because of AIHA associated with mild leucopenia and positive serology. When she was first admitted to the hospital for cytopenia during pregnancy, SLE diagnosis was excluded because of the absence of signs and symptoms of systemic disease and the negative lupus serology.

In the presence of unexplained concomitant cytopenia, the differential diagnosis should consider thrombotic microangiopathies (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) that were ruled out by ADAMTS13 normality and the absence of central nervous system and renal end-organ injuries [26]. Despite the persistent LA positivity, CAPS was excluded due to the absence of multiple organ thrombosis [30]. Furthermore, PE, eclampsia, and HELLP syndrome were excluded because of the absence of concomitant hypertension and the early stage of pregnancy at the onset [31]. ES diagnosis was based on the association of AIHA and ITP.

Table 3. Differential diagnosis for simultaneous anemia and thrombocytopenia in pregnancy: refs. [26,32].

	Peripheral Blood Smear	Creatinine	Specific Tests
ES	Polychromasia, macrocytosis, spherocytes, or poikilocytosis No schistocytes	Normal	Elevated reticulocyte count Elevated LDH Low haptoglobin Elevated indirect bilirubin Positive DAT for IgG or complement component
TMA (TTP, HUS)	Schistocytes > 10% of RBC	Increased	ADAMTS13 activity: decreased in TTP
CAPS	Schistocytes > 10% of RBC	Increased	aPL positivity Low complement component
Gestational hypertensive disorders	Schistocytes > 10% of RBC	Increased	Suspected during the second/third trimester of pregnancy Increased GOT/GPT (HELLP syndrome) High blood pressure
Vitamin B12 deficiency	Schistocytes	Normal	Macrocytic anemia with markers of hemolysis
Anemia due to bleeding complicating ITP	Normal	Normal	Non-regenerative normocytic anemia in acute bleeding or microcytic anemia in chronic bleedings Normal markers of hemolysis Negative DAT

Acronyms: aPL: antiphospholipid antibodies; CAPS: catastrophic antiphospholipid syndrome; DAT: direct antiglobulin test; GOT: glutamic-oxalacetic transaminase; GPT: glutamic pyruvic transaminase; HELLP: hemolysis with elevated liver enzymes and low platelet count syndrome; HUS: hemolytic uremic syndrome; ITP: immune thrombocytopenia; LDH: lactate dehydrogenase; RBC: red blood cells; TMA: thrombotic microangiopathies; TTP: thrombotic thrombocytopenic purpura.

summarizes possible differential diagnoses.

As concerns ES treatment, high-dose oral GCs represent the first-line treatment due to their high efficiency and rapidity [32]. In life-threatening conditions, pulses of methylprednisolone (up to 15 mg/kg/day for 3 days) may be necessary. GCs are generally considered to be compatible with use during pregnancy [18]. However, if administered at high dosage, they are associated with an increased risk of gestational diabetes, hypertension, PE, and osteoporosis in the mother, while in the fetus exposed in the third trimester, they favor fetal growth restriction and preterm birth [33,34,35]. In addition to an increased risk of infections, intrauterine exposure to GCs is also associated with potential long-term effects on infants, including altered structural brain development, dysregulation of the endocrine system (particularly the hypothalamic–pituitary–adrenal axis), and impairments in affective, behavioral, or cognitive functions; however, up to now, there are no conclusive data [36,37,38].

In our patient, oral therapy with 1 mg/kg/day prednisone was started, but only a partial response was achieved. In order to reduce GC exposure and control ITP, CyA and IVIG were added. Azathioprine could represent an alternative treatment option, having been shown to be safe both during pregnancy and lactation; however, its long onset of action makes it less suitable in cases of ES emerging during pregnancy [10]. Considering the lack of efficacy of the therapies, our patient also required RTX that apparently yielded a good response. This decision was based on the demonstrated efficacy of RTX in treating refractory isolated AIHA and ITP [39,40,41,42] as well as the contraindication to the use of other helpful therapies in pregnancy. In fact, most drugs used in ITP and AIHA treatment are to be avoided in pregnancy due to harmful effects on the fetus (e.g., danazol, vinca alkaloids, mycophenolate, cyclophosphamide) [10] or due to limited safety data (thrombopoietin receptor agonist, fostamatinib) [43,44]. RTX use during pregnancy is limited due to lack of evidence; however, available data do not suggest RTX to be teratogenic. According to the current guidelines, RTX should be stopped 6 months before conception; however, its use during pregnancy may be considered for severe maternal disease refractory to conventional therapies [18,45]. RTX use in pregnancy is associated with a theoretical increased risk of infection in both the mother and the newborn; however, several studies confirmed its safe use in refractory isolated ITP or in oncologic patients, showing an overall low risk of neonatal infection [46,47,48,49,50]. After the third dose of RTX, our patient developed a granulicatella adiacens sepsis successfully treated by antibiotics, while the newborn did not present any infection. When RTX is administered in the third trimester, the newborn vaccination schedule should avoid live vaccines in the first 6 months of life because of the possible neonatal B lymphocyte depletion [47]. In our case, fetal exposition to RTX occurred in the second trimester, and no alterations were shown in the newborn blood cells count and lymphocyte immunophenotype; therefore, the baby was regularly vaccinated with inactivated and live vaccines.

Another issue is represented by anticoagulation prophylaxis due to the risk of thrombosis associated with active AIHA [16,32]. Currently, guidelines for anticoagulation prophylaxis during isolated AIHA are lacking, but thromboprophylaxis should be considered for inpatients with active AIHA, taking into account their general risk factors for venous thromboembolic events [51]. In our patient, thromboprophylaxis with LMWH (4000 IU/day) in association with LDA was administered because of AIHA and persistent LA positivity [51].

Her management required a close monitoring of maternal and fetal health with a multidisciplinary approach, involving hematologists, rheumatologists, obstetricians, and neonatologists, that was essential in order to optimize pregnancy outcomes.

5. Conclusions

The onset of ES in pregnancy is a very rare event, with only 16 available cases from 1966 to 2024, but it should be suspected in pregnant patients with unexplained thrombocytopenia and anemia. ES treatment includes several drugs that are compatible with pregnancy and breastfeeding, such as GC, CyA, azathioprine, and IVIG. In severe refractory disease, RTX should be considered.

Obstetric complications may include postpartum hemorrhages, abruptio placentae, gestational hypertensive disorders, and preterm delivery. ES diagnosis does not influence the mode of delivery, which depends on obstetric indications. To note, ES can limit the use of spinal analgesia or instrumental vaginal delivery. However, the majority of the reported pregnancies had a favorable outcome, with a livebirth rate of 81%.

Considering maternal–fetal risks, a close monitoring by a multidisciplinary team is advisable during pregnancy and in the postpartum. The sharing of new cases of ES in pregnancy should allow for more data to be collected on appropriate management in these challenging patients.