Autoimmune Hemolytic Anemia during Pregnancy or Post-Partum: An International Multi-Center Experience

Autoimmune hemolytic anemia (AIHA) developing or relapsing during pregnancy or postpartum is a rare finding, and few is known about maternal and fetal outcomes. Furthermore, AIHA management during pregnancy and lactation is not standardized and drug use is often limited by safety concerns.

Here, we report the results of a multi-center retrospective cohort study evaluating AIHA impact on pregnancy focusing on disease severity, treatment need and maternal and fetal outcome. Forty-one pregnancies occurring in 31 women were registered from 1997 to 2022 at 11 European centers in Italy, Denmark, France, the Netherlands, USA, and Spain. AIHA was classified according to the direct antiglobulin test as warm, cold, mixed or atypical. Outcomes were compared with a control group of 56 healthy women matched for age at pregnancy and decade of pregnancy.

Overall, we observed 21 warm AIHA (13 IgG; 8 IgG+C3d), 2 cold agglutinin diseases, 3 mixed and 5 atypical forms (Table 1). Evans syndrome (i.e., association of AIHA and immune thrombocytopenia or neutropenia) was present in 5 women. Mean age at AIHA diagnosis was 27 (3-39) years and at pregnancy 32 (21-41) years.

AIHA diagnosis predated pregnancy in 16 women and had required at least 1 therapy line in all of them, and ≥2 lines in 13 (rituximab, N=8; cytotoxic immunosuppressants, N=6; splenectomy, N=5). Among these 16 patients, 7 had a relapse during pregnancy, 3 during postpartum and 9 were on active treatment at the time of pregnancy (steroids, N=7; cyclosporine, N=1; steroids plus azathioprine, N=1; the latter stopped after positive pregnancy test). A patient with a previous AIHA, relapsed as immune thrombocytopenia during pregnancy.

Further 9 patients developed AIHA during gestation and 2 in the postpartum. A patient had AIHA onset during the postpartum of the 1st pregnancy and relapsed during the 2nd one. In total, we observed 22 hemolytic events in 21 women during pregnancy/postpartum. Median Hb and LDH levels were 6.4 g/dL (3.1 - 8.7) and 599 IU/L (269-1631), respectively. Management consisted in blood transfusions (N=11, 50%) and prompt establishment of steroid therapy +/- intravenous immunoglobulins (N=22, 100%), all with response (complete N=15, partial N=7). After delivery, rituximab was necessary in 4 patients and cyclosporine was added in one. Anti-thrombotic prophylaxis was given in 7 patients. Overall, we registered 10 maternal complications (10/41, 24%), including 4 early miscarriages, a premature rupture of membranes, a placental detachment, 2 preeclampsia, a postpartum infection and a biliary colic. Notably, 8/10 complications occurred during active hemolysis and treatment for AIHA. Ten fetal adverse events (10/41, 24%) were reported: a transitory respiratory distress of the newborn in a mother with active AIHA; 4 cases of fetal growth restriction; a preterm birth; an infant reporting neurologic sequelae; a case of AIHA of the new-born requiring intravenous immunoglobulins, blood transfusions and plasma exchange; and 2 perinatal deaths. The latter two occurred in women on active AIHA therapy and were secondary to a massive placental detachment and a symptomatic SARS-CoV-2 infection. Finally, the comparison between AIHA women and the control group showed a similar prevalence of maternal complications (24% in AIHA versus 18% in controls). At variance, AIHA was marked by a significant increase of fetal adverse events versus control group (24% versus 5%, p=0.008), with more severe complications in the former.

In conclusion, AIHA developing/reactivating during pregnancy or postpartum is rare but mainly severe, requiring red cell transfusions in half of cases and steroid therapy in all patients. Notably, severe maternal and fetal complications may occur in up to a quarter of cases mostly associated with active hemolysis. Finally, AIHA was significantly associated with severe fetal complications compared with healthy population, further pinpointing the importance of maintaining a high level of awareness.

Glenthøj:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Saniona: Research Funding; Pharmacosmos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding. Michel:UCB: Other: Boards, speaker at educational sessions; argenx: Other: Boards, speaker at educational sessions; Novartis: Other: Boards, speaker at educational sessions; Sobi: Other: Boards, speaker at educational sessions; Amgen: Other: Boards, speaker at educational sessions. Napolitano:Bayer: Consultancy, Speakers Bureau; BIOFVIIIx: Consultancy; NovoNordisk: Consultancy, Speakers Bureau; Sobi: Consultancy; Amgen Novartis: Consultancy; CsL Behring: Consultancy; Kedrion: Speakers Bureau; Octapharma: Speakers Bureau; Takeda: Speakers Bureau; CSLBehring: Speakers Bureau. McDonald:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Grifols: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel to conferences, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; argenx: Other: travel to conferences; Rigel: Research Funding. Murakhovskaya:Sanofi: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Kezar: Research Funding; Annexon: Research Funding; Alexion: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Research Funding. Vos:Celgene: Other: Travel support; Sanofi: Consultancy; Beigene: Research Funding. Patriarca:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Sanofi: Honoraria. Barcellini:Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Apellis: Honoraria; Biocryst: Honoraria; Momenta: Honoraria; Alexion: Honoraria; Novartis: Honoraria; SOBI: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Sanofi: Honoraria, Speakers Bureau. Fattizzo:Alexion: Speakers Bureau; Sobi: Speakers Bureau; Novartis: Speakers Bureau.