Acute leukemia during pregnancy: a single center experience with 23 cases, 2012-2022 and literature review.

Introduction
Acute Leukemia (AL) is an uncommon and potentially devastating diagnosis with high mortality rates [1]. AL is driven by a spectrum of complex genetic mutations and cytogenetic abnormalities, which contribute to its profound tumoral heterogeneity and make the disease difficult to treat [2]. The advent of targeted therapeutic agents and immunotherapy has revolutionized the clinical management of leukemia [3]. However, the management of Acute Leukemia complicated by pregnancy remains highly challenging. AL in pregnancy is a rare occurrence, with an incidence estimated between 1 in 75,000 and 1 in 100,000 [4,5]. The most common presenting symptoms of AL during pregnancy, such as fatigue, nausea, anemia, and dizziness, are poorly specific and may lead to delayed diagnosis [6]. Starting treatment immediately after a definitive diagnosis is generally recommended due to the poor prognosis of AL. However, the optimal timing for initiating treatment for AL during pregnancy remains controversial. The management and treatment of AL during pregnancy is particularly challenging, especially in the early trimester, as both maternal and fetal outcomes need to be considered [7]. Reports on pregnancy outcomes in AL patients are scarce or under outmoded therapies. The Chinese clinical guidance has been established following a degree of consensus reached by the hematologist task force despite the limited evidence base. More clinical reports and research are urgently needed. Our study aimed to describe the characteristics, clinical outcomes, and management of AL patients who were diagnosed during pregnancy in our center from May 2012 to March 2022. We hope that these cases and the data described in this study will contribute to further clarifying the management of AL in pregnant.

Materials and methods
Retrospective study: 23 cases were collected from our center by reviewing the electronic medical records from May 2012 to March 2022 was analyzed on May 2024. The Xiangya Hospital Institutional Review Board approved a protocol for retrospective review of patient data (No. 202403046). According to the WHO criteria [8], only the patients diagnosed with Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML) during pregnancy were included. The study involved 16 cases of AML and 7 cases of ALL. Information was extracted from medical records of all identified cases. The variables information contained Reporting year, Date of diagnosis, Gestational age at diagnosis, Pregnancy history, AL subtype, Peripheral blood (PB) counts at diagnosis (White blood count, Hemoglobin, Plate count, PB blasts), Bone marrow (BM) blasts, Cytogenetic, Mutation, Fusion Gene, Lactate Dehydrogenase (LDH), Treatment regimen, Response to the induction therapy, Overall Survival (OS), Delivery or abortion, Maternal and fetal outcomes. OS was counted from the beginning of diagnosis until death from any cause, or, for patients still alive, as of January 2024. As defined by the 2017 European LeukemiaNet (ELN), Complete remission (CR) requires fewer than 5% blasts by morphological, no Auer rod, peripheral ANC, and Platelet counts at least 1.0 × 109/L and 100 × 109/L, respectively [9]. Each case was checked to prevent double-counting. The pregnancy was divided into three stages: less than the 12th week marks the first trimester, the second trimester is between 13 and 27 weeks, and the third trimester begins around the 28th week and lasts until birth. All characteristics were analyzed using descriptive statistical analysis.
Literature review: Clinic studies on AL patients diagnosed during pregnancy were identified via PubMed, Embase, and Web of Science. Searches of electronic databases yielded 17 studies after excluding duplicates. The following inclusion criteria for meta-analysis were used in this study: (1) All study types (cases more than five) were considered. (2) The study clearly reported the case number and CR rate. To avoid biases, we collected the original data from some studies according to the extra criteria for further analysis. (3) The study patients were Chinese with Acute Leukemia. (4) The study clearly reported the clinical characteristics of each case. (5) The study enrolled patients diagnosed between 2010 and 2022. Forest plot showing a random effect model with CR rate of Total AL patients diagnosed during pregnancy. Meta-analyses were performed using a random-effects model or fixed-effects model [10]. Statistical significance was set at a 2-sided p < 0.05 by χ2 test or Fisher’s Test. p-Values less than 0.05 were considered statistically significant.

Results

Characteristics of patients
Between 2012 and 2022, 23 cases were enrolled, including 16 cases of AML (69.6%) and 7 cases of ALL (30.4%). The median age of AL patients diagnosed during pregnancy was 32 years (range, 19–42 years), with the median gestation at the time of diagnosis was 23 weeks (range, 3 weeks-41weeks + 1day). Seven patients had a history of anemia prior to the diagnosis of leukemia. Except for Patient Nos. 5, 15 and 18 who conceived via IVF (Artificial Insemination), all other patients had a natural conception. According to the conception of three stages of pregnancy, six patients were diagnosed in the first trimester (26.1%), seven in the second trimester (30.4%), and ten in the third trimester (43.4%). The Median values for white blood cell count (WBC), hemoglobin level, and platelet count were 3.3 × 109/L (range, 1.1–110.1 × 109/L), 80 g/L (range, 53–111g/L) and 44 × 109/L (range, 6–375 × 109/L), respectively. The baseline clinical features of the patients overall and individually are summarized in Table 1. 12 of 23 patients had normal karyotpye. NPM1, NRAS, and WT1 mutation were observed in these patients. In this cohort, only one patient did not receive chemotherapy. All the patients diagnosed during the first or second trimester experienced intrauterine fetal death or abortion. All patients diagnosed in the third trimester unanimously postponed therapy after delivery. The interval time from diagnosis to delivery/abortion (days) and treatment was 8 days (range, 3–25 days) and 22 days (range, 7–40 days), respectively. The median overall survival was 26 months (range, 1–94 months). At a median follow-up of 26 months, approximately 56.5% of the patients were still alive. The clinical characteristics, cytogenetic, molecular genetic features and treatment of AL patients, along with maternal outcomes, are detailed in Tables 2 and 3. The medium fetal follow-up was 55 months (range, 28–134 months). Delivery mode, sex, birth weight, Apgar score, and fetal outcome are summarized in Table 4.

AML
Among the sixteen patients diagnosed with AML, the subtypes were as follows: one M1, six M2, three M3, two M4, one M5, one M6, and two AML-NOS. The distribution across pregnancy trimesters was 12.5% in the first, 43.8% in the second, and 43.8% in the third trimester. Thirteen patients of all AML cases were diagnosed with non-M3 AML. Nine of these patients received the ‘7 + 3’ regimen: seven days of cytarabine combined with three days of an anthracycline (idarubicin (IDA) in five cases, daunorubicin in three cases, and mitoxantrone in one case). Three patients were treated with a CAG regimen (cytarabine, aclarubicin, and G-CSF, CAG). The remaining patient refused chemotherapy. Patient 23 was diagnosed with AML-M1 in the first trimester, initiated therapy immediately, but experienced a spontaneous abortion after few days later. After two induction cycles, she failed to achieve remission and required salvage chemotherapy due to the high level of myeloid blasts in the bone marrow examination. Unfortunately, she died of a pulmonary infection. Six out of thirteen non-M3 AML patients were diagnosed in the second trimester. Patient No.20 experienced intrauterine fetal death, and others opted to discontinue the pregnancy. Except for Patient No. 3, who died after the first induction due to disease progression, all achieved CR after two induction therapy cycles and are still alive. In the third trimester, no patient accepted chemotherapy before abortion or delivery. All six patients underwent cesarean sections. They gave birth to five premature infants (Patient Nos. 2, 12, 15, and 18) and two full-term infants (Patient Nos. 4 and 13). Patients 7, 16, and 17 were diagnosed with APL, which is a hematological emergency disease due to the high risk of death in the early stage. Patient 16, diagnosed in the first trimester, started the ATRA and ATO before undergoing dilation and curettage. Patient 7, diagnosed during the second trimester, began induction therapy ATRA, ATO, and MTZ before a therapeutic abortion. Patient 17, diagnosed at 33 weeks + 5 days, underwent a Cesarean section before starting induction therapy with ATRA and ATO. All achieved CR after induction therapy, completed consolidation cycles and maintenance treatment successfully. At the last follow-up, they were still alive.

ALL
Of the twenty-three pregnant women, seven had ALL without CNS involvement. Two cases were Philadelphia-Chromosome-positive (Ph-positive), four were Philadelphia-Chromosome-negative, and one had unknown cytogenetics. Three patients were diagnosed in the first trimester, one was in the second trimester, and three were in the third trimester. All in the first trimester agreed to medical abortion or curettage. Patient No. 19, diagnosed with Philadelphia-positive ALL after pregnancy termination, received chemotherapy plus BCR-ABL inhibitor-Dasatinib. She achieved remission following three courses of the VDLP (vincristine, doxorubicin, L-asp, and prednisolone) and hyper-CVAD (vincristine, doxorubicin, cyclophosphamide and prednisolone) regimen. Patient No. 21 remained in remission after induction therapy and an allogeneic hematopoietic stem cell transplant (allo-HSCT). Patient No .22 was diagnosed with t(4;11) (q21;q23)/KMT2A-AFF1 (+) (MLL-AF4(+)) ALL in the early first trimester at seven weeks; She died 40 days later due to the Escherichia coli-induced sepsis. Patient Nos. 10 and 11 were diagnosed with Philadelphia-Chromosome-negative ALL during the second trimester and started the chemotherapy. Patient No.10 obtained complete remission after two cycles of VDCP (vincristine, pirarubicin, cyclophosphamide, and prednisolone) induction chemotherapy and underwent HSCT during the CR1. She died seven months post-HSCT due to disease relapse. Patient No.11 was refractory to two cycles of VDCLP (vincristine, pirarubicin, cyclophosphamide, L-asp, and prednisolone) treatment and underwent CD19-directed CAR T-cell therapy as salvage treatment but still experienced long-term disease progression and died. Patient No. 5 received a VDP regimen after delivering a full-term infant weighing 3350 g at 41 weeks of gestation. Patient No. 9 experienced intrauterine fetal death in the third trimester and initiated conventional VDCLP therapy. Despite she achieved CR after induction therapy, she relapsed and died from refractory leukemia 13 months after diagnosis.

HSCT
Six AML and four ALL patients successfully achieved primary engraftment in this cohort. The alternative donor sources included matched sibling donors (MSDs) (n = 4), unrelated donor (URD) (n = 1), and haploidentical donors (HIDs) (n = 5). The BuCy-based conditioning regimen was the most commonly used in our cohort, accounting for 90% of the HSCTs. Patients who underwent matched-donor HSCT all received a GVHD prevention regimen based on cyclosporin A (CsA) combined with mycophenolate mofetil (MMF) and short-term methotrexate (MTX), while haploidentical donor transplant recipients received ATG + CsA + MMF + short-term MTX regimen for GVHD prevention. The median count for total CD34+ transfusion was 7.2 × 106/kg (range, 3.95–13.63 × 106/kg), and for MNC it was 8.5 × 106/kg (range, 6.93–18.12 × 108/kg). All ten patients achieved both neutrophil and platelet engraftment. The median time for platelet engraftment was 12 days (range, 10–15 days), while that for neutrophil engraftment was 14 days (range, 11–26 days). Acute GVHD (aGVHD) of skin developed in patient Nos. 5, 6, and 18. At the last follow-up, eight of ten patients were still alive. Transplant characteristics are provided in Table 3.

Neonatal outcome
We summarized the outcomes of nine neonatal cases in Table 4. Six were premature and three were full-term infants. The median birth weight was 2320 g (range, 1650–3595g), and five babies were classified as low-birth-weight infants. Patient No. 15, who underwent IVF, gave birth to twin sisters via elective cesarean section at 35 + 2 weeks. Twin A had an Apgar score of five at one minute, improving to eight at five minutes, while Twin B scored ten at both one and five minutes. The Apgar scores of singleton newborn infants were equal to or greater than seven at one minute after birth and equal to or greater than eight at five minutes. Perinatal complications, including hyperbilirubinemia, anemia, neonatal hypoglycemia, respiratory distress syndrome, and hemolytic disease of newborns, were found in the newborns of patients Nos. 2, 4, 12, 15, and 18. However, all the babies achieved average blood counts within two months of delivery. The infant of Patient No. 18 received thyroid hormone replacement therapy for congenital hypothyroidism immediately after diagnosis, and the baby is doing well with no neurological disturbances. The median fetal follow-up was 55 months (range, 28–134 months). All nine infants were alive and without abnormalities. To date, none of the nine newborns have developed cancer or hematological diseases, and all remain alive (Table 4).

Literature summary
Although some, randomized controlled trials of AL in pregnancy are limited. We summarized relevant literature that had been reported (Table 5) (Supplemental Figure 1) [11–27]. We conducted a meta-analysis of the literature, and the summary relative total CR rate was 76.9% (95%CI 69.1–84.6%) (Random Effects Model I^2 = 62%, p < 0.001) (Figure 1(A)). The relative CR rate of the treatment-after-delivery/abortion cohort was 71.3% (95%CI 64.1–78.5%) (Fixed Effects Model I^2 = 31.2%, p = 0.15) (Figure 1(B)). Chinese studies were included for further analysis (Supplemental Figure 1). For non-M3 AL patients, the CR rate of the chemotherapy-first cohort was 63.6%, compared with 68.6% in the treatment-after-delivery/abortion cohort (p = 0.657). For M3 AML patients, the rate was 100 and 83.3%, respectively (p < 0.001) (Table 6). All newborns were alive without blood disease or intellectual disabilities. Among these, 44 live newborns were delivered, with some delivered by Spontaneous Vaginal Delivery (SVD) and some by Caesarean Section (CS). The characteristics and outcomes of live neonates born to maternal diagnosed during pregnancy are shown in Table 6. The fetus seems to be more likely to be exposed to chemotherapy when the mother is diagnosed in the second trimester, but the difference is not statistically significant. The median maternal age was 28 years (range, 18–42 years). As a result, no statistical significance of CR rate was found between the two groups. Fetuses non-exposed to chemotherapy in utero had higher neonatal gestational age at diagnosis (median, 34 weeks vs. 27 + 4 weeks, p = 0.004) and neonatal birth weights (median, 2000 vs. 2350 g, p = 0.042) (Table 7).

Discussion
Cancer and pregnancy coexist infrequently. As blood cancer, AL typically occurs in elderly patients, but it also may happen in women of childbearing age. AL during pregnancy is uncommon, and the management of Acute Leukemia complicated by pregnancy is a poorly studied area, presenting a therapeutic dilemma. The use of chemotherapy during pregnancy is a double-edged sword due to the potential teratogenic and toxic effects of the therapy, necessitating consideration of both maternal and fetal outcomes. In our retrospective review of 23 cases of AL during pregnancy between 2012 and 2022, AML was more common than ALL. The distribution of AML to ALL cases was approximately 2/3 to 1/3, which is consistent with the previous study. We found that 26.1% of AL patients diagnosed during pregnancy were in the first trimester, 30.4% in the second trimester, and 43.4% in the third trimester. Most studies reported fewer cases in the first trimester, but the correlation between AL incidence and the gestational period remains unclear. Normal karyotype constitutes 40–50% of AML and 20% ALL. In our cohort, 12 of 23 patients had normal karyotpye. NPM1, NRAS, and WT1 were observed in these patients, but the prognosis of these mutations in this subtype patients is still undefined.
Providing a definitive indication for therapy in such cases is challenging. Some studies have reported that the timing of treatment initiation does not impact the response and long-term survival of AL patients [28]. It is well-recognized that chemotherapy in the early trimester is highly teratogenic [29]. In cases diagnosed with AL in the first or second trimester, there was a high incidence of abortion and premature delivery. Most recommendations suggest terminating a pregnancy for AML diagnosed in the first trimester to enable rapid treatment with chemotherapy. Some experience suggests that in the second and third trimesters, cytotoxic chemotherapy for AL can be safely administered under strict fetal monitoring. In our study, all the patients diagnosed during the first or second trimester experienced intrauterine fetal death or abortion, tending to receive therapy after abortion. The patient who received chemotherapy immediately after diagnosis in the first trimester suffered a spontaneous abortion. Studies have shown that chemotherapy might increase the risk of spontaneous abortion. However, in this case, abortion is more likely a leukemia-disease related complication than chemotherapy-induced. This risk declines as pregnancy progresses. Anti-leukemia therapies in the late trimester may differ from those in the first trimester. The impact of fetal exposure to cytotoxic drugs during the second and third trimesters remains controversial. According to the 2015 guideline [4], delivery before initiation of chemotherapy has been highly recommended when diagnosed after 30 weeks. In the third trimester, there is no fetal exposure to chemotherapy, differing from previous reports. The patients diagnosed after 30 weeks underwent induced vaginal delivery or cesarean section before the chemotherapy, possibly explaining the higher incidence of premature delivery. Additionally, some studies reported patient deaths before chemotherapy due to delayed diagnosis. In the meantime, blood and platelet transfusions should be administered to correct anemia and platelet deficiency. The most effective and valuable overall therapeutic regimen is against leukemia. With the best supportive care, no patient died of infection or bleeding before receiving chemotherapy in our center. The interval time from diagnosis to treatment was 22 days (range, 7–40 days). Notably, this small-size study supports that shortly delays in initiating anti-leukemia treatment is not associated with a negative impact on prognosis.
In the last two decades, the prognosis of Leukemia has improved dramatically owing to the clinical application of molecularly targeted cancer therapy. Like patients diagnosed with AL, pregnant woman diagnosed with Chronic Myeloid Leukemia (CML) or Chronic Lymphocytic Leukemia (CLL) also poses challenging situation with both psychological and clinical difficulties. Initiating treatment depends on CML phase, tumor burden, and disease kinetics [30]. IFN is the preferred option for new diagnosis during pregnancy CML patient. Given the current evidence and experience, chemotherapeutic agents, such as hydroxyurea, should be avoided. Although tyrosine kinase inhibitor(TKI) therapy is generally non-genotoxic, the United States prescribing information (USPI) advises patients to avoid TKI use, particularly during organogenesis (less than 12 weeks of pregnancy), due to the risk of causing teratogenic effect or pregnancy loss [31–33]. In the case of CLL, it is an indolent disease that progresses slowly—this means a ‘wait-to-see’ approach is often appropriate during pregnancy. If the treatment is needed, leukapheresis may be safer option. When drug treatment is required, delaying therapy until the second or third trimesters. Some studies reported that BTKIs, Idelalisib and Fludarabine may cause teratogenic and embryo-lethal. Rituximab seems to be the most promising agent in terms of use in pregnancy [33,34]. Data on the safety and efficacy of emerging therapeutic drugs in AL pregnant patients are limited.
The traditional treatment approach for Acute Leukemia has primarily included chemotherapy and HSCT [35]. However, targeted therapy and immunotherapy have advanced rapidly over the past decade. For AML, the approval of targeted drugs such as FLT3 inhibitors (e.g. midostaurin, gilteritinib), IDH1/2 inhibitors (e.g. enasidenib), and BCL-2 inhibitors (venetoclax) has significantly enhanced survival outcomes of patients with specific AML subtypes. Additionally, the application of immunotherapies—such as CD33-targeted antibody-drug conjugates (ADCs) (e.g. gemtuzumab ozogamicin)—and CAR-T cell therapy in patients with refractory or relapsed AML represent important research and clinical directions [36,37]. For ALL, vincristine, prednisone, and asparaginase-based regimens have long been centered in multi-agent chemotherapy, and HSCT remains a cornerstone of curative therapy for high-risk and R/R ALL. the approval of tyrosine kinase inhibitors (TKIs) (e.g. imatinib, dasatinib) for BCR-ABL1-positive ALL has drastically enhanced response rates and long-term survival. Imunotherapies-CD19-targeted CAR-T cell therapies and bispecific antibodies (e.g. blinatumomab, a CD19/CD3 bispecific antibody) - have transformed ALL treatment [38]. Despite the general advancements in both AML and ALL treatment, the patients in this study are predominantly receiving conventional chemotherapy regimens. APL is a hematological emergency disease due to the high risk of death in the early stage. ATO-included regimens are highly recommended standard treatments for APL patients. Several studies have indicated that ATO is highly teratogenic and should not be used in the early trimester. ATO treatment should be withheld during pregnancy. ARTA is highly recommended for APL patients diagnosed in the second or third trimester, even for suspected APL patients. We analyzed five Chinese studies together, in which all patients received an ATRA-based regimen. The CR rate was 100% in the cohort that underwent chemotherapy first, whereas it was 83.3% in the cohort that received treatment after delivery or abortion. Patients who received therapy in the first trimester failed to achieve a live birth. 4/6 patients who received ATRA in combination with ATO during the second trimester failed to achieve a live birth. 6/7 patients successfully delivered live babies when treated with ATRA-based regimens without ATO in the second and third trimesters. Based on the above studies, we maintain the view that ATRA is relatively safe for patients in the second and third trimesters of pregnancy. For non-APL AML patients, the combination of cytarabine with anthracycline is known as the standard chemotherapy. In our group, all patients received the ‘7 + 3’ or CAG regimen (cytarabine, aclarubicin, and G-CSF, CAG). Previous studies have demonstrated that cytarabine can cross the placental barrier, potentially resulting in adverse effects including the prominent frontal skull, mild macrognathia, moderated-sized membranous, and chromosomal abnormalities [39,40]. Doxorubicin and daunorubicin were considered relatively safe within the standard doses, though they may involve cardiotoxicity [41]. A retrospective analysis of anthracycline use during pregnancy reported malformations in five of 160 fetuses exposed to anthracycline [42]. Several studies reported the use of molecular targeted treatments such as hypomethylating agent 5-azacytidine and Sorafenib during pregnancy with no major fetal complications [43,44]. There was a reported case of FLT3-ITD-positive pregnant patient who was treated with midostaurin in her first trimester. Although the fetus experienced severe Intrauterine Growth Retardation (IUGR) at 28 and 30 weeks, it recovered well after a cesarean section [45]. Another patient received venetoclax, cytarabine, and mitoxantrone as salvage chemotherapy in her 24th gestational week and underwent a cesarean section in her 28th week. The newborn weighed 1190 g, and three-month examination reported normal development [46]. However, more evidence is needed to evaluate the safety of these treatments during pregnancy. For ALL patients, treatment is more complicated due to the standard induction regimen consisting of at least four drugs. Chemotherapy for AL patients during pregnancy should balance anti-leukemia efficacy with the lowest possible toxicity to the fetus [47]. The optimum use of cytotoxic and target drugs in AL pregnant patients remains undefined. In our cohort, only one patient did not receive chemotherapy due to economic factors. The patients were treated similarly regimen to AL patients not diagnosed during pregnancy. The ORR was 77.3%, similar to that of the general population. Our study also summarized some experiences from the previous studies. We summarized 17 studies (each with more than five cases) of AL diagnosed during pregnancy, analyzing data on their clinical features, pregnancy, and fetal outcomes. We conducted a meta-analysis of the literature, and the summary relative total CR rate was 76.9% (95%CI 69.1–84.6%) (Random Effects Model I^2 = 62%, p <0.001). The relative CR rate of the treatment-after-delivery/abortion cohort was 71.3% (95%CI 64.1–78.5%) (Fixed Effects Model I^2 = 31.2%, p = 0.15). To avoid bias, we included four Chinese studies from 2010 to 2022 combined with our research for further analysis according to some criteria. For non-M3 AL patients, the CR rate of the chemotherapy-first cohort was 63.6%, compared with 68.6% in the treatment-after-delivery/abortion cohort (p = 0.657). This may be attributed to the lower chemotherapy dosage and duration in the chemotherapy-first cohort. The CR rate and fetal survival rate of patients with acute leukemia (AL) diagnosed during pregnancy can be effectively improved if we accumulate more clinic experience regarding the optimal timing and drug selection of chemotherapy, enhance treatment efficacy through combined targeted therapy, and establish a rigorous monitoring system to implement personalized treatment strategies for this patient population in the future. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a precision medicine approach, with specific-donor selected for one individual patient based on human leukocyte antigen (HLA) molecule. As a post-remission therapy, allo-HSCT potentially offers the highest chance of long-term survival for AL patients. In our study, ten of the twenty-three patients underwent HSCT from their HLA-matched donors, with six patients having 10/10 or 9/10 HLA-matched sibling donors. Eight of these ten patients were alive at the last follow-up. With the continuous refinement of guidelines for AL, the establishment of risk stratification helps clinic doctor identify patients who may need HSCT. Although the small sample size precludes analysis, we can observe that HSCT has improved the survival outcome of AL patients diagnosed during pregnancy with leukemia in our cohort over the past ten years. The conditioning regimen for hematopoietic stem cell transplantation (HSCT) in pregnant patients with acute leukemia (AL) is identical to that in AL patients not diagnosed during pregnancy. We remain uncertain whether specific considerations or adjustments are required for the conditioning regimen in this unique patient population.
We reported the clinical outcome of nine newborns, six premature and three full-term infants. Premature birth as a result of delivery before chemotherapy initiation was common in our center. In our cohort, no negative fetal outcome was recorded after follow-up. Up to now, all of the nine newborns were alive. Few reports exist of transmission from mother to fetus [47,48]. The baby was diagnosed with congenital primary hypothyroidism due to hypothyroidism of maternal in our cohort. The early and adequate treatment can prevent poor neurodevelopmental outcome. We analyzed four Chinese studies from 2010 to 2022 combined with our research, All patients who received chemotherapy during the first trimester failed to achieve a live birth. We also summarized that 44 live newborns were delivered, with 13 delivered by SVD and 31 by CS. The median maternal age was 28 years (range, 18–42 years). The median gestation at diagnosis was 33 weeks + 5 (range, 29 weeks +4–41 weeks). As a result, no statistical significance of CR rate was found between the two groups. It has been reported that low birth weight and anemia at birth may result from preterm birth or fetal exposure to chemotherapy in utero. We found that fetuses non-exposed to chemotherapy in utero had higher neonatal gestational age at diagnosis (median, 34 weeks vs. 27 + 4 weeks, p = 0.004) and neonatal birth weights (median, 2000 vs. 2350 g, p = 0.042). Some study reported that the anti-leukemia treatment during pregnancy may be associated with severe adverse fetal outcomes. All newborns were alive without blood disease or intellectual disabilities in these five studies.
The limitation of this study is the singular focus on assessing the treatment of AL during pregnancy. In our center, most patients diagnosed during the first or second trimester tended to receive chemotherapy after abortion, we have limited experience with fetus exposed to chemotherapy drugs during pregnancy. In this study, we analyzed AML and ALL as a single cohort without conducting a detailed comparison of the differences between the two subtypes. This will be the focus of our future research. Management of AL during pregnancy requires collaboration between hematologists and obstetricians, with decisions based on the patient’s fertility desires. Although we conducted a comprehensive analysis, providing a definitive indication for therapy in such cases is challenging. Therefore, more professional and rigorous clinical trials are needed to guide future treatments.

Conclusion
The management of acute leukemia (AL) diagnosed during pregnancy is challenging. Our study aimed to comprehensively characterize the clinical management approaches and outcomes of AL patients during pregnancy. Our findings suggest that for non-M3 AL patients can sometimes be managed during pregnancy, deferring initiation of chemotherapy until after delivery might be a safe strategy for those diagnosed after 30 weeks of gestation. For M3 patients, early treatment potentially yield favorable outcomes for both the mother and fetus, using ATRA-based regimens without arsenic trioxide(in the second and third trimester) or standard chemotherapy(in the second trimester) may considered a treatment option.

Supplementary Material

Supplemental Figure 0128.docx