Can a Pregnant Woman With Leukemia Pass It to the Baby
Introduction
Acute leukemia (AL) is a cancerous blood disease that arises from either the myeloid cells (acute myeloid leukemia, AML) or the lymphoid cells (acute lymphoblastic leukemia, ALL). The incidence of AL increases dramatically with historic period and peaks at 80–85 [ane]. Although elderly patients are at high risk of AL, the affliction can besides be observed in women of childbearing age. The incidence of leukemia in pregnancy has been reported as ane in 75,000–100,000 [2–4]. During pregnancy, some of the early features of AL, such equally fatigue and shortness of breath, or alterations of peripheral claret counts, as anemia and thrombocytopenia, may be interpreted as pregnancy-related symptoms, leading to delayed diagnosis and inappropriate therapy [5,half dozen]. If it is untreated immediately, the illness would outcome in rapid maternal and fetal mortality [seven,8]. In improver, delaying induction chemotherapy negatively impacts the likelihood of remission [9]. Although a guideline for the diagnosis and direction of astute myeloid leukemia in pregnancy had been published by British Commission for Standards in Hematology in 2015 [vii], management conclusion is influenced by many factors, such as the type of leukemia, severity of illness, fiscal situation, and patient's personal beliefs.
In this report, we reported 21 cases of acute leukemia diagnosed during pregnancy between April 2010 and June 2019, and analyzed their clinical characteristics, treatments and outcomes, in order to make useful suggestions for the management of acute leukemia in pregnancy.
Patients and methods
Later approval by the Institutional Review Board, information was nerveless retrospectively using institutional electronic medical records on all patients with AL who met the diagnosis during pregnancy in the 2nd Xiangya Hospital of Central Due south Academy from April 2010 to June 2019. All procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2013.
The diagnosis and classification of AL were based on the French-American-British criteria and the revised WHO criteria, 2016 [ten,11]. Co-ordinate to the WHO criteria, diagnosis of AL requires at to the lowest degree xx% blasts amid no erythroid cells in bone marrow or claret. Handling of patients with AL is divided into two chemotherapy phases: remission induction and consolidation. After two cycles of induction chemotherapy, virtually patients achieved a status with no symptoms or signs of the affliction, fewer than 5% blast cells in bone marrow and normal blood prison cell counts, which is named complete remission (CR). Patients who practise not attain complete remission after induction chemotherapy are normally diagnosed as having "refractory AL".
Inclusion and exclusion criteria: but patients with acute leukemia diagnosed during pregnancy were included; Patients with pregnancies that occurred during or after handling for AL were excluded.
The information nosotros nerveless includes the patient'due south age at diagnosis, gestational historic period at diagnosis, peripheral blood counts at diagnosis, blasts in bone marrow, cytogenetics and molecular markers, whether or not delivery, type of delivery or abortion, postnatal condition, induction therapy regimen, response to chemotherapy, maternal and fetal outcomes. The first trimester is defined as before the end of calendar week 12 and the third trimester is after calendar week 27 of pregnancy.
Results
Characteristics of patients
Nosotros identified 21 patients with acute leukemia occurring during pregnancy. Eighteen patients had AML, and 3 had ALL. The median age at leukemia diagnosis was 28 years (range 19–41 years). The median gestational age at diagnosis was 22 weeks (range <four to 36 weeks). The details of the patients were shown in Table 1 and Supplementary Table S1. As described in Table two, six, eight and vii patients were diagnosed during the first, 2nd, and third trimester, respectively. Amidst the 21 patients, six patients experienced elective ballgame (5 cases of medical abortion and 1 of curettage ballgame) and 1 had spontaneous abortion, 9 gave nascence to babies (4 through vaginal deliveries and 5 underwent Caesarean sections), and 5 patients died (four died before consecration chemotherapy, one declined chemotherapy and died after discharge). The interval between diagnosis of AL and the commencement of chemotherapy ranged from 1 24-hour interval to 11 days (median, v days). The hateful length of follow-upward was 23.6 months. Five patients had severe extra-hematologic complications (WHO Grade
3) after induction chemotherapy, including infections (4 patients) and hemorrhage (1 patient, No.9). No venous or arterial thrombus was establish.
Table ane. Clinical features of 21 patients with acute leukemia diagnosed during pregnancy.
Tabular array 2. Characteristics of different stages of pregnancy.
Astute promyelocytic leukemia
Four patients were diagnosed with astute promyelocytic leukaemia (APL), the M3 subtype of AML. 3 of them received all-trans retinoic acid (ATRA) and daunorubicin (DNR) or ATRA and idarubicin (IDA) therapy, and accomplished CR. Patient No.2, diagnosed in the first trimester, received ATRA and DNR therapy followed by therapeutic ballgame. She achieved CR and completed consolidation and maintenance chemotherapy. This patient is nonetheless alive. Patient No.xviii, diagnosed in the second trimester, died due to intracranial hemorrhage before induction therapy. Two patients were diagnosed during the 3rd trimester. One (patient No.14) was diagnosed with high-risk APL (WBC count >10 × 109/50) and started induction therapy (ATRA + DNR) first. She experienced an induced vaginal commitment at 38 weeks when neutrophil and platelet recovery. The 2nd patient (patient No.16) opted to receive single-amanuensis ATRA and underwent an induced vaginal commitment of a full-term infant, and so proceeded to initiation of IDA chemotherapy because of a marked increase in WBC numbers. Both of them obtained a CR. Unfortunately, patient No.14 relapsed three times and died of refractory leukemia at 47 months after diagnosis. Patient No.16 relapsed at ten months after diagnosis, and died from pulmonary infection after re-consecration chemotherapy. Both patient No.xiv and No.xvi gave birth to good for you babies.
Acute myeloid leukemia
A total of 14 patients were diagnosed with non-APL AML. Eleven patients received induction chemotherapy with DNR and cytarabine (Ara-C) (9 patients) or IDA and cytarabine regimen (2 patients). Vii of the 11 cases achieved CR, but four patients eventually relapsed and died. Two patients remain live. The remaining 4 cases who received chemotherapy had refractory disease.
Trimester-specific outcomes
Kickoff trimester
Four of the 14 AML patients were diagnosed in the starting time trimester of pregnancy. Two patients received induction chemotherapy (DNR + Ara-C), one of them (patient No.six) began therapy immediately later diagnosis and had a spontaneous abortion, the other one (patient No.11) experienced elective termination first and so initiated chemotherapy. Unfortunately, both of them were refractory to consecration chemotherapy, and died iv months and 2.5 months after diagnosis respectively. Two patients (patient No.10 and No.12) died from intracranial hemorrhage earlier chemotherapy. None of the patients diagnosed in the first trimester fabricated information technology to a successful delivery.
Second trimester
Vi patients were diagnosed with AML during their second trimester. Five AML patients received chemotherapy (4 with DNR + Ara-C and 1 with IDA + Ara-C), and all of them obtained CR. Unfortunately, four patients developed recurrent disease and died. Four patients diagnosed before twenty weeks of gestation opted to initiate chemotherapy after diagnosis and underwent elective ballgame after neutrophil and platelet recovery. One patient (patient No.1) diagnosed at 26 weeks began consecration therapy first and delivered a low-birth-weight baby at xxx weeks by Caesarean section. Patient No.13 died from massive haemoptysis before induction chemotherapy.
Third trimester
Four patients were diagnosed in the tertiary trimester. All of them received induction chemotherapy later on delivery (iii with DNR + Ara-C and ane with IDA + Ara-C). 3 of them underwent Caesarean section and 1 had an induced vaginal commitment. They gave nascency to 2 preterm (patient No.3 and No.20) and two total-term infants (patient No.17 and No.19). 2 patients (patient No.17 and No.xx) achieved CR, 1 of them (patient No.20) died after allogeneic hematopoietic stem cell transplantation due to acute gut graft-versus-host illness at 7 months afterwards diagnosis. The other 2 patients (patient No.3 and No.nineteen) died of refractory AML. All of the 4 patients gave birth to healthy babies, and no congenital malformations were observed.
Acute lymphoblastic leukemia
Three patients were diagnosed with Philadelphia chromosome negative B cell ALL, without primal nervous organization involvement. 1 patient (patient No.4) diagnosed in the first trimester of pregnancy, declined therapy and died shortly subsequently discharge. The other ii patients (patient No.5 and No.fifteen) diagnosed at 34 weeks and 27 weeks respectively, opted for firsthand induction chemotherapy (Cyclophosphamide + Daunorubicin + Vincristine + Prednisone), and then underwent induced vaginal delivery and Caesarean section respectively later neutrophil and platelet recovery. Both of them achieved CR, but relapsed. Patient No.15 died of refractory ALL at 16 months and patient No.v died of respiratory failure caused by pulmonary infection at 8 months. Ii babies were healthy and no malformation.
Neonatal outcomes
All of the nine babies were live (Summarized in Tabular array 3). Four were premature and v were full-term infants. 4 of the ix newborns had been exposed to chemotherapeutic agents (two diagnosed in the 2d trimester and 2 diagnosed during the third trimester). The 1-minute Apgar scores for the nine newborns were greater than or equal to 7, and the 5-infinitesimal Apgar scores were greater than or equal to 8. No foetal malformations were establish in our study. The median length of follow-upwardly was 42 months. Long-term follow-upwardly showed that at that place were no abnormal blood images, no aberrant cardiac role and other discomforts, and normal growth and evolution.
Tabular array 3. Characteristics of 9 newborns.
Discussion
Since the get-go report of pregnancy with acute leukemia was published in the twelvemonth 1845, patients with gravid acute leukemia had been increasingly reported [12]. However, due to the rarity of pregnancy complicated with acute leukemia, relevant literature had been published mainly in the form of pocket-size series and instance reports. We summarized literature (cases ≥ 5) regarding acute leukemia diagnosed in pregnancy (Table 4) [2,13–24]. In this study, we reviewed retrospectively and analyzed 21 cases of acute leukemia during pregnancy. Our results were in accordance with previous results that AML accounts for more than two-thirds of acute leukemia during pregnancy [14,25]. Patients diagnosed in the first, 2nd and third trimester were vi, 8 and 7, which were also similar to previous report [22]. Our result of CR charge per unit was at the same level as previously reported results [17,22], and delayed consecration chemotherapy reduced the CR rate.
Table four. Literature (Cases
5) regarding astute leukemia diagnosed in pregnancy.
Although in general, delayed initiation of chemotherapy is associated with poor maternal outcome [9], a slight filibuster in handling to let for delivery first may be reasonable for patients diagnosed in the late stage of pregnancy (>30 weeks) [17]. There are many reasons support this suggestion. Kickoff, though no major malformations were observed in infants who were exposed to chemotherapy in the tertiary trimester, cases of hematopoietic suppression, growth restriction, intellectual impairment and reduced fertility have been reported [14,26–31]. In addition, when cytotoxic chemotherapeutic agents are administered later on 30 weeks, the delivery may be initiated during the bone marrow suppression period that may increase the incidence of infection and hemorrhage [32]. Furthermore, there has been reported that neonatal survival rates are higher than 90% when delivery at or after 28 weeks' gestation in most comprehensive hospitals, and fifty-fifty higher (>95%) when delivery at or beyond 32 weeks' gestation [seven]. As a result, delivery before initiation of chemotherapy when the diagnosis is made subsequently thirty–32 weeks' gestation, has been proposed in the 2015 guideline for AML in pregnancy [seven]. When patients are diagnosed with AL after 30 weeks' gestation, delivery beginning will minimize fetus chemotherapy exposure while keeping a high neonatal survival charge per unit. In our series, patients diagnosed in advanced gestational age (>30 weeks) after 2015, had induced vaginal delivery or Caesarean section first, and then proceeded to initiation of chemotherapy.
For the patients in the kickoff trimester, administration of cytotoxic chemotherapeutic agents during pregnancy has been constitute to be associated with unfavorable fetal outcomes, including spontaneous ballgame, intrauterine fetal death, and major malformations in 10–20% of patients [22,33]. The critical flow for teratogenicity of chemotherapy is between calendar week three and 10 of gestation, since this period correlates with active organogenesis and foetal development [34]. Loftier teratogenicity of cytotoxic agents during pregnancy had been shown in some animal experiments [8]. Standard protocols to treat AML include anti-metabolite cytarabine and an anthracycline [32]. Daunorubicin is the anthracycline of choice, because it may induce less foetal toxicity than idarubicin, a derivative of daunorubicin. Idarubicin is more lipophilic, longer half-life, and with increased placental transfer [32]. Withal, both cytarabine and daunorubicin are well recognized to cause foetal abnormalities, including limb deformities, ventral septal defect, and cardiomyopathy [12]. If AML presents during the first trimester, a successful pregnancy is unlikely [7], therefore information technology is strongly recommended to terminate pregnancy rather than allowing spontaneous abortion during a potential thrombocytopenic or neutropenic stage [3]. When AML occurs in the second and third trimesters, chemotherapy with daunorubicin and cytarabine can be successfully administered and should start without delay [three], with extensive and continuous monitoring of foetus vital signs, cardiac part and congenital abnormalities (peculiarly limb development). For ALL patients, the standard regimen of induction therapy consists of 4-drug or 5-drug for 4 weeks, which makes the management further complicated. Therefore, termination of pregnancy should be considered before conventional therapy for ALL patients diagnosed in first trimester and early second trimester (before 20 weeks' gestation) [12,35]. Additionally, as an of import part of ALL therapy, methotrexate, is highly teratogenic and contraindicated in the first and second trimester [22,36]. Although intensive chemotherapy is crucial for the prognosis of acute leukaemia, there is evidence that proper modification of the chemotherapy regimen during pregnancy benefits the patient without affecting the health of the fetus [32]. In our study, four AML patients diagnosed earlier xx weeks in the 2d trimester all opted for therapeutic abortion, due to worry almost the harmful effect of cytotoxic agents on the fetus.
APL, the M3 subtype of AML, is always associated with coagulopathy. ATRA, a pivotal drug for APL treatment, is highly teratogenic and administered in the commencement trimester led to almost 14% malformation [37]. Use of ATRA during the starting time trimester has likewise been associated with miscarriage in 40% of patients [38,39]. Consequently, the electric current recommendation for the early stage of pregnancy is to reject the use of ATRA [12]. While handling with ATRA alone during the second and third trimester until complete remission was proposed for low-risk patients, delaying the administration of chemotherapy (or arsenic trioxide) until commitment [23,forty,41]. In our study, patient No.two diagnosed in the first trimester received ATRA and DNR therapy followed by planned therapeutic abortion. Patient No.fourteen diagnosed with loftier-risk APL (WBC count >10 × 10ix/50) at 34 weeks started induction therapy (ATRA + DNR) first and delivered a full-term babe at 38 weeks. While patient No.16 diagnosed with low-risk APL at 35 weeks opted to receive ATRA alone and had a commitment of a full-term healthy babe, and so initiated IDA cytoreductive chemotherapy because of a marked increase in WBC counts. All of these iii patients achieved CR. Arsenic trioxide (ATO) is some other effective drug for handling of APL, and its application has fabricated considerable improvement in APL therapy over the past two decades [42]. Nevertheless, ATO is highly embryo toxic and is contraindicated at any stage of pregnancy due to increased gamble of fetal malformations, intrauterine growth restriction, stillbirth and spontaneous abortions [41,43,44]. While the combination of ATRA and ATO is recommended for patients after termination or delivery, information technology'southward noted that breastfeeding is contraindicated in this example.
Unfortunately, four patients died before chemotherapy. This result may advise that, symptoms caused by acute leukemia, such as fatigue, pale and shortness of breath, or alterations of peripheral blood counts, might be misinterpreted as pregnancy-related symptoms [23], resulting in delayed diagnosis. Early on diagnosis and treatment may improve the outcome of these patients.
Nine healthy babies were delivered, four of them exposed to chemotherapeutic agents. It has been reported that fetal exposure to chemotherapy is associated with an increased risk of low birth weight [45]. In the present study, all of the nine were depression-nascence-weight newborns, including 5 full-term infants. The principal reason may be maternal anemia and/or nutritional deficiencies, caused by leukemia and chemotherapy-induced anorexia [32].
In general, for patients with acute leukemia diagnosed during pregnancy, initiation of chemotherapy every bit soon every bit possible may increase the CR rate. While for patients who diagnosed in the first trimester, constituent termination followed by standard-dose chemotherapy is a good choice to ensure ameliorate maternal outcomes. For patients diagnosed in the advanced stage of pregnancy (>xxx weeks' gestation), induced commitment earlier starting chemotherapy to reduce fetal chemotherapy exposure may exist reasonable for better maternal and fetal outcomes. The proposed treatment strategy is summarized in Effigy 1.
Acute leukemia in pregnancy: a single institutional experience with 21 cases at 10 years and a review of the literature
Published online:
06 Apr 2021
Figure ane. Proposed management of acute leukemia during pregnancy.
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Limitation
The diagnosis and direction of acute leukaemia in pregnancy remain a substantial challenge. Due to the characteristics of pregnancy, we are unable to prospectively study the well-nigh appropriate management for patients diagnosed with AL during pregnancy.
Future prospects
Given the rarity of pregnancy with acute leukemia, the experience of treating this dilemma is limited. Therefore, it is urgent to institute a national or multicenter database to collect the data of patients with pregnancy complicated with acute leukemia. The existence of such a database will provide a better footing for clinical studies and epidemiological follow-up, and besides provide a better reference for the development of futurity guidelines and standardized treatment.
Source: https://www.tandfonline.com/doi/full/10.1080/07853890.2021.1908586
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