Treatment of Acute Myeloid Leukemia During Pregnancy

Abstract

Objectives: Systematically review the literature assessing outcomes of acute myeloid leukemia (AML) treatment during pregnancy. Data Sources: A Pubmed literature search (January 1969 to June 2014) for articles written about AML and pregnancy, and bibliographies/citations of previously published reviews. Study Selection and Data Extraction: Articles written in the English language that administered active AML chemotherapy during pregnancy were included. Data Synthesis: Eighty-five fetuses were exposed to chemotherapy from 83 mothers: 8 mothers began induction chemotherapy in the first trimester, 61 mothers in the second trimester, and 14 mothers in the third trimester. Chemotherapy resulted in more fetal deaths and spontaneous abortions during the first trimester (37.5%) compared with the second (9.7%) and third trimesters (0%). All cases included cytarabine; 47 fetuses were exposed to daunorubicin and 8 fetuses to idarubicin. The percentages of fetal defects and death for cytarabine and daunorubicin combinations were 8.5% and 6.4%, respectively. With cytarabine and idarubicin combinations, the percentages of fetal defects and death were 28.6% and 12.5%, respectively. Complete remission (CR) rates were 100%, 81%, and 67% in the first, second, and third trimesters. Conclusions: Treatment during the second and third trimesters resulted in fewer fetal complications than the first trimester. However, delaying AML treatment may adversely affect the mother’s outcomes. In the reported cases, induction during pregnancy resulted in CR rates comparable to that in nonpregnant patients. The choice of anthracycline is still unclear, but the decision should be made with careful consideration, weighing the outcomes for the mother and fetus.

Keywords

acute myeloid leukemia pregnancy chemotherapy

Introduction

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemia in the United States. It is characterized by a clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. The age-adjusted incidence rate of AML is 3.7 cases per 100,000 men and women per year, and the median age of diagnosis is 66 years.¹

The treatment of AML in adults is divided into induction and postremission (consolidation) chemothe-rapy. Without postremission therapy, patients will usually relapse within 6 to 9 months.² Management of adult AML is initially based on age, younger (<60 years of age) and older (≥60 years of age).² In patients older than 60 years of age, there is a higher prevalence of unfavorable cytogenetics, antecedent myelodysplasia, and multidrug resistance and an increased frequency of comorbid medical conditions, all of which limit the patient’s ability to tolerate intensive chemotherapy.³

The goal of induction chemotherapy is to produce a major reduction in the leukemic burden and to restore normal hematopoiesis.² Although it is not fully understood if delaying treatment may affect patient outcomes, retrospective data suggest that treatment outcomes might be adversely affected when time from diagnosis to start of treatment increases beyond 5 days.⁴ The induction regimens for younger patients are based off a backbone of cytarabine and an anthracycline. Daunorubicin has historically been the most commonly used anthracycline. Recently, idarubicin has shown comparable remission rates. In a study that compared idarubicin 12 mg/m² for 3 to 4 days versus daunorubicin 80 mg/m² for 3 days in patients 50 to 70 years old, overall survival rates were similar, with complete remission (CR) rates of 83% and 70% (P = 0.024), respectively.⁵ Cytogenetics also plays a large role in the efficacy of the induction regimen. In a study with high-dose cytarabine and daunorubicin, CR rates ranged from 62% for poor-risk to 87% for favorable-risk groups.⁶ However, because of longer turnaround times, they do not play a significant role in treatment selection for induction therapy.

Cytarabine

Cytarabine is a pyrimidine analog that is commonly used in leukemia and lymphoma regimens. Its primary mechanism of action is inhibiting DNA polymerase, resulting in decreased DNA synthesis and repair. The common adverse reactions of cytarabine are myelosuppression, nausea, diarrhea, rash, fever, and hepatotoxicity. Some adverse reactions of high-dose cytarabine include CNS toxicities, pulmonary edema, conjunctivitis, and cardiomyopathy. Cytarabine has been shown to be teratogenic in animals. It readily passes through the blood-brain barrier, and although no measurements have been performed in human placentas, it would also be expected to penetrate the blood-placental barrier.⁷

Daunorubicin

Daunorubicin is an anthracycline that has been well studied in combination with cytarabine for AML treatment. It has a category 1 recommendation from the National Comprehensive Cancer Network (NCCN) guidelines in combination with cytarabine for first-line treatment of AML in adult patients younger than 60 years. The cytotoxic effects of daunorubicin are related to nucleotide base intercalation. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. Daunorubicin also inhibits the topoisomerase II enzyme, forming DNA-cleavable complexes. Additionally, daunorubicin enhances the catalysis of oxidation-reduction reactions, promoting the generation of oxygen free radicals. Major adverse effects of daunorubicin include cardiotoxicity and myelosuppression. Studies in mice have shown that daunorubicin is teratogenic in mice, but to a lesser extent than doxorubicin.⁸

Idarubicin

Idarubicin is an anthracycline that is also well studied in the treatment of AML. Like daunorubicin, it is also a category 1 recommendation for primary treatment of AML in adult patients younger than 60 years, when used in combination with cytarabine.² Idarubicin is more lipophilic compared with the other anthracyclines, which may theoretically increase the concentration crossing the placenta.⁹ A summary of alternative chemotherapeutic agents that are used in the treatment of AML are listed on Table 1.

Table 1.

Chemotherapeutic Agents Used in the Treatment of AML.

Chemotherapeutic	Mechanism of Action	Adverse Effects	Teratogenicity	Pregnancy Rating¹⁰
Cytarabine	Pyrimidine analog: inhibiting DNA polymerase, resulting in decreased DNA synthesis and repair	Myelosuppression, nausea, diarrhea, rash, fever, hepatotoxicity	Shown to be teratogenic in animals; no measurements have been performed in human placentas, but it would be expected to penetrate the blood-placental barrier⁷	D
Daunorubicin	Anthracycline: intercalation of nucleoside bases inhibits nucleotide replication and action of DNA and RNA polymerases; inhibits topoisomerase II enzyme, forming DNA-cleavable complexes; enhances the catalysis of oxidation-reduction reactions, promoting the generation of oxygen free radicals	Cardiotoxicity, bone marrow suppression, mucositis, alopecia, nausea, vomiting	Daunorubicin is teratogenic in mice but to a lesser extent than doxorubicin⁸	D
Idarubicin	Anthracycline: intercalation of nucleoside bases inhibits nucleotide replication and action of DNA and RNA polymerases; inhibits topoisomerase II enzyme, forming DNA-cleavable complexes; enhances the catalysis of oxidation-reduction reactions, promoting the generation of oxygen free radicals	Cardiotoxicity, bone marrow suppression, mucositis, alopecia, nausea, vomiting	Idarubicin is more lipophilic compared with the other anthracyclines, which may theoretically increase the concentration crossing the placenta⁹	D
Doxorubicin	Anthracycline: intercalation of nucleoside bases inhibits nucleotide replication and action of DNA and RNA polymerases; inhibits topoisomerase II enzyme, forming DNA-cleavable complexes; enhances the catalysis of oxidation-reduction reactions, promoting the generation of oxygen free radicals	Cardiotoxicity, bone marrow suppression, mucositis, alopecia, nausea, vomiting	Crosses placenta and can distribute into fetal tissues, including fetal liver, kidneys, and lungs⁷	D
Mitoxantrone	Anthracenedione: intercalation of nucleoside bases inhibits nucleotide replication and action of DNA and RNA polymerases; inhibits topoisomerase II enzyme, forming DNA-cleavable complexes; enhances the catalysis of oxidation-reduction reactions, promoting the generation of oxygen free radicals	Cardiotoxicity, alopecia, hepatotoxicity	Fetal growth retardation when administered to rats during organogenesis phase of pregnancy; increases incidence of premature delivery in rabbits¹¹	D
Etoposide	Topoisomerase inhibitor: inhibits topoisomerase II and causes DNA strand breaks	Bone marrow suppression, hypotension, alopecia	Decreased albumin, which may occur during pregnancy, has the potential to result in elevated free drug levels and toxicity¹²	D
Vincristine	Vinca alkaloid: binding to tubulin, which inhibits microtubule formation and disrupts mitosis	Neurotoxicity, alopecia, SIADH	Highly protein bound, which may limit their penetration of barriers such as the blood-placental barrier⁷	D
Fludarabine	Purine analog: inhibits DNA polymerase and ribonucleotide reductase, DNA primase, and DNA ligase I	Autoimmune effects, bone marrow suppression, progressive multifocal leukoencephalopathy caused by JC virus	Teratogenic in rats and rabbits; an increased incidence of skeletal malformations was found in rats¹³	D
Cyclophosphamide	Alkylating agent: prevents cell division by cross-linking DNA strands and decreases DNA synthesis	Hemorrhagic cystitis, alopecia, nausea, vomiting, cardiotoxicity	Observed to cross the placenta in mice¹⁴ and to be teratogenic in mice, rats, and rabbits^7,15	D

Abbreviations: AML, acute myeloid leukemia; SIADH, syndrome of inappropriate antidiuretic hormone; JC virus, John Cunningham virus.

The incidence of leukemia during pregnancy has been estimated to range from 1 case in 75,000 to 1 case in 100,000.^16,17 Although the exact incidence of AML during pregnancy has not been reported, there have been many case reports in the literature that can be used to assess outcomes.

Acute leukemia during pregnancy can present a rare and challenging situation not only for health care providers but also for the mother. Although chemotherapy is widely considered teratogenic, some agents have been shown to be administered safely during pregnancy in other diseases and malignancies.¹⁸ If the leukemia is left untreated, the patient will have a short life span, have a higher probability of spontaneous abortion or fetal death, and have a lower probability of a healthy neonate.¹⁹ Therefore, we sought to systematically review the literature for published articles assessing the outcomes of the neonate and mother in the treatment of AML during pregnancy

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines²⁰ for this systematic review. The objective of the review was to identify all reports published in PubMed between January 1969 and June 2014, which assessed fetal and maternal outcomes from the treatment of AML during pregnancy. The year 1969 was chosen because it was the year that cytarabine was approved by the FDA. The following PubMed search strategy was used: (Leukemia, Myeloid, Acute [Mesh]) AND (Pregnancy [Mesh]) AND (1969/01/01:2014/06/30 [dp]). Additionally, bibliographies of reports found during the search were assessed to find all available reports. After identifying all chemotherapy agents used for AML treatment during pregnancy, another search of PubMed between January 1969 and June 2014 was performed to identify reports of these agents discussing fetal and maternal outcomes in other malignancies. The following PubMed search strategy was used: (Daunorubicin [Mesh]) OR Cytarabine [Mesh]) OR (Doxorubicin [Mesh]) OR (Daunorubicin [Mesh]) OR (Idarubicin [Mesh]) OR (Mitoxantrone [Mesh]) OR (Etoposide [Mesh]) OR (Vincristine [Mesh]) OR (Fludarabine [Mesh]) OR (Cyclophosphamide [Mesh])) AND (Pregnancy [Mesh]) AND (1969/01/01:2014/06/30 [dp]).

Reports were considered eligible for inclusion in this review according to the following criteria: report published in English; report with regimens that contained chemotherapeutic agents considered active and recommended by the NCCN guidelines; and only cases in which chemotherapy was given during pregnancy. Reports that did not contain current chemotherapy regimens were excluded to allow better context of fetal outcomes among current regimens. Reports were excluded in which the mother completed chemotherapy before conception or received chemotherapy after birth or therapeutic abortion because of the inability to assess the direct effect of chemotherapy on a developing fetus.

The reports were reviewed independently by 2 investigators. The data collected and analyzed included the age of the mother at diagnosis of AML, the gestational week at diagnosis, chemotherapy regimen received, survival outcomes of mother, and survival and developmental outcomes for the fetus.

Results

In total, 421 articles were identified through the PubMed search and 31 articles through bibliography and citations of previously published articles. After excluding duplicate articles, articles that were not in the English language, and articles that did not meet inclusion or exclusion criteria based on their title and abstract, 115 articles were assessed for eligibility by full text. It was found that 29 articles did not include cases of AML, 9 articles did not treat with chemotherapy during pregnancy, 7 used nonstandard regimens, and 28 did not mention any cases. After excluding those articles, 42 articles were included in our analysis (Figure 1).

Figure 1.

Flowchart of the systematic review process of identifying articles for the review.

A total of 85 cases of fetal exposures to chemotherapy from 83 mothers were included in our literature review, with a median age of 28 years (range = 16-45 years; ages of 11 mothers were not reported). Of these, 8 mothers (9.6%) presented in the first trimester, 61 (73.5%) mothers in the second trimester, and 14 (16.9%) in the third trimester. The regimen, gestational age when treated, mother’s outcome, and infant’s outcome are presented in Table 2. The outcomes of the mothers are presented out of a total of 83, and the outcomes of the fetuses are presented out of a total of 85.

Table 2.

Published Cases of AML Treated During Pregnancy, Divided by Regimen

	Gestational Age (weeks)
Number	Diagnosis	Delivery	Mother’s Age (years)	Regimen	Maternal Outcome	Fetal Outcome	Delivery Method
Cytarabine
1²¹	16	39	28	• Induction: cytarabine 200 mg daily ×5 days • Reinduction: cytarabine 300 mg daily ×5 days; 6-thioguanine	CR not achieved; died 14 months after delivery as a result of disease progression	Live birth, normal child	Cesarean
2²²	Unknown	38	25	Cytarabine	Unknown disease status; was alive 4 months after childbirth	Live birth; normal development at 1 year	Unknown
Cytarabine, daunorubicin
3²³	11	Fetal death	32	Daunorubicin, cytarabine	CR; relapsed after 21 months of CR, had BMT and second CR	Fetal death at 17.5 weeks
4²⁴	12	Fetal death	28	Cytarabine 2240 mg; daunorubicin 180 mg	Unknown	Spontaneous abortion at week 15
5²⁵	16	32	20	• Induction: daunorubicin 140 mg on day 1; cytarabine 175 mg on days 1, 2 at weekly intervals (3 courses; induction twice)• Maintenance: 6-mercaptopurine	Died from pneumonia day after birth	Live birth, normal infant	Vaginal
6²⁶	17	28	Unknown	Daunorubicin; cytarabine	Unknown	Live birth, intubated, but healthy child	Cesarean
7²³	18	41	20	Daunorubicin; cytarabine	CR	Live birth with no malformations	Unknown
8²⁷	18	Unknown	30	Daunorubicin; cytarabine	CR	Term infant	Vaginal
9²⁸	19	39	Unknown	Cytarabine; daunorubicin	Unknown	Live birth, no complications or abnormal development	Unknown
10²⁹	20	Fetal death	26	• Induction: cytarabine 100 mg/m² on days 1-7; daunorubicin 45 mg/m² on days 1-3• Second induction: mitoxantrone 12 mg/m² days 1-3; cytarabine 2000 mg/m² q12h on days 1-4• Consolidation: idarubicin 10 mg/m² on days 1-2; cytarabine 2000 mg/m² q12h on days 1-4	CR	Dead fetus of normal gestational age
11³⁰	20	37	38	• Initial induction and consolidation (6 courses): daunorubicin 120 mg on day 1; cytarabine 160 mg on day 1-5• Reinduction: daunorubicin, cytarabine ×1 course• Second consolidation (2 courses): 6-thioguanine 160 mg daily; cytarabine 160 mg daily	CR; died from relapse	Live birth; normal hair follicles	Vaginal
12³¹	21	32	39	• Induction: daunorubicin 25 mg/m² on days 1, 2, 5, and 6; cytarabine 70 mg/m² on days 1-10; methylprednisolone 60 mg/m² on days 1-10• Reinduction: idarubicin 12 mg/m² on days 1-3; cytarabine 100 mg/m² on days 1-7	CR	Live birth; no signs of cardiac failure, but signs of myelosuppression, hepatopathy, elevated CK	Cesarean
13³²	21	29	24	Cytarabine 160 mg ×7 days; daunorubicin 50 mg ×3 days	CR; relapsed	Live birth; perinatal period complicated by seizures, type 1 respiratory distress syndrome, and right upper lobectomy for persistent pneumothorax	Cesarean
14²⁷	22	Unknown	33	Daunorubicin; cytarabine	CR	Term infant	Vaginal
15³³	22	39	23	Cytarabine 80 mg ×3 days; daunorubicin 40 mg; discontinued daunorubicin on third cycle, continued with only cytarabine	Died 4 months after delivery from disease progression	Live birth; normal karyotype	Vaginal
16³⁴	22	36	22	• Induction: daunorubicin 60 mg for 3 days; cytarabine 140 mg for 7 days• Reinduction: cytarabine 4.5g/m² for 3 days; mitoxantrone 7.5 mg/m² for 5 days; etoposide 100 mg/m² for 5 days; G-CSF 150 µg for 15 days	CR	Live birth; emergency delivery as a result of fetal distress; pancytopenia at birth	Cesarean
17²⁵	22	34	27	Daunorubicin 45 mg on day 1; cytarabine 200 mg on days 1-5; 6-thioguanine 120 mg bid on days 1-5 at 3-weekly intervals	CR	Down’s syndrome	Cesarean
18³⁵	23 weeks, 4 days	28 weeks, 1 day	24	Cytarabine 100 mg/m²/day on days 1-7; daunorubicin 60 mg/m²/d on days 3-5 (repeated on day 22)	CR and continued on to allogeneic HSCT	Child was anemic and recovered fully after blood transfusions	Cesarean
19³⁶	24	38	25	Daunorubicin 45 mg/m² on days 1, 3, 5; cytarabine 100 mg/m² on days 1-7; 6-thioguanine 100 mg/m² on days 1-7	CR	Live twins; no physical abnormalities; normal growth and development; inverted chromosome 9 on 1 child.	Vaginal
20³⁷	25	29	21	Daunorubicin; cytarabine	CR; died 16 months from diagnosis as a result of graft vs host disease after BMT	Live birth; suffered frequent upper-respiratory-tract infections, congenital adherence of iris to posterior cornea in left eye	Vaginal
21²⁷	26	Unknown	38	Daunorubicin; cytarabine	CR	Term infant	Vaginal
22²⁷	26	Unknown	24	Daunorubicin; cytarabine	CR	Term infant	Vaginal
23²⁷	26	Unknown	25	Daunorubicin; cytarabine	CR	Premature birth	Cesarean
24²⁷	26	Unknown	29	Daunorubicin; cytarabine	CR	Term infant	Vaginal
25²⁷	27	Unknown	25	Daunorubicin; cytarabine	Toxic death	Premature birth	Vaginal
26²⁷	28	Unknown	33	Daunorubicin; cytarabine	CR	Term infant	Cesarean
27²⁶	28	28	Unknown	Daunorubicin; cytarabine	Unknown	Live birth; intubated, hypospadia, respiratory distress syndrome	Cesarean
28²⁷	30	Unknown	35	Daunorubicin; cytarabine	CR	Term infant	Vaginal
29²⁷	32	Unknown	31	Daunorubicin; cytarabine	CR	Term twins	Cesarean
30²⁷	36	Unknown	45	Daunorubicin; cytarabine	Refractory to treatment	Term infant	Cesarean
31²⁷	37	Unknown	23	Daunorubicin; cytarabine	CR	Term infant	Vaginal
32²²	Unknown	39	23	Daunorubicin; cytarabine	Unknown disease status; was alive 4 months after childbirth	Live podalic birth; normal development at 3 years	Unknown
Cytarabine, daunorubicin, etoposide
33³⁸	25	32	36	Cytarabine 1 g/m² on days 1-3; daunorubicin 45 mg/m² on days 1-3; etoposide 400 mg/m² on days 8-10	CR	Live birth; very pale and required active resuscitation, cord blood count confirmed anemia and demonstrated leucopenia with profound neutropenia; given 2 doses of G-CSF, and hematological abnormalities resolved by day 4	Cesarean
Cytarabine, daunorubicin, mitoxantrone
34²⁷	13	Fetal death	22	Daunorubicin; cytarabine; mitoxantrone	CR	Spontaneous abortion
35²⁷	36	Unknown	36	Daunorubicin; cytarabine; mitoxantrone	CR	Term infant	Cesarean
Cytarabine, daunorubicin, 6-thioguanine
36³⁹	15	Fetal death	31	TAD-9 regimen: 6-thioguanine; cytarabine; daunorubicin	Died; unknown reason for death	Fetal death 5 weeks after chemotherapy; no abnormalities and no leukemia infiltration in fetus
37³⁹	16	30	33	TAD-9 regimen: 6-thioguanine; cytarabine; daunorubicin	CR was not achieved	Live birth; developed normally	Unknown
38³³	20	32	26	Cytarabine; daunorubicin; 6-Thioguanine	CR was not achieved	Live birth; morphologically normal	Vaginal
39³⁹	23	42	29	TAD-9 regimen: 6-thioguanine; cytarabine; daunorubicin	CR	Live birth; 6 toes on right foot, but family has history of polydactyly	Cesarean
40⁴⁰	25	38	29	6-Thioguanine; cytarabine; daunorubicin	CR; relapsed	Live birth; cytogenetics and visual inspection of infant were normal	Vaginal
41²³	25.5	38	32	Daunorubicin; cytarabine; 6-thioguanine	CR	Live birth with no malformations	Unknown
42²⁵	26	34	32	Daunorubicin 45 mg on day 1; cytarabine 200 mg on days 1-5; 6-thioguanine 120 mg bid on days 1-5; repeated after 3 weeks	CR; died in third relapse 3 years after presentation	Live birth; normal infant	Vaginal
43⁴¹	27	42	34	• Induction: 6-thioguanine 100 mg/m² q12h on days 1 and 7; cytarabine 100 mg/m² q12h on days 1-7; daunorubicin 60 mg/m² on days 5, 6, and 7• Consolidation: 3 courses of first 5 days of induction regimen separated by 21 days	CR	Live birth; normal full blood count and karyotype	Vaginal
44²²	Unknown	32	26	Daunorubicin; cytarabine; 6-thioguanine	PR	Live birth; normal development at 6 months	Unknown
Cytarabine, daunorubicin, 6-thioguanine, vincristine, prednisone
45²⁴	10	Fetal death	37	Daunorubicin; cytarabine; 6-thioguanine; vincristine; prednisone	Unknown	Spontaneous abortion 20 days postchemotherapy
46²⁴	20	37	20	Daunorubicin; cytarabine; 6-thioguanine; vincristine; prednisone	Unknown	Live birth; normal at 3+ years’ follow-up	Cesarean
47²⁴	24	Unknown	32	Daunorubicin; cytarabine; 6-thioguanine; vincristine; prednisone	Unknown	Live birth; normal at 3+ years’ follow-up	Unknown
48⁴²	27	31	28	• Daunorubicin 70 mg/m² ×3 days; cytarabine 90 mg/m² q12h ×7 days; vincristine 1 mg/m² on days 1 and 7; 6-thioguanine 90 mg/m² q12h ×7 days; prednisone 40 mg/m² ×7 days• Second induction: dose increased by 30%	Died 9 months after childbirth from disseminated Aspergillus fumigatus infection	Live birth; anemia, but gradually improved by 7 months; had 2 mild infections in first 4 months of life; Denver Developmental Screening Tests at 4.5 and 13.5 months were normal	Vaginal
Cytarabine, daunorubicin, 6-mercaptopurine, prednisolone
49⁴³	23	34	23	Cytarabine 170 mg/m² ×10 days; daunorubicin 25 mg/m² ×6 days; 6-mercaptopurine 70 mg/m² ×10 days; prednisolone 25 mg/m² ×4 days	CR	Live birth; anemic, no neurological and hematological abnormalities	Cesarean
Cytarabine, daunorubicin, doxorubicin, 6-thioguanine
50⁴⁴	24	32	36	Cytarabine 60 mg bid ×5 days; daunorubicin 90 mg ×1; doxorubicin 60 mg ×1; 6-thioguanine 160 mg bid ×7 days; repeated 3 weeks later	CR	Live birth; no obvious clinical abnormalities; feeding and weight gain were satisfactory	Vaginal
Cytarabine, idarubicin
51⁴⁵	21	37	37	• Induction: cytarabine 100 mg/m² on days 1-7; idarubicin 12 mg/m² on days 1-3; filgrastim 5 µg/kg ×9 days• Consolidation: cytarabine 3 g/m² q12h on days 1, 3, and 5; filgrastim 16 µg/kg daily for 6 days starting day 14 of consolidation	CR; relapsed 100 days after autologous transplantation	Survived, fetal abnormalities included acrocyanosis, shallow sacral dimple, short digits and limbs, and prominent frontal skull with mild macrognathia	Cesarean
52⁴⁶	21	33	Unknown	• Induction: idarubicin 10 mg/m² on days 1, 3, and 5; cytarabine 100 mg/m² on days 1-10• Consolidation: cytarabine 1000 mg/m² q12h on days 1-6	CR	Live birth; hyperbilirubinemia, EKG normal, no abnormalities in Ophthalmoscopic evaluation and radiological examination of bones; brain ultrasound showed no anatomical defects	Cesarean
53²⁷	26	Unknown	30	Idarubicin; cytarabine	CR	Term infant	Vaginal
54²⁷	28	Unknown	38	Idarubicin; cytarabine	CR	Premature infant	Cesarean
55⁴⁷	29-30	33-34	27	Idarubicin; cytarabine	Unknown; continue remission-induction chemotherapy after birth	Live birth	Cesarean
Cytarabine, doxorubicin
56⁴⁸	Unknown	Unknown	Unknown	Cytarabine; doxorubicin	CR	Live birth; developed normally without physical or psychological abnormalities when studied 4-22 years after birth. School performance and intelligence testing were considered normal. Hematological evaluation, including bone marrow examination, was normal, and there was no increase in childhood infections	Unknown
57⁴⁸	Unknown	Unknown	Unknown	Cytarabine; doxorubicin	CR	Live birth; developed normally without physical or psychological abnormalities when studied 4-22 years after birth. School performance and intelligence testing were considered normal. Hemalotogical evaluation, including bone marrow examination, was normal, and there was no increase in childhood infections	Unknown
58⁴⁹	17	40	23	• Induction: cytarabine 100 mg/m² on days 1-7; doxorubicin 45 mg/m² on days 1-3• Consolidation: 6-thioguanine 100 mg/m² on days 1-5; cytarabine 100 mg/m² SQ on days 1-5 at 4-week intervals	CR	Live birth; no hearing or visual deficits, normal peripheral blood and bone marrow, no abnormality in cytogenetic analysis of marrow	Vaginal
59³⁷	18	34	30	• Induction: doxorubicin; cytarabine• Maintenance: cyclophosphamide; cytarabine; vincristine	CR; died 5 months after BMT from disseminated candidiasis	Live birth; healthy	Vaginal
60⁵⁰	Unknown	39	30	Doxorubicin; cytarabine	PR; died 6 months after delivery	Live birth; alive at 15 years, no congenital malformations	Cesarean
61⁴⁸	Unknown	Unknown	Unknown	Cytarabine; doxorubicin	CR; died of relapse	Live birth; developed normally without physical or psychological abnormalities when studied 4-22 years after birth. School performance and intelligence testing were considered normal. Hemalotogical evaluation, including bone marrow examination, was normal, and there was no increase in childhood infections
62⁵¹	Unknown	Unknown	Unknown	Cytarabine; doxorubicin	Unknown	Live birth; “alive and well”	Unknown
Cytarabine, doxorubicin liposomal
63²⁷	23	Unknown	30	Doxorubicin liposomal; cytarabine	CR	Premature birth	Cesarean
Cytarabine, doxorubicin, 6-thioguanine
64⁵²	20	29	27	• Induction: D2AT7 regimen; doxorubicin 35 mg/m² on days 1-2; cytarabine 100 mg/m² bid on days 1-7; 6-thioguanine 100 mg/m² bid on days 1-7• Consolidation: doxorubicin 50 mg/m² day 1; vincristine 1.3 mg/m² on day 2; cytarabine 500 mg/m² bid on days 3-8	CR; continued on to BMT	Live birth; hyaline membrane disease, moderate meningeal hemorrhage, hemogram was normal; normal at 3.5 years old, no neurological damage, hematological parameters normal	Cesarean
65⁵¹	Unknown	Fetal death	Unknown	Cytarabine; doxorubicin; 6-thioguanine	Unknown	Still birth at 26 weeks; born with bruising and petechia over multiple areas
Cytarabine, doxorubicin, 6-thioguanine, prednisone
66²³	24	31.5	29	Doxorubicin; cytarabine; 6-thioguanine; prednisone	CR	Live birth with no malformations	Unknown
Cytarabine, doxorubicin, 6-mercaptopurine, prednisone
67⁵⁰	Unknown	35	28	Doxorubicin; cytarabine; 6-mercaptopurine; prednisone	PR; died 2 months after birth	Live birth; alive at 8 years, no congenital malformations	Vaginal
Cytarabine, doxorubicin, vincristine
68⁵³	17	37	34	Doxorubicin 50 mg/m² on day 1; vincristine 2 mg on day 2; cytarabine 80 mg/m² q12h on days 3-9	CR	Live birth; no congenital abnormalities, and blood count was normal with a shift to the left. Follow up at 37 months revealed normal growth and development	Vaginal
69⁵³	31	38	25	Doxorubicin 37.5 mg/m² on day 1; vincristine 2 mg on day 2; cytarabine 60 mg/m² q12h on days 3-6	PR	Live birth; normal child; blood profile was normal	Cesarean
70⁵³	34-36	35-37	18	Doxorubicin 50 mg/m² on day 1; vincristine 2 mg on day 2; cytarabine 80 mg/m² q12h on days 3-9	CR	Live birth; delivered on day 9 of chemotherapy; normal blood count and no cytopenia; growth and development was normal at 36 months	Vaginal
Cytarabine, doxorubicin, prednisone, 6-mercaptopurine, methotrexate
71⁵⁰	Unknown	36	22	Doxorubicin; cytarabine; prednisone; 6-mercaptopurine; methotrexate	CR, but died 10 months after birth	Live birth; alive at 16 years, no congenital malformations	Vaginal
Cytarabine, doxorubicin, vincristine, prednisone
72⁵⁴	12	40	27	Doxorubicin 80 mg on day 1; cytarabine 140 mg on days 1-10; vincristine 2 mg on day 1; prednisone 100 mg on days 1-5; had 2 courses of induction, and 3 courses of consolidation therapy	CR	Live birth; normal karyotype	Vaginal
73⁴⁸	Unknown	Unknown	Unknown	Cytarabine; doxorubicin; prednisone; vincristine	CR; died of relapse	Live birth; developed normally without physical or psychological abnormalities when studied 4-22 years after birth. School performance and intelligence testing were considered normal. Hemalotogical evaluation, including bone marrow examination, was normal, and there was no increase in childhood infections	Unknown
74⁵⁵	16	Fetal death	16	Doxorubicin 65 mg on day 1; vincristine 2 mg weekly; prednisolone 100 mg daily; cytarabine 160 mg ×4 days	Patient was febrile and hemorrhagic and died shortly after spontaneous abortion of baby	Spontaneous abortion at 17th week
Cytarabine, doxorubicin, vincristine, prednisone
75⁵⁶	22	33	32	• Induction: cytarabine 2 ×1 g/m² on days 1-3; mitoxantrone 10 mg/m² on days 2-328): cytarabine 1000 mg/m² on days 2-6; idarubicin 10 mg/m² on days 2-4; fludarabine 30 mg/m² on days 2-6; gemtuzumab-ozogamicin 3 mg/m² on day 1	Died 8 months after delivery as a result of CMV pneumonia	Live birth; transcranial ultrasound and echocardiography detected no abnormalities; no clinical signs of dysmorphia. Follow-up exam after 6 months found no residual signs of cardiomyopathy or hydrocephalus	Cesarean
Cytarabine, 6-thioguanine
76²¹	22	Fetal death	25	Cytarabine 200 mg q12h; 6-thioguanine 160 mg q12h ×5 days	CR; relapsed	Fetal death 22 days after admission
77⁵⁷	26	39	22	• Induction: cytarabine 200 mg on days 1-14; 6-thioguanine 160 mg on days 1-14• Maintenance: cytarabine 200 mg weekly; thioguanine 120 mg daily for 5 d/wk	CR	Live birth; normal karyotype, development	Vaginal
78⁵⁸	27	35	23	Cytarabine 100 mg/m² q12h ×5 days; 6-thioguanine 80 mg/m² q12h ×5 days; regimen repeated for 4 cycles	CR; died from relapse	Live birth; normal weight	Vaginal
79⁵⁹	27	39	28	Cytarabine SQ 100 mg bid ×7 days; 6-thioguanine 100 mg bid ×7 days	CR; relapsed and died 27 months after initial diagnosis after 2 remissions	Live birth; normal physical and mental development	Vaginal
80⁶⁰	28	38	36	Cytarabine 125 mg bid ×5 days; 6-thioguanine 160 mg bid ×5 days; regimen repeated after 5 days of rest for 3 courses	CR	Live birth; normal infant; no evidence of leukemia, no bone marrow depression, normal male karyotype	Vaginal
Cytarabine, vincristine, prednisone
81⁶¹	30-31	39	20	Vincristine 2 mg on day 1; cytarabine 100 mg/m² on day 1-10; prednisone 100 mg on days 1-10; induction, consolidation, 2 courses	CR	Live birth; normal peripheral blood count and karyotype	Vaginal
82⁶²	7 Months	38	27	Cytarabine 1200 mg; prednisone 150 mg; vincristine 2 mg	PR	Live birth; normal chromosome studies, Hgb, Hct, WBC	Vaginal
83⁴⁸	Unknown	Unknown	Unknown	Cytarabine; prednisone; vincristine	CR	Live birth; developed normally without physical or psychological abnormalities when studied 4-22 years after birth. School performance and intelligence testing were considered normal. Hemalotogical evaluation, including bone marrow examination, was normal, and there was no increase in childhood infections	Unknown

Cytarabine

All 83 mothers received cytarabine as a component of their induction regimen during pregnancy. Because of 2 sets of twins, there were a total of 85 infants exposed to cytarabine in utero. Among the pregnancies, 9 resulted in spontaneous abortions or fetal death,^{23,24,27,29,39,21,51,55} of which 3 cases started induction chemotherapy during the first trimester, whereas the other 6 cases initiated chemotherapy in the second trimester.

First trimester: In all, 8 mothers received induction chemotherapy in the first trimester and 6 were reported to have CR, with 2 subsequent relapses (2 unreported). There were 5 babies born and 3 cases of fetal death.

Second trimester: In all, 61 mothers initiated chemotherapy in the second trimester; 43 achieved CR, with 9 relapses; 2 achieved partial remission (PR); 3 mothers died from disease progression; and 5 mothers died from treatment-related complications or infections (8 unreported). A total of 56 live births (including a pair of twins in case 19³⁶) and 6 fetal deaths were reported.

Third trimester: In all, 14 mothers began treatment in the third trimester, and 7 achieved CR, with no relapses. Three mothers achieved PR; 1 mother was refractory to treatment and died from disease progression. Also, 3 mothers’ statuses were not reported. All 15 babies born were alive, including a pair of twins in case 29.²⁷

The most common side effect that the newborns experienced was anemia. Other adverse effects to the newborn included myelosuppression, hepatopathy, elevated CK, seizures, acrocyanosis, hyaline membrane disease, moderate meningeal hemorrhage, respiratory distress symptoms, and infections. Two cases (case 17 and 19) have reported chromosomal abnormalities: Down’s syndrome²⁵ and inversion on chromosome 9.³⁶ Growth defects were observed in 4 infants. Case 51 had shallow sacral dimples, short digits and limbs, and a prominent frontal skull with mild macrognathia.⁴⁵ The infant in case 39 had 6 toes on the right foot, but this was associated with the family history of polydactyly.³⁹ Case 37 developed with hypospadia; he also had respiratory distress syndrome and was intubated at birth.²⁶ The last infant (case 20) suffered from a congenital adherence of the iris to the posterior cornea in the left eye.³⁷ It is difficult to ascertain whether these defects were directly caused by cytarabine because in all these cases, cytarabine was used in combination with other agents.

Case 2 was the only case of sole cytarabine exposure during pregnancy.²² In this case, the child had normal development at the 1-year follow-up, and the mother had a CR and was alive at follow-up 4 months after delivery.

The dose of cytarabine can vary dramatically depending on regimen. Some regimens use high-dose cytarabine, whereas others may use the traditional dosing of cytarabine. With high-dose cytarabine, high concentrations can be achieved in spinal fluid to treat central nervous system leukemia.⁶³ Although there are no studies, it is thought that concentrations reaching the fetus may be dose dependent.⁷ There were 6 cases where the use of high-dose cytarabine was reported. In these cases, the 2 births in cases 75 and 82 were uncomplicated, and there were no abnormalities in the infant.^56,62 The fetus in case 4 was spontaneously aborted after chemotherapy was started in the first trimester.²⁴ Another infant (case 51) was born with shallow sacral dimples, short digits and limbs, and a prominent frontal skull with mild macrognathia.⁴⁵ Two other infants in cases 16 and 33 were born with hematological deficiencies.^34,38

Daunorubicin

There were 48 cases of daunorubicin use in pregnancy to treat AML, and 5 cases resulted in fetal death. Of these, 2 cases of fetal death occurred when chemotherapy began in the first trimester, whereas in the other 3 cases, it was started in the second trimester.

First trimester: A total of 4 mothers were exposed to daunorubicin in the first trimester of pregnancy. There was 1 CR and 3 unreported disease results among the mothers. Two live births and 2 fetal deaths were reported.

Second trimester: A total of 38 mothers began induction therapy with daunorubicin in the second trimester. Among them, 27 mothers achieved CR, 1 achieved PR, 3 died from disease progression, 3 died from infections, and 4 mothers’ disease statuses were not reported. There were 36 live births, including a pair of twins, and 3 fetal deaths.

Third trimester: There were 6 mothers who began treatment with daunorubicin in the third trimester. Among them, 4 achieved CR, 1 died as a result of disease progression, and the results for 1 were not reported. All mothers delivered live babies.

Some reported adverse effects in the infants included anemia, myelosuppression, pancytopenia, hepatopathy, elevated CK, seizures, respiratory tract infections, and respiratory distress syndrome. The child in case 17 was reported to have Down’s syndrome²⁵ and another child (case 19) had an inverted chromosome 9.³⁶ Two patients with congenital malformations were reported in cases 20 and 37. These malformations included congenital adherence of the iris to the posterior cornea in the left eye³⁷ and hypospadia.²⁶

Idarubicin

In all, 8 cases of idarubicin were used to treat AML during pregnancy. Of the 7 mothers who started idarubicin in the second trimester, 6 mothers achieved CR, and 1 mother died from cytomegalovirus (CMV) pneumonia after delivery.⁵⁶ There were 6 live births reported, with 1 fetal death.²⁹ One case of idarubicin use was reported in the third trimester.⁴⁷ The mother had received 1 cycle of idarubicin and cytarabine (7 + 3) before cesarean section was performed. The baby was born alive. The mother continued induction therapy after birth, but her outcome was not reported. No cases were reported of idarubicin use in the first trimester.

Some of the reported adverse effects were myelosuppression, hepatopathy, elevated CK, acrocyanosis, and hyperbilirubinemia. Two infants had limb defects. The infant in case 51 had shallow sacral dimples, short digits and limbs, and a prominent frontal skull with mild macrognathia.⁴⁵

Doxorubicin

In all, 19 pregnant patients were exposed to doxorubicin as part of their chemotherapy regimen. In all but 2 cases, the infant survived.

First trimester: In all, 5 mothers began treatment in the first trimester, and they all achieved CR, with 1 relapse. All 5 babies born to these mothers were alive.

Second trimester: A total of 11 mothers began treatment in the second trimester; 7 mothers achieved CR, with 1 relapse; 1 mother achieved PR; 1 mother died from infection during chemotherapy; and 2 mothers’ conditions were not reported. There were a total of 9 live births and 2 fetal deaths. Case 65 resulted in a stillborn fetus with bruising and petechia over multiple areas.⁵¹

Third trimester: There were 3 mothers who were treated with doxorubicin during their third trimester. One mother achieved CR, and the other 2 mothers achieved PR. All babies were born alive.

There were no growth defects in any of the babies exposed to doxorubicin. The only adverse effects reported at birth were hyaline membrane disease and moderate meningeal hemorrhage in case 64⁵² and a left shift in blood count in case 68.⁵³ Both infants developed normally in subsequent follow-up.

Mitoxantrone

Mitoxantrone was used in 5 cases to treat AML during pregnancy. In the second trimester, 3 cases resulted in CR. The mothers gave birth to 1 live baby, with 2 fetal deaths. Another mother died of CMV pneumonia after a successful delivery. In the third trimester, 1 mother achieved CR and had a live birth. There were no cases of mitoxantrone use in the first trimester.

One infant in case 39 was born with 6 toes on the right foot, but this was attributed to the family’s history of polydactyly.³⁹ Another infant in case 16 was born with pancytopenia.³⁴ In the other cases with mitoxantrone in the regimen, no adverse effects were reported.

Etoposide

Etoposide has been used in 2 regimens for AML during pregnancy. Both cases were administered during the second trimester. Both mothers achieved CR and gave birth to live infants. In both cases 16 and 33, the infants were born with hematological abnormalities. One infant was born pancytopenic,³⁴ and the other was born anemic with profound neutropenia.³⁸

Vincristine

Vincristine has been used in combination regimens in 15 cases of AML during pregnancy. Of these, 13 cases resulted in live births, with 2 fetal deaths. One fetal death was when chemotherapy was initiated in the first trimester, and the other fetal death was from the second trimester.

First trimester: In all, 5 mothers were exposed to vincristine in the first trimester; there were 2 CRs reported and 3 unreported outcomes for mothers. Also, 4 live births and 1 fetal death were reported.

Second trimester: In the second trimester, 5 cases of vincristine use were reported. Of these, 3 cases resulted in CR, with all babies being born live. Two mothers died from treatment-related mortality, with 1 live birth and 1 death.

Third trimester: There were 5 cases of vincristine initiation during the third trimester; 3 patients achieved CR, and 2 achieved PR. All 6 babies were born alive. Some adverse events reported from infants born after exposure to vincristine included hyaline membrane disease with moderate meningeal hemorrhage,⁵² left shift in leukocytes,⁵³ and anemia with mild infections.⁴²

Fludarabine

Fludarabine was used in case 75. It was used in the second trimester in combination with the cytarabine, idarubicin, and gemtuzumab-ozogamicin as part of the Go-Flag-Ida induction therapy. The mother died 8 months after delivery from CMV pneumonia. The infant had no abnormalities.⁵⁶

Cyclophosphamide

Cyclophosphamide was used in one case of AML during pregnancy. The mother began induction therapy with doxorubicin and cytarabine and received maintenance therapy with cyclophosphamide, cytarabine, and vincristine. The chemotherapy began during the second trimester. The mother achieved CR and delivered a healthy baby.³⁷

Discussion

Treatment of AML during pregnancy is a therapeutic dilemma. Any delays in therapy may harm the mother, but treatment with chemotherapy is not without considerable risk to the developing fetus. Although our study did not look at whether delays in chemotherapy initiation affected outcomes, previous studies have investigated the effect of time to diagnosis to chemotherapy initiation. Two studies in the United States⁴ and Denmark⁶⁴ have found that delays in treatment past 5 to 10 days negatively affect the prognosis in younger AML patients. One study from France has found that waiting a short period of time to characterize leukemias does not harm the overall survival or response rate in the patient.⁶⁵ The first trimester is when fetal development is most active, so the infant is most sensitive to the effects of chemotherapy during this time. In the 8 reported pregnancies with chemotherapy for AML during the first trimester, 3 (37.5%) resulted in fetal death. In contrast, the outcomes for babies in the second and third trimester seem relatively favorable. Of the 62 exposures to chemotherapy in the second trimester, 6 (9.7%) cases resulted in fetal death. All 15 infants who were exposed to chemotherapy in the third trimester were born alive. This is further evidence that medication exposures during the first trimester incur more risk.^66,67

Infants who are born small for gestational age or prematurely have an increased risk for perinatal morbidity and mortality.⁶⁸ In a recent analysis of pregnancies complicated by cancer, it was found that small-for-gestational-age infants were more common in hematological malignancies.⁶⁹ However, it is not known whether this is a result of the disease or the treatment. In AML, the combination of cytarabine with daunorubicin or idarubicin are both preferred as first-line induction therapy based on NCCN guidelines.² We noted more cases with daunorubicin use (47) over idarubicin use (8). Daunorubicin was associated with only 3 incidences of fetal death out of 47 pregnancies (6.4%), compared with idarubicin, where there was 1 death in 8 cases (12.5%). Daunorubicin was also associated with a relatively lower incidence of reported birth defects (4 cases; 8.5%) compared with idarubicin (2 cases, 28.6%). Doxorubicin is another anthracycline with activity in AML. However, it is not currently a recommended treatment. A CALGB study comparing daunorubicin with doxorubicin in AML found that daunorubicin was at least equally effective, with less toxicity.⁷⁰ One retrospective study comparing various breast cancer chemotherapy conventional and dose-dense regimens found that the overall incidence of birth defects was not higher than the overall prevalence in the noncancer population in the United States. The majority of those regimens contained doxorubicin.¹⁸ A review by Azim et al⁷¹ recommended using doxorubicin instead of daunorubicin or idarubicin because it has been extensively studied in gestational breast cancer. In the 19 published cases with doxorubicin, there were 2 cases (10.5%) of fetal death^51,55 and 1 case (5.3%) where the baby was born with hyaline membrane disease and moderate meningeal hemorrhage.⁵²

For younger patients, the CR rates are 60% to 80%. In our cases, we found that the overall CR rate from induction chemotherapy in evaluable patients was 80% (100% in the first trimester, 81% in the second, and 67% in the third). This suggests that mothers receiving induction therapy during pregnancy have rates of CR comparable to that in nonpregnant patients. Delays in treatment may occur when the risk to the fetus is balanced with benefit to the mother in regard to treatment. However, it has been found that postponing chemotherapy until after delivery decreased survival for the mother compared with those who initiated chemotherapy during pregnancy.⁷²

Some of the chemotherapies for AML have also been used in other diseases during pregnancy. High-dose cytarabine has also been used successfully in the CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, mesna, etoposide, cytarabine) regimen in the treatment of Burkitt’s lymphoma starting at 26 weeks’ gestation.⁷³ The cyanotic infant was delivered via cesarean section at 32 weeks’ gestation. Other than respiratory distress, the physical examination of the infant revealed no anomalies. The child’s hearing screening test and brain ultrasound were normal. At 9 months, the child showed delayed motor skills but was considered healthy. The mother had no evidence of disease 14 months after childbirth.

Daunorubicin use during pregnancy has also been reported during acute promyelocytic leukemia (APL).⁷⁴ Three cases in the first trimester resulted in live births, with 1 baby having congenital defects and respiratory distress. One case in the first trimester resulted in spontaneous abortion. In the second trimester, 9 cases resulted in live births. One of the cases in the second trimester resulted in spontaneous abortion, and another baby died 1 day after birth from pulmonary hemorrhage. Some adverse effects reported in the survivors included moderate hyperbilirubinemia and hemorrhage, bone marrow aplasia, and seizures. Two cases are reported in the third trimester. One infant was born healthy, and the other died 4 days after chemotherapy was started.

Idarubicin use has been reported in a case of rhabdomyosarcoma during pregnancy. The patient began treatment during the second trimester with the O-TIE regimen, which included oral low-dose chemotherapy containing trofosfamide (a non-FDA approved alkylating agent), idarubicin, and etoposide. A healthy infant was born 5 days after the last course of chemotherapy, and the infant showed no evidence of any malformations. The baby exhibited normal neurological development during follow-up over 2 years.⁷⁵ Idarubicin has also been used in combination with arsenic trioxide for the treatment of APL in pregnant mothers. In one case, the chemotherapy was started during the second trimester. The APL reached remission, and the child was born premature and required a 2-month stay in the hospital but developed to have good general health and neurological conditions.⁷⁶ In another APL case treated with idarubicin and arsenic trioxide, the mother was treated during the second trimester. After reaching remission, the child was born with a small patent ductus arteriosus. The ductus arteriosus spontaneously closed a week later, and the infant was found to have no clinical signs of congestive heart failure.⁷⁷

The other chemotherapy agents (doxorubicin, mitoxantrone, etoposide, vincristine, cyclophosphamide) have also been used successfully in other diseases during pregnancy, and these are summarized in Table 3.

Table 3.

Examples of Chemotherapy Use in Other Diseases During Pregnancy.

Chemotherapy	Disease	Regimen	Fetal Outcomes
Doxorubicin	Ewing’s sarcoma⁷⁸	Doxorubicin, ifosfamide	No chemotherapy-related adverse effects at 2 years old
	Hodgkin lymphoma⁷⁹	ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine	Delivered with normal weight and size
	Breast cancer^80,81	Doxorubicin, methotrexate, vincristine	Normal infant, successfully treated for sepsis and mild respiratory distress; no doxorubicin in placenta, blood, or fetal lymphocytes 3 weeks after the last treatment
	Breast cancer^80,81	TA: docetaxel, doxorubicin	Healthy with no detectable malformations
Mitoxantrone	Multiple sclerosis^11,82	Mitoxantrone	• Fetus 1: Oligohydramnios, fetal growth restriction• Fetus 2: Pierre Robin sequence: mandibular micrognathia, glossoptosis, retrogenia, and orofacial clefts
Etoposide	Hodgkin disease⁸³	EVA: etoposide, vinblastine, doxorubicin	Normal psychomotor development
	Small-cell lung cancer⁸⁴	Etoposide, cisplatin	No abnormalities
	Ovarian immature teratoma^85,86	Etoposide, bleomycin, cisplatin	Normal physical and neurological development at 1.5 years
	Ovarian immature teratoma^85,86	Etoposide, cisplatin	Normal clinical examination
Vincristine	Non-Hodgkin’s lymphoma^87-89	VACOP-B: vincristine, cyclophosphamide, doxorubicin, etoposide, bleomycin	Healthy baby
		R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone	No developmental delays or physical abnormalities at 20 months’ follow-up
		CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone	No clinical abnormalities at birth and 2 months after birth
Cyclophosphamide	Breast cancer^90,91	FAC: fluorouracil, doxorubicin, cyclophosphamide	Good condition with normal blood cell counts
Cyclophosphamide	Breast cancer^90,91	AC: doxorubicin, cyclophosphamide	Healthy infant

One limitation of this study is that there are no controlled trials assessing treatments of AML during pregnancy. The only sources of data in this study are published case reports and case series. One limitation of case reports is publication bias because negative data would be less likely to be published. This could potentially skew the incidences of fetal defects or deaths. Another limitation is that the search would only result in AML studies that specifically included pregnant patients. It would lack AML studies that included pregnant patients but without specific mention of pregnancy. One valuable piece that was missing is that only a few case reports had long-term follow-up with the children. While many infants may be healthy at initial examination, the adverse effects from chemotherapy exposure may not appear until many years after birth. The outcomes of the patient and the fetus must be considered carefully when selecting the chemotherapy regimen used to treat the leukemia. Furthermore, most of the patients received combination chemotherapy, so it is difficult to distinguish which agent may be the cause for certain birth defects or adverse effects in the infant. Additionally, many of the articles did not report the chemotherapy doses, making it difficult to assess outcomes from chemotherapies with a wide range of doses (eg, cytarabine). Some of the combination chemotherapy regimens reported in the older case reports included chemotherapeutic agents that are no longer recommended in the treatment of AML, such as 6-mercaptopurine and 6-thioguanine.

Conclusion

The diagnosis of AML as such can be challenging for many patients; however, diagnosis during pregnancy can be even more challenging for patients and health care providers. The literature on this topic is sparse, consisting only of case reports. Although it is difficult to draw strong conclusions from these reports, it was noted that treatment during the second and third trimester resulted in fewer fetal complications than the first trimester. It was also found that induction during pregnancy resulted in CR rates comparable to that in nonpregnant patients. The choice of anthracycline is still unclear, but the decision should be made with careful consideration, weighing the outcomes of the mother and the fetus.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Authors’ Note

Article’s significance: this article reviews the published literature dealing with the treatment of acute myeloid leukemia during pregnancy and reports the outcomes for the mother and fetus.

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