Anthracyclines during pregnancy: embryo–fetal outcome in 160 patients

N. Germann1, F. Goffinet2 and F. Goldwasser1,*

1 Unité d’Oncologie Médicale, Service de Médecine Interne, Paris; 2 Maternité Port Royal, Groupe Hospitalier Cochin, AP-HP, Paris, France

Received 7 April 2003; revised 18 July 2003; accepted 13 August 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

Anthracyclines are essential for the treatment of malignancies observed in pregnant patients. Knowledge of the potential side-effects of chemotherapy on the developing fetus is essential for patient counseling.

Patients and methods:

We collected information concerning patients treated with anthracyclines during pregnancy from a review of literature between 1976 and 2001 and our experience. The events analyzed were malformations, fetal death and spontaneous abortion. A {chi}2 test with a Yates correction was used to compare the distribution of severe events.

Results:

A total of 160 patient pregnancies were analyzed. The fetal outcome was frequently normal (73%). Abnormalities included malformations (3%), fetal death (9%), spontaneous abortion (3%), fetal complications (8%) and prematurity (6%). Fetal death was often directly consecutive to maternal death (40%). Unfavorable fetal outcome was significantly more frequent in leukemia patients (P = 0.001). In patients with solid tumors, the first trimester was significantly associated with more complications (P = 0.029). The risk of severe fetal toxicity was increased 30-fold when the dose of doxorubicin per cycle exceeded 70 mg/m2 (P = 0.037).

Conclusions:

Anthracyclines may induce embryo–fetal toxicity. Nevertheless the risk seems low, especially after the first trimester and using doses of doxorubicin below 70 mg/m2.

Key words: anthracyclines, fetal outcome, pregnancy, transplacental passage


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
With the increasing trend for women to delay childbearing, the co-occurrence of cancer and pregnancy, reported with an average frequency of 1 in 1000 births, is increasing [1]. The co-occurrence of a malignancy and a pregnancy requires a multidisciplinary approach because optimal maternal treatments have to be balanced with fetal well-being. Main parameters for the decision-making are: the type of malignancy, the date of pregnancy, the opinion of the parents concerning therapeutic abortion, and treatment-associated morbidity. This latter factor is the least documented and little information is available concerning the effects of anticancer chemotherapy during pregnancy, especially regarding drug delivery to the fetus. The systemic treatment of the most frequent malignancies occurring during pregnancy—leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, breast cancer, Ewing sarcoma—gives a major role for anthracyclines [26].

Anthracyclines damage DNA through different mechanisms, including topoisomerase II poisoning [7]. Anthracyclines are mutagenic and carcinogenic in vitro and in animals [8]. Since topoisomerase II{alpha} is overexpressed in rapidly growing tissues [9], poisoning topoisomerase II is a potential source of major damage for the embryo, or to a lesser extent to the fetus. On the other hand, only low concentrations of anthracyclines have been detected in fetal tissues, and their cytotoxic potential remains unknown [1013 and present article].

We retrospectively analyzed the data available in the literature and in our institution concerning pregnancy and fetal outcomes following chemotherapy with an anthracycline-containing regimen in pregnant cancer patients. In this database of 160 patients, we were able to identify parameters suitable to help the physician in this specific setting.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
A registry created in 2000 contained cases from both the literature and our experience. We analyzed the literature from 1976 to 2001 using Medline, Pascal and Current Contents databases and references therein, using ‘pregnancy’ and ‘anthracyclines’ as key words. A total of 150 cases were found in the literature (67 as single case-reports). Another 10 patients (6% of the patients entered in the database) were treated in our institution over a period of 3 years, between 2000 and 2002. Anthracyclines were doxorubicin, daunorubicin, epirubicin, idarubicin and rubidazone. Severe events were defined as malformations, fetal death and spontaneous abortion. A {chi}2 statistical analysis was used to compare severe event distributions depending on either date of administration, chemotherapy regimen, dose per cycle or maternal disease. The Yates correction was applied to all calculations to take into account the small size of the population. Tissue concentrations of daunorubicin were measured in one leukemia patient who died under therapy. Tissues samples were solid-phase extracted after addition of internal standard. A high performance liquid chromatography method with fluorometric detection was applied for the quantitative determination of daunorubicin. The metabolites were not studied.


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
A total of 160 patients who received anthracyclines during pregnancy were analyzed. The median maternal age at diagnosis was 27 years (range 16–42). Malignancies were mostly hematological (72%); breast cancer constituted the most frequent solid tumor (21%) requiring anthracyclines (see Table 1). Unfavorable fetal outcome was significantly more frequent when the mother had an acute leukemia rather than any other malignancy (20 of 79 versus four of 79, P = 0.001, see Figure 1). Doxorubicin or daunorubicin were administered in most patients, in 99 (62%) and 50 (31%) cases, respectively. Most patients (90%) received a combination of at least two agents. The other chemotherapeutic agents used were: antimetabolites (37%), alkylating agents (20%), mitotic spindle poisons (20%) or others (10%). Table 2 summarizes the results of several studies of measurements of anthracyclines concentrations in fetal tissues, amniotic fluid and placenta reported in the literature [1013] and one original result from our own experience. Thirty-one patients received an anthracycline during the first trimester (19%) including 10 around the time of conception, 103 (64%) during the second and 26 (16%) during the third trimester. Table 3 presents the fetal outcome depending on the date of initiation of chemotherapy. In patients with solid tumors, anthracyclines were significantly more toxic during the first trimester than during the two other trimesters (P = 0.029): two severe events in five patients were reported in the first trimester compared with one severe event amongst 39 patients in the other trimesters. Median duration of doxorubicin and daunorubicin treatment was 12 (range 1–24) and 4 weeks (range 1–26), respectively. The median duration of treatment with doxorubicin and daunorubicin were 12 and 5 weeks, respectively and decreased to respectively 1 or 3 weeks when fetal complication occurred. The risk of severe fetal toxicity was increased 30-fold when the dose per cycle of doxorubicin exceeded 70 mg/m2 per cycle (P = 0.037): two severe events in five patients (40%) versus three events in 66 patients (4.5%) using ≤70 mg/m2. The duration of exposure to anthracyclines was not associated with the occurrence of severe fetal toxicity.


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Table 1. Maternal disease in the 160 pregnant cancer patients
 


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Figure 1. Normal (black rectangles) and abnormal (white rectangles) fetal outcomes are represented in pregnant patients with either acute leukemia or other malignancies (P = 0.001).

 

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Table 2. Transplacental passage of anthracyclines in vivo
 

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Table 3. Fetal outcome depending on the date of initiation of the anthracyclines
 
A total of five malformations were reported [1418]. Teratogenic effects were consecutive to combination regimens, most often with antimetabolites (three cases) and alkylating agents (two cases). The anthracycline was either daunorubicin (three cases) [15, 17, 18] or doxorubicin (two cases) [14, 16]. The malformations were highly variable and could concern any organ. Three malformations were associated with a treatment during the first trimester, the two others during the second trimester. The functional status of the child was reported in two cases: normal in one case, the other child had underweight, mild hypotonia and retarded motor milestones at 13 months.

The outcomes of the pregnancies are reported in Table 4. Amongst 15 fetal deaths, six were associated with maternal death (40%). The median time to fetal death was 2 weeks after the first anthracycline infusion. Fetal death was more frequent after daunorubicin (73%) and in patients with acute leukemia (87%). Administrations during the second and third trimesters could be associated with any of the anthracycline-induced toxicities. Cardiac toxicity was seen in two cases (two cases of myocardial distress; one lethal, one with recovery and one reversible intermittent sinusoidal fetal heart). The lethal cardiac toxicity was consecutive to the injection of 8 mg/kg daunorubicin during the third trimester. The most frequent pathological conditions in preterm newborns were respiratory distress (73%), ventricular hemorrhage (18%) and enterocolitis (9%).


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Table 4. Outcome of the 160 pregnancies following an anthracycline-containing regimen
 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
We report the results of a retrospective analysis of the effects of anthracyclines during pregnancy. From 160 observations, several parameters associated with increased risk for the fetus could be identified.

Progressive maternal disease was the first cause of fetal death. This may account for the significantly higher frequency of unfavorable fetal outcomes in patients with acute leukemia.

A total of five malformations (3%) were reported: three in the first trimester (80%), the period of organogenesis, and two following chemotherapy during the second trimester, one Down’s syndrome unrelated to chemotherapy [17], one eye malformation (congenital adherence of the iris to the cornea, without consequence) [18]. In rats, doxorubicin exposure in utero induced fetal esophageal atresia, trachea–esophageal fistula, and axial alterations [19]. These findings were not reported in pregnant patients. The combination chemotherapy regimens resulting in malformations included ara-C or cyclophosphamide, two agents able to easily cross the placenta [20, 21]. In contrast to other anticancer agents, which may rapidly cross the placenta and have a complete transfer, anthracyclines cross the placenta incompletely for the following reasons: (i) The molecular weights of doxorubicin and daunorubicin are 580 and 564 Da, respectively. Drugs with molecular weights >500 Da have an incomplete transfer across the human placenta [22]. (ii) Anthracyclines are substrates of the P-gp [23], a placental drug-transporting glycoprotein of great importance in vivo in limiting the fetal penetration of potentially harmful compounds [24]. (iii) Placental transfer of relatively hydrophilic molecules is slow, especially for doxorubicin, where a single maternal dose is concerned [22]. (iv) The transplacental transfer of doxorubicin and 4'epi-iadriamycine ex vivo is very low (2.96 ± 0.75% and 3.66 ± 1.07%, respectively) [25, 26]. (v) After intravenous injection of anthracyclines, only barely detectable concentrations can be found in the fetus (Table 2). These concentrations are 100- to 1000-fold below those found in adult tissues or in the tumor in similar conditions [27]. (vi) Fetal uptake of anticancer agents can be profoundly altered by the changes in both uterine and umbilical blood flows observed in various pathophysiological conditions [28]. Placental transfer diminishes under conditions that decrease the surface area or increase the thickness of the placenta. All the changes related to evolutive malignancy are able to affect this parameter, influencing drug penetration.

The risks associated with chemotherapy depend on the date of administration. Both the level of fetal exposure to anthracyclines and the susceptibility to anthracyclines are likely to vary during pregnancy. In patients with solid tumors, chemotherapy during the first trimester, as expected, was significantly associated with more damage than during other trimesters. While the toxicity of anthracyclines during the first trimester is not fully demonstrated, their toxicity during the second and third trimesters is clearly documented. Cardiotoxicity is a specific feature of anthracycline toxicity, and was observed in several cases of late administration.

When exposure to anthracyclines during pregnancy cannot be avoided, we suggest using standard doses. We exclude both dose reduction or the use of very high doses (>70 mg/m2 doxorubicin) in pregnant patients. Bolus or short infusion should be preferred to continuous infusion. Another anthracycline, 4'epi-iadriamycine should be alternatively used in pregnant cancer patients with breast cancer [29] or lymphoma [30] to reduce the risk of fetal myocardiopathy. In leukemia patients, the main risk for the fetus is maternal disease progression and chemotherapy should not be postponed. In other malignancies, whenever possible, anthracyclines should be administered in a therapeutic window which starts with the second trimester (to prevent malformations) until 2 weeks before the delivery (to prevent neonatal infection or neutropenia).

The collection of more information concerning the effects of anticancer agents during pregnancy is an important issue, and the implementation of registries such as ours is useful to generate new information and improve the guidelines.


    Acknowledgements
 
The authors thank B. Mourvilliers, Versailles, France, for providing useful information.


    FOOTNOTES
 
* Correspondence to: Prof. F. Goldwasser, Unité d’Oncologie Médicale, Service de Médecine Interne, Groupe Hospitalier Cochin, AP-HP, 27 Rue du Faubourg St Jacques, 75679 Paris cedex 14, France. Tel: +33-1-58-41-17-47; Fax: +33-1-58-41-15-79; E-mail: francois.goldwasser{at}cch.ap-hop-paris.fr Back


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 Discussion
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