Cytotoxic therapy and pregnancy

Phnrmacol. Ther. Vol. 74, No. 2, pp. 207-220, 1997 Copyright 0 1997 Elsevier Science Inc.

ISSN 0163.7258197 $32.00 PII SOl63-7258(96)00018-l

ELSEVIER

Cytotoxic Therapy and Pregnancy U. Ebert,” H. I_dfjler,+ad W. Kirch*~ *INSTITUTE

OF CLINICAL PHARMACOLOGY,

MEDICAL SCHOOL TECHNICAL UNIVERSITY, FIEDLERSTRAEE 27,01307 DRESDEN, GERMANY

‘DEPARTMENT OF INTERNAL MEDICINE II, CHRISTIAN-ALBRECHTS-UNIVERSITY,

KIEL, GERMANY

ABSTRACT. The use of cytotoxic agents during pregnancy may be unavoidable in order to ensure maternal survivaldespite the dangers to the developing fetus. We review 217 such cases published between 1983 and 1995, classifying them into 5 groups according to whether the cytotoxic drugs were used to treat leukaemias, malignant lymphomas, severe rheumatic diseases, gynaecological/hreast neoplasms, or other grave conditions. Various factors, such as the drug type, dose, and timing to exposure to gestational age, are analysed with respect to the outcome of these pregnancies (teratogenicity, stillbirths, spontaneous abortions, prematurity, etc.). These results are then integrated in order to determine whether one can predict the individual risk of abnormality for the newborn when cytotoxic agents must be administered to pregnant women faced with a malignancy or other serious condition. PHARMACOL. THER. 74(2): 207-220.1997. 0 1997 Elsevier Science Inc. KEY WORDS. Cytotoxic

drugs, cancer, rheumatic disorder, pregnancy.

CONTENTS 1. INTRODUCTION. . . . . . . . . . . . . . .207

1.1.ABNORMALCONGENITAL DEVELOPMENTINHUMANS . . . . .207 1.2.DRUGTREATMENT DURINGPREGNANCY. . . . . . . . .207 1.3.CYTOTOXICTREATMENT DURINGPREGNANCY. . . . . . . . .210 2. CLINICALFINDINGS. . . . . . . . . . . .210 2.1.LEUKAEMIAS.. . . . . . . . . . . . .210 2.2.MALIGNANTLYM~H~MA~ . . . . . .212 ABBREVIATION.

1.

NSAID, nonsteroidal

anti-inflammatory

Abnormal

Congenital Deuebpment

in Humans

and organ rudiments -

Numerous cases of abnormal congenital development been reported in humans. The occurrence abnormalities

have

of many of these

has been ascribed to gene mutations,

chro-

mosomal mutations, and exogenic causes. In the large majority of cases, however,

the cause is unknown.

For their

part, the exogenic causes can be subdivided into infections, X-rays, metabolic diseases, and drug- or xenobiotic-induced injuries. Approximately velopment

7% of all abnormal congenital

de-

appears to be related to drugs, viruses, or envi-

ronmental factors (Persaud, 1990; Thompson et al., 1991). In the course of embryogenesis,

each organ has one or

more periods during which it is especially sensitive to noxious exogenic the moment

substances

(sensitive

in fetal development

fluences are introduced,

phase).

Depending

on

when these harmful in-

they can provoke death, abnormal-

ities of varying degrees, developmental retardations, or functional defects. Apart from a few exceptions (e.g., infections), the abnormalities cannot be initiated before nidation. In the early phase of fetal development, the embryo seems to react according to an “all-or-none law”, i.e., it either dies or will survive unimpaired. SComsponding author.

drug.

phase of embryogenesis

INTRODUCTION

1.1.

2.3. RHEUMATICDISORDERS . . . . . . .212 2.4.G~NAECOLOGICAIJBREAST NEOPLASMS . . . . . . . . . . . . . .212 2.5.SEVEREMISCELLANEOUS DISORDERS . . . . . . . . . . . . . .214 3. CYTOTOXICDRUGS,ADMINISTRATION PERIODSANDFETALOUTCOME . . . . . .214 4. DISCUSSION.. . . . . . . . . . . . . . . .216 REFERENCES . . . . . . . . . . . . . . . . . .219

In the subsequent

velop abnormalities formation

-

the phase of organ development the embryo will either die or de-

of differing severities. Each type of mal-

can only occur at specific times. Disturbances

differentiation

to

of the fetus at more advanced developmen-

tal stages manifest as retardations

or dysfunctions.

Finally,

towards the end of gestation, the fetus reacts like a newborn exposed to a noxious substance.

Indeed, in this phase, the

same undesirable drug effects are possible as those encountered in the newborn. They may be even more accentuated due to the immaturity of the organs affected. Factors influencing tal disturbance

the degree and type of developmen-

include the drug or substance

in question,

the doses of the agent, as well as the genotype of the organism. Drugs administered before gestation can also affect the unborn child because of their often long elimination

half-

lives. Some drugs such as cytostatics are mutagenic and may give rise to chromosomal or gene alterations. Nevertheless, the incidence of these mutations is rather low, even after intensive cytostatic treatment (Kleinebrecht et al., 1990). 1.2.

Drug Treatment

Drug treatment

During Pregnancy

during pregnancy presents physicians with

particular challenges. For one thing, the continually changing metabolic and hormonal environment of the pregnant

208

TABLE

U. Ebert et al. 1. Cases With Cytotoxic

Drug Treatment

for Leukaemia

Used Before and During Gestation

Treatment

Diagnosis (reference)

(n = 96, references

Time of treatment

1983-1995)

Fetal outcome

6-Mercaptopurine, vincristine, aminopterin, cyclophosphamide, prednisone Cyclophosphamide, prednisone

Before pregnancy, conception, first, second, third trimester

Twins, male infant with multiple anomalies

From first trimester

Cytarabine

From gestational week 5 From gestational week 22

Acute lymphatic leukaemia (Wiebe and Sipila, 1994)

Cyclophosphamide, cytarabine, daunorubicin, vincristine, L-asparaginase, methotrexate, 6_mercaptopurine, prednisone, radiation treatment Cyclophosphamide, vincristine, methotrexate, L-asparaginase, daunorubicin, 6_mercaptopurine, prednisone, radiation treatment Vincristine, doxorubicin, L-asparaginase, cyclophosphamide, 6-mercaptopurine, methotrexate, prednisone Methotrexate, 6-mercaptopurine, vincristine, doxorubicin, cytarabine, prednisone Cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, methotrexate, prednisone Methotrexate, vincristine, 6-mercaptopurine, daunorubicin, prednisone 6_Mercaptopurine, cytarabine, vincristine, daunorubicin, prednisone

Twins, male infant with multiple anomalies Multiple anomalies, normal karyotype Chromosomal gaps and rings found on karyotyping

Acute lymphatic leukaemia (Wiebe and Sipila, 1994)

Cytarabine, 6-thioguanine, allopurinol

Acute lymphatic leukaemia (Aviles et al., 1991; Wiebe and Sipila, 1994), 13 cases

Vincristine, doxorubicin, 6-mercaptopurine, methotrexate, cyclophosphamide, cytarabine, L-asparaginase, daunorubicin, prednisone, radiation treatment Cytarabine, daunorubicin, 6-thioguanine

First, second, third trimester

Maternal death at gestational week 23, normal placenta, fetus at autopsy Normal development, death following preeclamptic toxemia Normal development

From gestational week 20

Normal development

Doxorubicin, vincristine, prednisone L-asparaginase, methotrexate intrathecal, radiation treatment Cytarabine, doxorubicin, 6-thioguanine, vincristine, daunorubicin, prednisone

From gestational week 2 1 From gestational week 21

Normal development

Conception, trimester

Normal development

Cytarabine, Cytarabine,

daunorubicin 6-thioguanine

Conception 35-37 days post-conception

Cytarabine,

daunorubicin,

Cytarabine,

6-thioguanine

Acute lymphatic leukaemia (Zemlickis et al., 1993) Acute lymphatic leukaemia (Wiebe and Sipila, 1994) Acute lymphatic leukaemia (Wiebe and Sipila, 1994) Acute lymphatic leukaemia (Wiebe and Sipila, 1994)

Acute lymphatic leukaemia (Wiebe and Sipila, 1994)

Acute lymphatic leukaemia (Wiebe and Sipila, 1994)

Acute lymphatic leukaemia (Wiebe and Sipila, 1994) Acute lymphatic leukaemia (Wiebe and Sipila, 1994), 2 cases Acute lymphatic leukaemia (Wiebe and Sipila, 1994)

Acute non-lymphatic leukaemia (Wiebe and Sipila, 1994) Acute lymphoblastic leukaemia (Karp et al., 1983) Acute promyelocytic leukaemia (Wiebe and Sipila, 1994), 4 cases Acute myelocytic leukaemia (Artlich et al., 1994)

Acute myelocytic leukaemia (Wiebe and Sipila, 1994) Acute myelocytic leukaemia (Wiebe and Sipila, 1994)

daunorubicin,

6-thioguanine

From gestational week 12.5

Severe bone marrow hypoplasia

From gestational week 16

Normal development, slight leukopenia

Conception

Normal development, polycythemia, hyperbilirubinemia Normal development, pancytopenia, septicemia, respectively, gastroenteritis Twins, normal development, diarrhea at 24 hr

First, second, third trimester

From gestational week 18

Conception

From gestational week 15

second, third

From gestational week 25 Conception, first, second, third trimester

Choanal stenosis, mild hypotelorism, severe brachycephaly with hypoplasia of naso- and oropharynx, bilateral four finger hands with hypoplastic thumbs Iris adhered to cornea Multiple skeletal anomalies

Cytotoxic Therapy and Pregnancy

209

TABLE 1. Continued Diagnosis (reference) Acute myelocytic leukaemia (our case)

Treatment

Time of treatment

Fetal outcome

Acute myelocytic leukaemia (Wiebe and Sipila, 1994) Acute myelocytic leukaemia (Morishita et al., 1994)

Cytarabine, daunorubicin, 6-thioguanine, mitoxantrone Vincristine, doxorubicin, cytarabine, prednisone Methotrexate, vincristine, 6_mercaptopurine, prednisone Cytarabine, daunorubicin, 6-mercaptopurine, prednisone

Acute myelocytic leukaemia (Wiebe and Sipila, 1994) Acute myelocytic leukaemia (Wiebe and Sipila, 1994)

Cytarabine, daunorubicin, vincristine, 6-thioguanine Cytarabine, vincristine, doxorubicin, prednisone

Acute myelocytic leukaemia (Wiebe and Sipila, 1994) Acute myelocytic leukaemia (Wiebe and Sipila, 1994) Acute myelocytic leukaemia (Reynoso and Huerta, 1994)

Cytarabine, daunorubicin, vincristine, prednisone, hydroxyurea Cytarabine, 6-thioguanine

From gestational week 17

Cytarabine, ldarubicin

From gestational week 20 From gestational week 35

Acute myelogenous leukaemia (Zemlickis et al., 1992)

Doxorubicin,

Acute myelocytic leukaemia (Aviles et al., 1991; Wiebe and Sipila, 1994; Zemlickis et al., 1992; our case), 21 cases Acute myelomonocytic leukaemia (Wiebe and Sipila, 1994) Acute monocytoma (Wiebe and Sipila, 1994) Lymphoblastic leukaemia (Feldkamp and Carey, 1993) Lymphoblastic leukaemia (Feldkamp and Carey, 1993), 3 cases Lymphatic leukaemia (Feldkamp and Carey, 1993) Myeloid leukaemia (Feldkamp and Carey, 1993) Myelomonocytic leukaemia (Feldkamp and Carey, 1993) Chronic myeloid leukaemia (Wiebe and Sipila, 1994) Chronic myeloid leukaemia (Wiebe and Sipila, 1994) Chronic myeloid leukaemia (Zemlickis et al., 1992) Chronic myeloid leukaemia (Baer, 1991; Grump et al., 1992; Norhaya et al., 1994; Wiebe and Sipila, 1994; Zemlickis et al., 1992), 12 cases

Doxorubicin, cytarabine, 6-mercaptopurine, methotrexate, cytarabine, cyclophosphamide, vincristine, daunorubicin, 6-thioguanine, prednisone, allopurinol 6-Mercaptopurine, methotrexate, cytarabine

Conception, first, second, third trimester

First, second, third trimester

Normal development

Cytarabine,

From gestational week 23

Normal development

Methotrexate, vincristine, cyclophosphamide, 6_mercaptopurine, cytarabine, prednisone Methotrexate, cyclophosphamide, vincristine, 6-mercaptopurine, doxorubicin, cytarabine, prednisone Methotrexate, 6-mercaptopurine, vincristine, cytarabine, prednisone

First, second, third trimester

Pancytopenia

First, second, third trimester

Normal development

First, second, third trimester

Normal development

Methotrexate, vincristine, 6-mercaptopurine

First trimester (8 weeks)

Normal development

From gestational week 4-8

Normal development

From gestational week 29

Thrombocytopenia

Busulfan, radiation treatment

Not stated

Daunorubicin, cytarabine, 6-thioguanine, hydroxyurea Busulfan, 6-mercaptopurine, a-interferon, hydroxyurea, allopurinol, radiation treatment

First trimester

Spontaneous abortion at 4 months Therapeutic abortion

Methotrexate, cytarabine Cytarabine,

daunorubicin

cytarabine, 6-thioguanine

daunorubicin,

6-thioguanine

adriamycin,

6_mercaptopurine,

daunorubicin

Before pregnancy Before pregnancy, conception, until gestational week 8 From gestational week 32 From gestational week 24-29

From gestational week 27 From gestational week 16

From gestational week 22

Second trimester

Before pregnancy, conception, first, second, third trimester

Atria1 septum defect, bilateral radius and digit 5 absent, artificial respiration Cushingoid Normal development, decreased red blood cell count on day 10 of life Anemia, electrolyte imbalances Spontaneous abortion prior to maternal death at 18 weeks Elective abortion at 21 weeks Fetal death 14 days postchemotherapy Stillbirth at 35 weeks, without congenital abnormal development Stillbirth at 26 weeks, born with bruising and petechia over multiple areas Normal development

Normal development

U. Ebert et al.

210 TABLE 1. Continued Diagnosis

Chronic granulocytic leukaemia (Wiebe and Sipila, 1994) Chronic granulocytic leukaemia (Wiebe and Sipila, 1994) Chronic granulocytic leukaemia (Aviles et al., 1991; Wiebe and Sipila, 1994), 5 cases Erythroleukaemia (Wiebe and Sipila, 1994)

patient

may influence

namics.

More worrisome

First, second, third trimester

Multiple anomalies, death at 2 months

Busulfan

From gestational week 8

Mild anemia, neutropenia

Conception, first, second, third trimester

Normal development

From gestational week 24

Normal development

Busulfan, 6-mercaptopurine,

Cytarabine,

have

1992).

documented

prednisone

6-thioguanine

and pharmacody-

are the potentially

(Shepard,

only been

doxorubicin,

pharmacokinetics

that drugs may exert on the developing imal experiments

harmful

effects

fetus. Indeed, as teratogenic

However,

more in an-

fetotoxic

se-

for some of these

fac-

tors. This is partly due to the fact that the therapeutic

dose used in humans is lower than. the minimal teratogenic dose applied in animals. In addition, the genotype of the organism also plays an important role. Teratogens may exert specific effects on persons with a particular genetic make-up, but interindividual differences may also be observed among people of the same race. 1.3.

Cytotoxic Treatment

During Pregnancy

Despite their general contraindication during gestation due to the increased risk for teratogenicity/mutagenicity (Kalter, 1968; Nishimura and Tanimura, 1976; Shepard, 1992), the use of cytotoxic agents may be unavoidable since delays in their administration may compromise maternal survival. This is particularly true when leukaemias or cancer are diagnosed before or during pregnancy; their incidence in pregnant women has been estimated to vary between 0.07% and 0.1% (Zemlickis et al., 1992). In order to render possible a more accurate assessment of risk (Sweet and Kinzie, 1976; Shepard, 1992; Briggs, 1994) to the developing fetus, we present 2 reports and review the cases of cytostatic treatment during pregnancy that have been published between 1983 and 1995. The 217 cases described during this 12-year period were assigned to 5 groups according to whether the cytotoxic agents were used to treat leukaemias, malignant lymphomas, severe rheumatic disease, gynaecological/breast neoplasms, or other grave conditions (other cancers, infections, thrombocythaemia, etc.) for which such drugs are also indicated. 2. CLINICAL 2.1.

FINDINGS

Leukaemias

occurrence of leukaemia in women during the reproductive years is relatively rare, as the fertility of such

The

Fetal outcome

Busulfan, 6_mercaptopurine, radiation treatment

than 600 factors have been catalogued quelae

Time of treatment

Treatment

(reference)

women presumably decreases. Nevertheless, preconceptional exposure to cytostatics, or treatment during preg nancy, has been described frequently (Table 1). At the University Hospital in Kiel, Germany, we recently were confronted with two such cases. Case Report 1: A 25year-old pregnant woman consulted with us because of dizziness, loss of appetite, reduced physical fitness, and petechial haemorrhages on the thighs and the lower legs. She was soon diagnosed as having an acute myelogenous leukaemia (subtype M2). Remission induction treatment, initiated at gestational week 18119, involved the use of cytarabine (8 X 160 mg), daunorubitin (3 X 90 mg), and 6-thioguanine (14 X 160 mg). Antibiotic treatment with cefotaxime and piperacillin was also necessary. The patient remained in complete remission after the initial cytostatic induction treatment. A second induction cycle was carried out with the same set of cytotoxic agents used previously, followed by maintenance therapy consisting of cytarabine, daunorubicin, methotrexate, and dexamethasone during her term of pregnancy. The patient went into labor at gestational week 39 and delivered a healthy female infant. Case Report 2: Haematological examinations were carried out in another woman because of a severe menstrual period. The patient was tentatively diagnosed as having an Addisonian anemia. However, repeated bone marrow biopsies finally led to the diagnosis of an acute myelogenous leukaemia (subtype M3). After induction treatment with cytarabine, daunorubicin, and 6-thioguanine, the patient remained in complete remission. Additional antibiotic treatment with vancomycin, amikacin, imipenem, amphotericin B, and ofloxacin was necessary because of intermittent sepsis and pneumonia. Her cytostatic maintenance cycle consisted of vincristine, doxorubicin, cytarabine, and prednisone. Eight months after the diagnosis of leukaemia, the patient became pregnant. Cytostatic maintenance was terminated at gestational week 8. The patient went into labor, delivering a female infant suffering from an atria1 septum defect, as well as a bilateral loss of the radius and fifth digit. In addition

to the two aforementioned

cases, 94 reports

Therapy and Pregnancy

Cytotoxic

fetaloutcome 100%

211

-

T

80% --

.3%

2.7%

‘3.0%

0 livebirth infant, normaldevelopment

20% t 10%

0%

L

-_

leukaemia

FIGURE

1. Fetal outcome

of perigestational

after maternal cytotoxic

cytostatic

treatment

found in the literature between pregnant

treatment

of leukaemia

which

1994),

cytarabine,

vincristine,

prednisone.

A therapeutic

consisted

were

(Wiebe

of 6-mercaptopurine,

daunorubicin, abortion

doxorubicin,

diagnosis

severe misoellaneous diseases

before or during gestation.

1983 and 1995. Of these, 2

women died in the course of treatment

and Sipila,

gynaeoological neoplasm

rheumatic disorders

malignant lymphoma

and

was performed in two

est. In each case, a male and a female infant were delivered. Although

the females were born healthy,

were affected mothers

with

multiple

congenital

the male infants anomalies.

were treated with cyclophosphamide,

topurine,

vincristine,

aminopterin,

lickis et al., 1993; Thomley

and prednisone

and Manoharan,

other cases; the patients had received combination

therapy

1). Those pregnant women under treatment

involving

vincris-

who gave birth to stillborn

tine,

such drugs as cytarabine,

6-thioguanine,

prednisone,

lickis et al., 1992; Wiebe

daunorubicin, and hydroxyurea

and Sipila,

abortion occurred once after treatment with radiation treatment

(Wiebe

1994).

Spontaneous

with busulfan along

ceiving cytarabine,

daunorubicin,

and 6-thioguanine

(Zemlickis

their mothers re-

idarubicin,

et al., 1992;

1994). A chromosomal

doxorubicin, Reynoso

abnormality

mosomal

anomalies

and

was found in

congenital

development,

Among

ties or severe

(Wiebe

and Sipila,

prednisone,

cytara-

methotrex-

and radiation treatment

1994).

Eight other

children

demon-

strated abnormal congenital

development

of varying severi-

the mothers

the 96 cases, 9 newborns

with cyclophosphamide,

ate, 6-mercaptopurine,

development an-

(25%).

received

treatment

during the first trimester.

Her mother

L-asparaginase,

congenital

drugs most frequently: cyt-

In 7 of the 8 cases in which a child demonstrated an abnormal

phenotype

vincristine,

for leukaemia

or infants with chro-

arabine (9 of 12 cases, 75%), thiolated purines (66.6%),

gaps and rings on karyotyping).

bine, daunorubicin,

or abnormal

received the following cytotoxic

one infant (chromosomal was treated

children

(Zem-

1994; Table

thracycline antibiotics (50%), and cyclophosphamide

and Sipila, 1994).

In this series, 2 children were stillborn,

Huerata,

(Zem-

The

6-mercap-

Carey,

1993;

1994).

Their

including vincristine

without pathological

were found to have haematological bone

marrow hypoplasia

Morishita mothers

et al.,

1994;

had received

such drugs as cytarabine (66.7%)

and thiolated

abnormali-

(Feldkamp

Wiebe

and

and Sipila,

combination

therapy,

(7 of 9 cases, 77.8%), purines (66.7%),

as well

ties (Zemlickis et al., 1993; Artlich et al., 1994; Zemlickis et al., 1994; our Case Report 2). Their mothers had received combination therapy involving such drugs as 6-thiogua-

as cyclophosphamide, anthracycline antibiotics, methotrexate, and prednisone (each 55.6%). In 8 out of 9 cases, cytotoxic therapy was administered until the third trimester.

nine, cytarabine,

Two of the 9 children died of infection within 4 weeks after

daunorubicin,

tine, cyclophosphamide,

6-mercaptopurine,

aminopterin,

vincris-

busulfan, doxorubi-

tin, and mitoxantrone. Three of the latter patients were also treated with prednisone, and one received radiotherapy. Two reports of twin pregnancies were of special inter-

delivery;

their mothers

were treated

with cyclophospha-

mide, cytarabine, 6-mercaptopurine, vincristine, methotrexate, and prednisone during pregnancy (Wiebe and Sipila, 1994). A total of 39 of the 88 live-born children were pre-

U. Ebert et al.

212 term births with or without

malformations,

although

the

half of the live-born

infants for whom the gestational

duration of pregnancy was not noted carefully in all cases.

riod was recorded (22 of 42) were healthy full-term

Thirty-three gestational

infants (42.9%)

for whom the

borns (Fig. 1). In no cases were haematological

period was entirely documented

turned out to

ties observed

of 77 live-born

with regard to treated

be healthy, full-term infants (Fig. 1). Finally, among the large number of cytotoxic ministered

in the cases described,

the one (or combination) with adverse outcomes. presented

drugs ad-

it is difficult to identify

that is responsible for those cases Moreover,

in this group. Upon

in all leukaemia

(see Table 6), it is difficult to determine

cases defini-

pregnant

or spontaneous

the data

abnormal congenital

de-

abortion, the mothers had most

frequently received cytotoxic (6 of 10 cases, 60%),

abnormali-

summarizing

women with malignant

lymphomas resulting in stillbirth, velopment,

penew-

drug therapy with vincristine

glucocorticoids

(60%),

and procarba-

zine (40%).

tively whether the drugs used or the underlying disease led to the adverse developments

that were documented.

2.3.

Rheumatic

Disorders

In terms of frequency, 2.2.

Malignant

&nphumas

Hodgkin’s disease is a malignancy in women of childbearing age-specific

incidence

commonly

encountered

age. The disease has a bimodal

rate, with the earlier peak occurring

mostly in the third decade of life. Non-Hodgkin’s mas tend to manifest

themselves

ever, 57 cases involving lymphomas between

lympho-

during older age. How-

cytotoxic

treatment

prior to and during pregnancy

of malignant were reported

1983 and 1995. Hodgkin’s disease was diagnosed

in 24 of these cases (Table

2). Therapeutic

performed in 6 of the 57 pregnancies. tion were treated with vincristine, phamide, mechlorethamine omycin, vinblastine,

abortions were

The patients in ques-

procarbazine, cyclophos-

hydrochloride,

doxorubicin,

dacarbazine, prednisone,

ble-

and radiation

treatment (Sandvei et al., 1990; Zemlickis et al., 1992; Wiebe and Sipila, 1994). T wo of these fetuses showed multiple abnormalities;

their mothers had received combination

apy involving such drugs as vincristine, phosphamide,

prednisone,

ther-

procarbazine, cyclo-

and radiation treatment

and Sipila, 1994). Out of the 4 spontaneous

(Wiebe

abortions that

occurred (du Bois et al., 1990; Zemlickis et al., 1992; Wiebe and Sipila, 1994),

abnormal development

was observed in

one fetus, with the mother in question treated with vinblastine and procarbazine with pregnancies treated

(Wiebe

ending

with vinblastine,

hydrochloride,

procarbazine,

vincristine,

tin, and prednisone.

and Sipila,

1994).

in spontaneous

Patients

abortions

were

mechlorethamine

6-mercaptopurine,

doxorubi-

In 3 of the 4 cases, treatment

occurred

rheumatic

disorders stand in third

place behind diseases affecting the circulatory

and pulmo-

nary systems. Women

from rheu-

suffer more frequently

matic problems than do men. The most common treatment strategies for rheumatic diseases include curative and palliative therapy.

Cytotoxic

been prescribed

immunosuppressive

with some success-albeit

than is suggested for the treatment make the occurrence lating

agents

has

of tumors. This tends to

of undesirable effects less likely. Alky-

(cyclophosphamide)

(methotrexate)

therapy

at lower doses

and

are not infrequently

antimetabolites

used for the treatment

of serious rheumatic conditions. During the 12-year period under consideration, of cytotoxic

abortions occurred in 6 cases (Feldkamp Donnenfeld trexate.

Additionally,

these

anti-inflammatory

and hydroxychloroquine. were premature 1994).

and Carey, 1993;

et al., 1994), with all patients receiving methowomen

with such drugs as acetylsalicylic steroidal

(Fields

received

treatment

acid, glucocorticoids,

drugs (NSAIDs),

Two of the 10 live-born et al.,

1991;

non-

folic

acid,

infants

Donnenfeld

et al.,

The mothers of the premature infants were treated

with methotrexate

or cyclophosphamide/prednisone

the first and second trimester, respectively. genital development 2.4.

16 cases

therapy were described (Table 3). Spontaneous

rian carcinoma

during con-

was not observed (Fig. 1).

@naecologicd/J3reat

The simultaneous

Abnormal

occurrence

Neoplasms of pregnancy and either ova-

or breast cancer is relatively rare, with re-

within the first trimester. One pregnancy terminated with a

ported incidences of 2-5% and l-3%

stillborn

lignancies (King et al., 1991; Bami et al., 1992). A total of

infant at gestational

congenital

development

week 31 without abnormal

(Karp et al., 1983); the patient re-

ceived dexamethasone, radiation vincristine, and prednisone.

treatment,

doxorubicin,

of their respective ma-

26 such cases were described in the literature from 1983 to 1995 (Table 4). Of these, spontaneous abortions occurred in 3 cases; the mothers in question received treatment with

Three of the 47 live-born infants showed signs of abnormal development (Zemlickis et al., 1992; Wiebe and Sipila,

cisplatin,

1994).

and melphalan in the third (Curtin and Adcock, 1986; Zemlickis et al., 1992). The therapies were all started before

The combination

therapies used in these cases in-

cluded such drugs as mechlorethamine

hydrochloride, vincris-

tine, procarbazine, cyclophosphamide, vinblastine, and prednisone. The patients were treated into or as of the first trimester, or the treatment was started from gestational week 25. Approximately half of the pregnancies for which the gestational period was known resulted in the delivery of preterm infants, with or without malformations. More than

bleomycin,

phosphamide,

vinblastine

methotrexate,

in the first case; cyclo-

5-fluorouracil

in the second;

or during the first trimester. Four out of the 23 live-born infants showed abnormal developments of different severities (Feldkamp and Carey, 1993; Cullins et al., 1994; Donnenfeld et al., 1994; Wiebe and Sipila, 1994); their mothers were treated with methotrexate (2 cases), tamoxifen, and cyclophosphamide/radia-

213

Cytotoxic Therapy and Pregnancy TABLE 2. Cases With Cytotoxic Drug Treatment for Malignant Lymphomas Used Before and During Gestation (n = 57, references 1983-1995) Time of treatment

Treatment

Diagnosis (reference)

Hydrocephalus, died 4 hr after birth Multiple anomalies

Hodgkin’s disease (Zemlickis et al., 1992) Hodgkin’s disease (Wiebe and Sipila, 1994) Hodgkin’s disease (Wiebe and Sipila, 1994) Hodgkin’s disease (Wiebe and Sipila, 1994)

Mechlorethamine hydrochloride, vincristine, procarbazine, prednisone Cyclophosphamide

First trimester

Vinblastine,

vincristine,

From gestational week 25

Vincristine,

procarbazine,

Hodgkin’s (Wiebe Hodgkin’s (Wiebe

Cyclophosphamide,

disease and Sipila, 1994) disease and Sipila, 1994)

Hodgkin’s disease (Zemlickis et al., 1992) Hodgkin’s disease (Wiebe and Sipila, 1994) Hodgkin’s disease (Zemlickis et al., 1992) Hodgkin’s disease (Aviles et al., 1991), 14 cases Hodgkin’s disease (Wiebe and Sipila, 1994) Non-Hodgkin’s lymphoma (Sandvei et al., 1990) Non-Hodgkin’s lymphoma (Zemlickis et al., 1992) Non-Hodgkin’s lymphoma (du Bois et al., 1990) Non-Hodgkin’s lymphoma (Zemlickis et al., 1992) Non-Hodgkin’s lymphoma (Nantel et al., 1990) Non-Hodgkin’s lymphoma (du Bois et al., 1990), 4 cases Non-Hodgkin’s lymphoma (Toki et al., 1990) Non-Hodgkin’s lymphoma (Lambert et al., 1991) Non-Hodgkin’s lymphoma (Moore and Taslimi, 1991) Non-Hodgkin’s (Avileseral.,

lymphoma 1991), 18cases

Non-Hodgkin’s lymphoma (Wiebe and Sipila, 1994) T-Cell Lymphoma (Karp et al., 1983) Burkitt-Lymphoma (du Bois et al., 1990)

tion treatment,

respectively,

Vinblastine,

From first trimester

procarbazine

From first trimester

radiation treatment

First trimester

procarbazine

First trimester

6-Mercaptopurine vincristine,

First trimester

prednisone

before

or during

preg-

nancy. A total of 53% of newborns for whom the gestational period was known were premature infants with or without malformations. In these cases, doxorubicin, methotrexate,

Therapeutic abortion 15 hr after chemotherapy Spontaneous abortion

From gestational week 17

Cyclosphosphamide, vincristine, prednisone Methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone Cyclophosphamide, doxorubicin, vincristine, bleomycin, prednisone Adriamycin, cyclophosphamide, vincristine, prednisone Cyclophosphamide, doxorubicin, vincristine, bleomycin, teniposide, prednisone Cyclophosphamide, doxorubicin, vincristine, etoposide, bleomycin, methotrexate, prednisone Cyclophosphamide, adriamycin, vincristine, bleomycin, etoposide, methotrexate, cytarabine, prednisone Cyclophosphamide, doxorubicin, vincristine, prednisone Dexamethasone, radiation treatment Doxorubicin, vincristine, prednisone Cyclophosphamide, vincristine, doxorubicin, VP 26, prednisone

either

Atria1 septum defect, death day 2 Therapeutic abortion at 92 days, renal and cardiac abnormalities Therapeutic abortion at 6 months, multiple anomalies Spontaneous abortion at gestational week 24, multiple anomalies Therapeutic abortion

First trimester

prednisone

Mechlorethamine hydrochloride, vincristine, procarbazine, prednisone Doxorubicin, bleomycin, vinblastine, dacarbazine Mechlorethamine hydrochloride, vincristine, procarbazine, prednisone Mechlorethamine hydrochloride, vincristine, procarbazine, adriamycin, bleomycin, vinblastine, dacarbazine, prednisone Cyclophosphamide, vincristine, procarbazine, prednisone Cyclophosphamide, doxorubicin, vincristine, prednisone

Doxorubicin,

Fetal outcome

Before pregnancy, first, second, third trimester

Normal development

From gestational week 18

Normal development

Before pregnancy

First trimester

Therapeutic abortion After 2 years full-term newborn, normal development Spontaneous abortion

From gestational week 30

Spontaneous

Second trimester

Therapeutic

From gestational week 18

Twins, normal development

Conception, first, second, third trimester From gestational week 29

Normal development

From gestational week 22

Normal development

From gestational week 21

Normal development

First, second, third trimester

Normal development

Conception

Normal development

From gestational week 25 From gestational week 3 1 From gestational week 22

Stillbirth at gestational week 3 1, normal development Normal development

cyclophosphamide,

and

abortion abortion

Normal development

vincristine

were used most fre-

quently. One child showed intrauterine growth retardation (Zemlickis et al., 1992). Finally, upon summarizing the data from the women in this group with spontaneous abortions

U. Ebert et al.

214

TABLE 3. Cases With Cytotoxic Drug Treatment for Rheumatic Disorders Used Before and During Gestation (n = 16, references 1983-1995) Treatment

Diagnosis (reference) Rheumatoid arthritis (Donnenfeld et al., 1994) Rheumatoid arthritis (Donnenfeld et al., 1994) Rheumatoid arthritis (Donnenfeld et al., 1994) Rheumatoid arthritis (Feldkamp and Carey, 1993) Rheumatoid arthritis (Feldkampand Carey, 1993) Rheumatoid arthritis (Feldkampand Carey, 1993) Rheumatoid arthritis (Donnenfeld et al., 1994) Rheumatoid arthritis (Donnenfeld et al., 1994) Rheumatoid arthritis (Donnenfeld et al., 1994) Rheumatoid arthritis (Donnenfeld et al., 1994) Rheumatoid arthritis (Feldkamp and Carey, 1993) Rheumatoid arthritis (Feldkamp and Carey, 1993) Rheumatoid arthritis (Feldkamp and Carey, 1993) Rheumatoid arthritis (Feldkamp and Carey, 1993) Rheumatoid arthritis (Feldkamp and Carey, 1993) Wegener’s granulomatosis (Fields et al., 1991)

and infants with abnormal

Gestational

week O-9

Gestational

week O-8

Spontaneous

abortion

Gestational

week O-4

Spontaneous

abortion

Gestational

week 3-5

Gestational week 36 at birth, normal development Gestational week 40 at birth, normal development Gestational week 41 at birth, normal development Gestational week 42 at birth, normal development Full-term infant, normal development Full-term infant, normal development Full-term infant, normal development Full-term infant, normal development Full-term infant, normal development Premature infant, normal development

Before pregnancy

Methotrexate

Before pregnancy

Methotrexate,

Before pregnancy

prednisone

Methotrexate, aspirin, steroid, folic acid, NSAID, hydroxychloroquine Methotrexate, aspirin, folic acid, hydroxychloroquine Methotrexate, steroid, folic acid Methotrexate Methotrexate,

aspirin, plaquinal

Methotrexate

Up to gestational week 3 Before pregnancy

Methotrexate

Before pregnancy

Methotrexate, aspirin, steroid, folic acid, NSAID, hydroxychloroquine Methotrexate, aspirin, steroid, hydroxychloroquine Methotrexate, aspirin, steroid, hydroxychloroquine Methotrexate, aspirin, steroid, folic acid, NSAID, hydroxychloroquine Methotrexate, aspirin, steroid, folic acid, NSAID, hydroxychloroquine Cyclophosphamide, prednisone

Gestational

week O-3

Gestational 12 Gestational

week O-

Gestational

week O-2

congenital

developments

toxic drug therapy with methotrexate

the

prescribed cyto-

(42.8%

Fetal outcome Spontaneous gestational Spontaneous gestational Spontaneous gestational Spontaneous

Methotrexate

mothers in question were most frequently and cyclophosphamide

Time of treatment

of such cases)

week O-2

Gestational week O15 From gestational week 17

had received

cytotoxic

side, and cisplatin

treatment

with bleomycin,

in the third trimester.

anomaly was detected

in another

was treated with 5fluorouracil

(28.6%).

abortion at week 12 abortion at week 12 abortion at week 5 abortion

etopo-

A chromosomal

newborn whose mother intravaginally

during her

early weeks of pregnancy (Van Le et al., 1991). Of the chil2.5.

Severe Miscellaneous Diseases

Between

1983 and 1995, 22 cases of perigestational

toxic treatment (Table

were reported for varying severe illnesses

5). These

noma, melanoma, virus infections and nonspecified

cyto-

included

Ewing’s sarcoma,

thrombocythaemia, of the genital

liver carci-

psoriasis, papilloma-

tract, bacterial

infections,

diseases. In this series, one spontaneous

and one therapeutic abortion were reported: the mothers were treated with methotrexate and dacarbazine, respectively (Zemlickis et al., 1992; Donnenfeld et al., 1994), before and during the first trimester. Two newborns whose mothers were treated with methotrexate during gestation

dren whose gestation

period was known

third were premature

infants with or with&t

(n = 14), onemalforma-

tions, while 8 out of 14 live-born infants were healthy, fullterm newborns (Fig. 1). When those pregnancies abnormal malities,

congenital

development,

and spontaneous

abortion

mothers had received cytotoxic

chromosomal

involving abnor-

are considered,

the

drug therapy with methotr-

exate in 75% of the cases. 3. CYTOTOXIC DRUGS, ADMINISTRATION PERIODS AND FETAL OUTCOME Between

1983 and 1995, a total of 217 cases involving the

acquired congenital malformations that coincided with the “aminopterin syndrome”: oxycephaly, absent or delayed ossification of the skull, hypertelorism, and malformations of

use of cytotoxic treatment before or during pregnancy were described in the literature. Of these, 18 newborns showed multiple abnormalities of differing severities; additionally 2

the extremities (Feldkamp and Carey, 1993). One infant showed changes in blood count and loss of scalp hair at 10 days of age; at 1 year of age, a moderate sensorineural hearing loss was diagnosed (Raffles et al., 1989). The mother

other infants had chromosomal abnormalities. Twelve of these 18 mothers were treated with folic acid, purine, or py rimidine antagonists. In 15 of these cases, cytotoxics were administered along with other drugs during the first trimes-

Cytotoxic

TABLE

215

Therapy and Pregnancy

4.

Cases With Cytotoxic

Drug Treatment

for Gynaecological Neoplasma and Breast Cancer Used Before and During Gestation

(n = 26, references 1983-1995) Treatment

Diagnosis (reference)

Time of treatment

Hydatiform mole (Feldkamp and Carey, 1993)

Methotrexate

Papillary serous adenocarcinoma of the right ovary (King et al., 1991)

Operation,

Endodermal sinus tumor of the right ovary (Curtin and Adcock, 1986)

Operation, cisplatin, vinblastine

Immature teratoma of the left ovary (Schneider et al., 1988) Immature teratoma of the left ovary, mature teratoma of the right ovary (Lee et al., 1989) Papillary serous cystadenocarcinoma (Malfetano and Goldkrand, 1990) Immature teratoma of the right ovary (Christman et al., 1990) Papillary serous cystadenocarcinoma of the right ovary (Shaves et al., 1990)

Operation, vincristine, cyclophosphamide

actinomycin

D,

Before pregnancy

Operation, vincristine, cyclophosphamide

actinomycin

D,

Before pregnancy

Ovarian carcinoma (Zemlickis et al., 1992) Endodermal tumor of the ovary (Wiebe and Sipila, 1994) Choriocarcinoma (Bakri et al., 1991) Choriocarcinoma (Feldkamp and Carey, 1993) Progesterone-receptor-positive breast cancer (Cullins er al., 1994) Breast cancer (Donnenfeld et al., 1994) Breast cancer (Wiebe and Sipila, 1994) Intraductal breast carcinoma (Donnenfeld et al., 1994)

Operation,

Gestational

cisplatin,

cisplatin,

Operation Cisplatin, vinblastine,

week 8-32

cyclophosphamide

From gestational

bleomycin,

Before pregnancy

cyclophosphamide

bleomycin

week 16

doxorubicin,

Cyclophosphamide, vincristine, doxorubicin Cisplatin, etoposide, actinomycin methotrexate intrathecal Methotrexate Methotrexate Chlorambucil, actinomycin D Tamoxifen

cisplatin

week 16

Full-term infant, normal development

15 week gestation From gestational week 19

Full-term infant, normal development

Third trimester

Delivery 26 months following the intraperitoneal chemotherapy, full-term infant, normal development Normal development

From gestational

From gestational D,

Methotrexate

week 17

Before pregnancy Gestational week 1 l-l 2 I4 week gestation 15 week gestation Before pregnancy, first, second, third trimester Before pregnancy

Cyclophosphamide,

radiation treatment

From gestational Gestational

Methotrexate

Breast cancer (Zemlickis et al., 1992)

Cyclophosphamide, 5-fluorouracil

Breast cancer (Wiebe and Sipila,

Vincristine,

methotrexate,

methotrexate,

doxorubicin

week 2

week 37-38

Third trimester

From gestational

week 25

From gestational

week 14

1994)

Adenocarcinoma of the left breast (Dreicer and Love, 1991)

Cyclophosphamide, 5-fluorouracil

adriamycin,

Immature infant, hydrocephalus, hypoplasia frontal/ orbital bone, micrognathia, hypertelorism, short limbs Immature infant, without congenital abnormal development, respiratory support Spontaneous abortion at 12 weeks gestation 1 year later full-term development Full-term infant, normal development Full-term infant, normal development

Operation, cyclophosphamide, cisplatin (intraperitoneal administration)

Cyclophosphamide,

Fetal outcome

Delivery at 37 weeks gestation, normal development Full-term infant, normal development Twins, normal development

Delivery at 26 weeks gestation, Goldenhar’s syndrome Deliveq at 31 weeks gestation, cavernous hemangioma Delivery at 39 weeks gestation, multiple anomalies Delivery at 41 weeks gestation, without congenital abnormal development, pneumonia at 1 month of age Intrauterine growth retardation, without congenital abnormal development Delivery at 33 weeks gestation, without congenital abnormal development, apnea, asystole at delivery Cesarean section at 38 weeks gestation, normal development

U. Ebert et al. TABLE 4. Continued Diagnosis

(reference)

Time of treatment

Treatment

Adenocarcinoma of the left breast (Barri et al., 1992)

Doxorubicin

Breast cancer (Zemlickis et al., 1992) Breast cancer (Zemlickis et al., 1992) Breast cancer (Zemlickis et al., 1992) Breast cancer (Zemlickis et al., 1992) Breast cancer (Wiebe and Sipila, 1994)

Cyclophosphamide, 5-fluorouracil Melphalan

Breast cancer (Wiebe and Sipila, 1994)

Doxorubicin,

methotrexate,

vincristine,

prednisone

period was not noted exactly.

In 4 cases, the mothers were given cytotoxic

drugs only in

the third trimester. Approximately

without malformations.

Two of the mothers

underlying diseases during pregnancy.

with or

died of their

Eight children

were

stillborn or died after birth; their mothers were treated with antibiotics

cases), vincristine cocorticoids

cytarabine

abortions

of vincristine,

biotics, thiolated

(3

(3 cases), thiolated purines (2 cases), glu-

Nine therapeutic

bleomycin,

(3 of 8 cases),

(2 cases), and radiation treatment

ministration

First trimester

Spontaneous

First trimester

Without congenital abnormal development Without congenital abnormal development Cesarean section, without congenital abnormal development at 34.5 weeks gestation Delivery at 3 1 weeks gestation, without congenital abnormal development

Third trimester From gestational week 10.5

From gestational week 22

Western

European countries

(2 cases).

in delaying childbirth

woman is in her later reproductive

dacarbazine,

anthracycline

anti-

cyclophosphamide,

mechlorethamine

ment for a malignant disease during pregnancy poses special risks, but delays in treatment

might also be harmful

mother and child. All cytostatic

Between involving

1983 and 1995, a total of 215, and our 2, cases cytotoxic

treatment

during pregnancy

hy-

mal congenital

development

somal abnormalities. to cytotoxic

and 2 infants had chromo-

drugs during the first trimester.

whose newborn

showed chromosomal

treated with cyclophosphamide,

ment, and their various combinations.

Spontaneous

abor-

vincristine,

methotrexate,

vinblastine,

procarbazine,

hydrochloride,

vincristine,

6-mercaptopurine,

the use of

mechlorethamine

cyclophosphamide,

busulfan, 5-fluorouracil,

platin, bleomycin,

folic acid, acetylsalicylic

doxorubicin, melphalan,

cis-

acid, steroids,

NSAIDs, hydroxychloroquine, radiation treatment, and their various combinations. Most of the spontaneous abortions occurred after methotrexate administration Finally, 77 infants out of the 2 17 cases -

(8 cases). one-third of all

were healthy full-term children. More than 60% of

the newborns in each of the 5 groups described were liveborn infants with normal development (Fig. l), although 62 of these infants (37%) were preterm newborns.

4. DISCUSSION While (
were de-

Fifteen of these infants were exposed

treat-

tions were observed in 15 cases that involved

to ter-

the period of organogenesis.

or radiation

prednisone,

drugs are potentially

atogenic, especially when applied during the first trimester,

hydroxyurea

cases -

until a

years may increase the

scribed in the literature. Only 18 newborns showed abnor-

were reported after the ad-

cytarabine,

purines, procarbazine,

vinblastine,

drochloride,

abortion

rate of cancer in pregnancy (Wiebe and Sipila, 1994). Treathalf of all newborns for whom the gesta-

tional period was known were born prematurely -

anthracycline

First trimester

Cesarean section at 35.4 weeks gestation, without congenital abnormal development Spontaneous abortion

From gestational week 32

Cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, tamoxifen 5Fluorouraci1, doxorubicin, cyclophosphamide, tamoxifen Cyclophosphamide, doxorubicin, 5-fluorouracil, methotrexate

ter; in 1 case, the treatment

Fetal outcome

the incidence of cancer during pregnancy is low %), the current trend in the United States and

L-asparaginase,

rine, prednisone, ila, 1994);

cytarabine,

methotrexate,

and radiation treatment

One mother

abnormalities

6-mercaptopu(Wiebe

and Sip-

the other mother received 5-fluorouracil

Le et al., 1991).

was

daunorubicin,

In the first case, cytotoxic

treatment

(Van was

applied in the third trimester, with the mother delivering a female

infant

with

normal

karyotype,

but several

gaps

(Schleuning and Clemm, 1987). In the second case, the mother was treated during conception and the first trimester. 5-Fluorouracil is considered to be highly teratogenic, as animal studies have demonstrated the development of several anomalies when administered during pregnancy (Takehira and Kameyama, 1981). Van Le et al. (1991) reported that no specific anatomical defects were associated with the use of 5-fluorouracil in human pregnancy. By contrast, Wiebe and Sipila (1994) recommended that its use during pregnancy should be avoided because of its teratogenicity. In the 4 cases of stillbirth children, the mothers were treated with antimetabolites, anthracycline antibiotics, thiolated purines, vincristine,

glucocorticoids,

and radiation

Cytotoxic

TABLE 5. Cases With Cytotoxic references 1983-1995) Diagnosis

217

Therapy and Pregnancy Drug Treatment

for Severe Miscellaneous

Treatment

(reference)

Diseases Used Before and During Gestation Time of treatment

Ewing’s sarcoma (Wiebe and Sipila, 1994)

Cyclophosphamide, dactinomycin, doxorubicin, bleomycin, vincristine

From 25 weeks gestation

Adenocarcinoma of the liver (Raffles et al., 1989)

Bleomycin, etoposide, cisplatin

From 26 weeks gestation

Melanoma (Zemlickis et al., 1992) Essential thrombocythemia (Thornley and Manocharan, 1994)

Decarbazine

First trimester

Interferon-a

From 24 weeks gestation

Idiopathic thrombocythemia (Minkhorst et al., 1991) Essential thrombocythemia (Pardini et al., 1993)

Melphalan

Interferon-a2b

Conception gestation

Essential thrombocythemia (Petit et al., 1992) Essential thrombocythemia (Vianelli et al., 1994) Psoriasis (Feldkamp and Carey, 1993)

Interferon-cx2b Interferon-cY2a

Before pregnancy, first trimester From 12 weeks gestation

Methotrexate

O-8 weeks gestation

Methotrexate

6 years before pregnancy, up to 28 days prior to last menstrual period Conception, 3rd, 5th, 7th gestational week

Psoriasis (Donnenfeld 1994)

et nl.,

Human papillomavirus infection of the lower genital tract (Van Le et al., 1991) Genital condyloma (Odom et al., 1990) Cervical intraepithelial neoplasia, human papillomavirus infection, systemic lupus erythematosus (Odom et al., 1990) Human papillomavirus infection of the lower genital tract (Van Le et al., 1991) Human papillomavirus infection of the lower genital tract (Van Le et al., 1991) Human papillomavirus infection of the lower genital tract (Van Le et al., 1991)

for 4 days

5-Fluorouracil

(vagina)

5Fluorouracil

cream (vagina, cervix)

Before pregnancy to 8 weeks

First trimester

(n = 22,

Fetal outcome Cesarean section at 34 weeks gestation, without congenital abnormal development Immature infant, leucopenia, neutropenia (10th day after maternal chemotherapy), loss of the scalp hair at the age of 10 days, moderate sensorineural hearing loss bilaterally (at the age of 1 year) Therapeutic abortion Cesarean section at 36 weeks gestation because of intrauterine growth retardation and breech presentation without congenital abnormal development Delivery at 41 weeks gestation, normal development Cesarean section at 37 weeks gestation, normal development Full-term infant, normal development Delivery at 40 weeks gestation, normal development Delivery at 39 weeks gestation, oxycephaly, coronal sutures fused, wide frontal metopic suture, large anterior fontanel, widely separated eyes, nose wide and depressed, webbing between proximal phalanges second/third digits, karyotype normal Spontaneous abortion at gestational week 9 Chromosomal47,

XXX

Full-term infant, normal development Full-term infant, normal development

5-Fluorouracil (vagina)

Conception

5-Fluorouracil

(vagina)

Conception, week 4

gestational

Normal development

5-Fluorouracil

(vagina)

Conception, week 4

gestational

Normal development

5-Fluorouracil

(vagina)

Conception, 12-16

gestational week

Normal development

218

U. Ebert et al.

TABLE 5. Continued Diamosis

Human papillomavirus infection of the lower genital tract (Van Le et al., 1991) Bacterial infection (Donnenfeld et al., 1994) Unknown (Feldkamp and Carey, 1993)

5-Fluorouracil

Unknown 1994) Unknown 1994) Unknown 1994)

Conception, gestation

(vagina)

Fetal outcome

to 16 weeks

Normal development

Methotrexate

Gestational

week 556

Methotrexate

6-8 weeks during pregnancy

(Donnenfeld

et al.,

Methotrexate,

aspirin, plaquinal

(Donnenfeld

et al.,

Methotrexate,

dactinomycin

3 years before pregnancy, to gestational week 2 Before pregnancy

(Donnenfeld

et al.,

Methotrexate,

other chemotherapeutics

Before pregnancy

treatment.

One

neous abortions

death directly followed che-

intrauterine

motherapy (Wiebe

and Sipila, 1994). A total of 15 sponta-

were reported (6.9%);

observed after methotrexate malformations ministration

most of these were

administration.

study, fetal death, spontaneous

variety

Time of treatment

Treatment

(reference)

abortions,

In an earlier and congenital

have been reported after methotrexate as single agent (Powell and Ekert,

of case reports

Wiebe and Sipila (1994)

have

also been

anomalies

the

biosynthesis

They include folic acid antagonists antagonists

(6-mercaptopurine,

of DNA, teratogenic.

(methotrexate),

6-thioguanine),

idine antagonists (5-fluorouracil, cytosine arabinoside; Wiebe and Sipila, 1994). In the present survey, there were 12 cases of cytotoxic

treatment with folic acid antagonists, antagonists

in combi-

5-fluorou-

formed (Table cytotoxic

malformed live-born children involved the use of cytotoxic with antimetabolites

in which

6). Therefore,

treatment

the

infants

the decision

around conception

purine or were mal-

to administer

and in the first tri-

mester must be taken most carefully, although many cases - as the present review shows - have resulted in the delivery of phenotypically

are given in early pregnancy.

purine

and pyrim-

pyrimidine

In the present survey, 83.3% of the cases (n = 15) with drugs in the first trimester. Treatment

with

appear to be particularly

by

is particularly

such as cytarabine,

interfere

or proteins

A

drugs were used. They postu-

lated that the risk of congenital high when antimetabolites, racil, and methotrexate,

documented

in which methotrexate

nation with other cytotoxic

ad-

1971).

Drugs that RNA,

Delivery at 42 weeks gestation, normal development Gestational week 35 at birth, oxycephaly, absent coronal and lambdoid sutures, wide posterior fontanel, absent frontal bone, broad nose, flattened facies, hypertelorism, micrognathia, toes absent except 1 on left foot, 3 phalanges and 1 metatarsal left, 1 phalanx right foot, dextrocardia Delivery at 40 weeks gestation, normal development Delivery at 38 weeks gestation, normal development Normal development

fants without (19.8%

healthy, full-term or premature in-

any signs of haematological

of all pregnancies,

abnormalities

39.4% of all live-born children).

It has been suggested that embryonal

or fetal exposure to

was applied in 50% of theses cases. Of the live-born or still-

cytotoxic

born infants whose mothers

sis or fetal toxicity will occur (Wiebe and Sipila, 1994). Two

drugs during pregnancy, lier, Nicholson

(1968)

were treated with cytotoxic

9.2% showed malformations.

Ear-

reported a 7.5% rate of fetal malfor-

mations in a review of 53 cases with antineoplastics administered during the first trimester of pregnancy. In another study, Doll et al. (1988) noted that 17% of fetuses exposed to chemotherapy developed fetal malformations. Ten of the live-born infants were found to have haematological abnormalities or severe bone marrow hypoplasia. In one child,

drugs does not necessarily imply that teratogene-

reports of twin pregnancies interesting,

(male + female) were especially

as the male infants showed multiple abnormali-

ties, whereas

the female

newborns

were phenotypically

healthy (Zemlickis et al., 1993; Wiebe and Sipila, 1994). It was especially noteworthy that while spontaneous abortions occurred in several patients with rheumatic disorders, abnormal congenital development never resulted after

and a loss of the scalp hair were

treatment with low-dose methotrexate. This appears to indicate that only higher doses of methotrexate cause the ab-

noted. These authors assumed that the neutropenia and hair loss were directly related to the maternal chemotherapy, which consisted of bleomycin, etoposide, and cisplatin. Etoposide is the most myelosuppressive agent of these 3 drugs, and the most likely cause of the pathological findings in the child.

normalities seen in women with leukaemia, lymphomas, or other neoplasms. Thus, in addition to the time period during gestation when treatment with cytotoxic agents is begun (especially first trimester), the dose of the cytotoxic drugs administered is also relevant for the development of congenital abnormalities. Wiebe and Sipila (1994) arrived

leukopenia,

neutropenia,

Cytotoxic

Therapy

and Pregnancy

219

TABLE 6. Cytotoxic Drugs Implicated in Adverse Fetal Outcome According to Disease Category Fetal outcome

Drug Imkuemias

Cyclophosphamide

Cytarabine

Anthracycline antibiotics’

Thiolated purines*

2 infants with abnormal congenital development 1 infant with chromosomal anomaly 4 infants with haematological anomalies 5 infants with abnormal congenital development 1 infant with chromosomal anomaly 6 infants with haematological anomalies 3 stillborn infants 3 infants with abnormal congenital development 1 infant with chromosomal anomaly 5 infants with haematological anomalies 4 infants with abnormal congenital development 1 infant with chromosomal anomaly 7 infants with haematological anomalies

Malignant lymphomas Anthracycline

antibiotics’

Thiolated purines* Vincristine

Vinblastine

Procarbazine

Rheumatic disorders Methotrexate Gynuecological/breast neoplasms Methotrexate

Cyclophosphamide

Anthracycline

antibiotics’

Severe miscellaneous disurders Methotrexate

a-Interferon

1 1 1 2

spontaneous abortion stillborn infant spontaneous abortion infants with abnormal congenital development 2 spontaneous abortions 1 stillborn infant 2 infants with abnormal congenital development 1 spontaneous abortion 3 infants with abnormal congenital development 2 spontaneous abortions 6 spontaneous abortions 2 immature infants

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