JJCO

Japanese Journal of
Clinical Oncology

Japanese Journal of Clinical Oncology, 2016, 46(9) 795–804
doi: 10.1093/jjco/hyw073
Advance Access Publication Date: 9 June 2016
Review Article

Review Article

Anticancer drugs during pregnancy
Shingo Miyamoto1,*, Manabu Yamada2, Yasuyo Kasai2, Akito Miyauchi2,
and Kazumichi Andoh2
Department of Medical Oncology, Japanese Red Cross Medical Center, Shibuya, Tokyo, and 2Department of
Gynecology, Japanese Red Cross Medical Center, Shibuya, Tokyo, Japan*For reprints and all correspondence: Shingo Miyamoto, Department of Medical Oncology, Japanese Red Cross Medical
Center, 4-1-22 Hiroo, Shibuya, Tokyo 150-8935, Japan. E-mail: aaa17580@pop06.odn.ne.jp
Received 30 March 2016; Accepted 17 May 2016

Abstract
Although cancer diagnoses during pregnancy are rare, they have been increasing with the rise inmaternal age and are now a topic of international concern. In some cases, the administration ofchemotherapy is unavoidable, though there is a relative paucity of evidence regarding the administration of anticancer drugs during pregnancy. As more cases have gradually accumulated andfurther research has been conducted, we are beginning to elucidate the appropriate timing for theadministration of chemotherapy, the regimens that can be administered with relative safety, various drug options and the effects of these drugs on both the mother and fetus. However, new challenges have arisen, such as the effects of novel anticancer drugs and the desire to bear children
during chemotherapy. In this review, we outline the effects of administering cytotoxic anticancer
drugs and molecular targeted drugs to pregnant women on both the mother and fetus, as well as
the issues regarding patients who desire to bear children while being treated with anticancer
drugs.
Key words: anticancer drugs, pregnancy, malformation

Introduction
Maternal age has risen in many developed countries and as cancer
morbidity increases with age, the number of women diagnosed withcancer during pregnancy is also growing. Cancer is detected at a frequency of approximately one in every 1000 women during pregnancy, the most frequent being breast cancer, cervical cancer,
malignant lymphoma and malignant melanoma (1).
There are some cases of cancer diagnosed in pregnant women inwhich the administration of chemotherapy is unavoidable; however,there is limited evidence for the effects of administering chemotherapy.
We assume that the primary reason is that performing clinical trials is
extremely challenging from an ethical perspective because there areconcerns regarding the effects of the anticancer drugs on the fetus.
The package inserts of several anticancer drugs state that administration during pregnancy is contraindicated, contraindicated as a
general rule or that chemotherapy can be administered if the benefitsof treatment outweigh the risks (Table 1). Since there is a lack of evidence for the administration of anticancer drugs during pregnancy,
it is challenging to know on what basis we should discuss thepossible benefits after explaining the risks to pregnant women being
assessed as to whether chemotherapy should be administered.
Unless it is a major facility where medical oncologists, hematologists
and obstetricians can cooperate closely for the patient’s sake, in
principle no anticancer drugs should be administered.
Congenital malformations can occur in approximately 20% ofcases if chemotherapy using cytotoxic anticancer drugs is administered during the first trimester and thus should be avoided (2).
However, from the second trimester onwards, if sufficient consideration is given to the safety and long-term effects of the mother andfetus and if it is determined that chemotherapy is required, thenchemotherapy that can be administered has also been reported inprevious observational studies. In addition, there are limited numbers of case reports regarding the use of molecular targeted therapy
for pregnant cancer patients. Recently, international guidelines havealso been published, indicating that this issue has become one ofmajor international concern (3,4).
In this paper, we review the effects of the main anticancer drugs
and molecular targeted agents on the mother and fetus during© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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Anticancer drugs during pregnancy

Table 1. The risks to the fetus when administering anticancer drugs to pregnant women in Japan (according to the package insert for eachdrug)
Contraindication

Paclitaxel (D)Docetaxel (D)Dacarbazine (C)Methotrexate (oral) (X)Carboplatin (D)Cisplatin (D)Hormonal agent
Molecular targeted agentsTamoxifen (D)Pertuzumab (D)T-DM1 (D)
Lapatinib (D)Imatinib (D)Sunitinib (D)Sorafenib (D)Bevacizumab (C)Administered if the benefits of thetreatment outweigh the risks

Should not be
administered
Doxorubicin (D)Epirubicin (D)Daunorubicin (D)Idarubicin (D)Cyclophosphamide (D)5-FU (D)Methotrexate (iv) (X)Cytarabine (D)Vinblastine (D)Vincristine (D)Gefitinib

Trastuzumab (D)Erlotnib (D)Cetuximab (C)Panitumumab (C)Rituximab (C)Risks according to the FDA in brackets:
C, risk cannot be ruled out; D, positive evidence of risk; X, contraindicated in pregnancy.

pregnancy. Furthermore, we explore the issues surrounding anticancer drug administration in patients who desire to bear a child.

General considerations
When administering chemotherapy during pregnancy, the extremely
difficult issue of providing maximum treatment benefit to themother while maintaining the safety of the fetus must be addressed.
Adverse effects from any drug on the fetus are also thought to beaffected by the timing of exposure to the drug, dose and placental
transfer of the drug. Drugs with high lipid solubility, low-molecularweight and a low plasma protein-binding rate have a higher placental
transfer (Tables 2 and 3) (5). There are ethical difficulties regarding
performing research on the placental transfer of anticancer drugs inhuman subjects and therefore, in most cases, data have been achieved
using animal experiments. In many cases, the placenta inhibits or
attenuates the passage of drugs through various mechanisms (6). For
example, p-glycoprotein, which is strongly expressed in the humanplacenta, may attenuate the placental transfer of taxanes (7).
Even if chemotherapy is initiated from the second trimester
onwards to avoid congenital malformations caused by anticancer
drugs, the risks of intrauterine growth retardation (IUGR), premature rupture of membranes (PROM) and premature labor are still
increased (20–22). For this reason, fetal monitoring during eachchemotherapy cycle throughout pregnancy is appropriate. In addition, if chemotherapy is administered during pregnancy, the rate ofpreterm delivery increases and, although negligible, delays in neonatal cognitive development have been identified. Therefore, it isrecommended that delivery should be at 37 weeks or later, if possible (3,23). However, some physicians are of the opinion that the
infant should be delivered slightly earlier in order to adequately treat
the mother. The delivery period in actual clinical practice is highly
controversial and greatly depends upon the condition of the motherand fetus as well as the type of cancer. Therefore, a thorough deliberation between the obstetrician, oncologist and pediatrician is vital.

Chemotherapy should not be administered from Week 35
onwards, or within 3 weeks of the scheduled delivery date, toavoid the risk of hematological complications during delivery(24). Regimens administered on a weekly basis (e.g. those fordoxorubicin, epirubicin and paclitaxel) demonstrate low hematological toxicity. However, if chemotherapy is administered up
until immediately before delivery, it may affect the neonate, who
retains only a limited ability to metabolize drugs after delivery.
Therefore, this should be avoided. In addition, the presence of placental cancer metastases must always be assessed after delivery
and, if chemotherapy is required after delivery, breastfeeding must
be avoided (6).
In terms of the effects of cancer treatment prior to delivery on
children, reports have found no differences regarding general andcognitive development, and cardiac function in early childhood (25).
However, there are few studies involving long-term observation andthe possibility of late-onset effects (e.g. cardiomyopathy, abnormal
reproductive function, drug-induced onset of cancer and psychomotor retardation) remains unknown.

Cytotoxic agents
In women who received chemotherapy during pregnancy, the rate ofcongenital malformation in the fetuses is approximately 5%.
However, the majority of cases received chemotherapy during thefirst trimester; the rate of these malformations occurring in thosereceiving chemotherapy from the second trimester onward is 3%,
which is the same as the percentage of fetuses observed to have congenital morphological abnormalities in normal pregnancies (8,26).
Furthermore, reports indicate that spontaneous abortion occurs inapproximately 15% of patients receiving chemotherapy (8,26).
The complications of chemotherapy during pregnancy often
include oligohydramnios and IUGR, but preeclampsia and PROM
may also occur. Approximately one-third of all cases deliver early,
with many deliveries via cesarean section, and an increased

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Cytotoxic agentsContraindicated in principleJpn J Clin Oncol, 2016, Vol. 46, No. 9797

Table 2. Effects of cytotoxic anticancer drugs on the fetus and their characteristics
Drug

Anthracycline
antibiotics
Taxanes
Alkylating agent
Antimetabolites

Platinum agents

Method

7.5% (9)4.0% (9)0% (10)1.5% (10)25.1% (9)Unknown
56.7% (11)28.7% (12)18.5% (9)Unknown
31–65% (13)57.5 (10)Baboon plasma
Baboon plasma
Baboon plasma
Baboon plasma
Baboon plasma

Major malformation (8)Mouse plasma
Rat plasma
Baboon plasma
Human umbilical cord
Baboon plasma

During the firsttrimester

After second
trimester

13% (5/39)
20% (1/5)
0% (0/2)—
18% (7/40)
11% (1/9)
19% (4/21)
31% (4/13)
31% (5/16)
9% (4/44)
20% (1/5)—

2% (6/383)
5% (3/58)
11% (2/19)
3% (1/38)
1% (5/366)
2% (1/45)
4% (4/109)
2% (3/161)
5% (3/57)
1% (1/159)
4% (4/99)
6% (1/17)

Small forgestational
agea (8)6% (26/417)
5% (3/62)
19% (4/21)
13% (5/38)
7% (28/400)
13% (7/53)
13% (17/131)
6% (11/171)
10% (8/80)
13% (25/199)
13% (13/102)
13% (2/16)aSmall for gestational age was identified as body weights that were <10th percentile of the normal population based on sex and gestational age at birth or asreported by the authors when clearly defined.

Table 3. Effects of molecular targeted agents on the fetus and their characteristics
Drug

Monoclonal
antibodies

Fetal/maternal drugconcentration ratio

Trastuzumab 85.0% (10)3.0%
Pertuzumab 30–40%b

Dose

Time after
Major malformation (8)the last
During theAfteradministration
first trimester second
trimester

Small forgestational
agea (8)Baboon plasma

8 mg/kg

0% (0/12)

0% (0/6)

5% (1/19)

Cynomolgus
serum

10 mg/kg
33.3 mg/kg
100 mg/kg
10 mg/kg
100 mg/kg
375 mg/m2

2 hours
26 hours
50 days———

3 days———3 months

20% (1/5)

0% (0/18)

5% (1/23)

0% (0/2)

0% (0/4)

66% (4/6)

12% (12/100)

0% (0/6)

2% (2/101)

Bevacizumab 2–9% (14)

Rabbit serum

Rituximab

Human cord
blood serum
Human neonatal
blood serum
Human cordblood
Human cordblood
Human neonatal
blood

328% (15)150% (16)Tyrosinekinaseinhibitors

MethodGefitinib

20% (17)

Erlotinib

25% (18)

Imatinib

31% (19)375 mg/m2

2 months

250 mg/m2

16.5 hours

150 mg/m2

72 hours

400 mg/body 16 hoursaSmall for gestational age was identified as body weights that were <10th percentile of the normal population based on sex and gestational age at birth or asreported by the authors when clearly defined.
b
Unpublished data.

likelihood of low birth weight (27). Additionally, reports have indicated that the rate of stillbirths is also increasing (27).
Moreover, there are also cases in which bone marrow suppression, thought to be caused by chemotherapy, is observed during theperinatal period. However, this spontaneously improves after a few
weeks (8).

Anthracycline antibiotics
Epirubicin and doxorubicin have demonstrated a low rate of placental transfer at approximately 1–10% during animal experiments(9,11). However, idarubicin is highly liposoluble and has a long
half-life. Therefore, this drug may demonstrate a high rate of placental transfer.

Doxorubicin is the most frequently used anthracycline antibiotic.
There is one reported instance in which a few subjects in a prospective study of breast cancer received 5-FU, doxorubicin and cyclophosphamide (FAC) therapy from the second trimester onwards.
There were no reported increases in short-term adverse events (e.g.
congenital anomalies) and thus it was believed that it could be administered relatively safely (4,28). However, a relationship has beensuggested between serious effects on the fetus, fetal mortality rate,
daunorubicin and idarubicin. The administration of cytarabine anddoxorubicin from the second trimester onwards has been proposed
for treating acute myeloid leukemia during pregnancy (29).
In addition, anthracyclines exhibit dose-dependent cardiotoxicity. No consensus has yet been reached regarding cardiotoxicity
in fetuses due to anthracyclines administered during pregnancy.

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Vinca alkaloids

Doxorubicin
Epirubicin
Docetaxel
Paclitaxel
Cyclophosphamide
Dacarbazine
Cytarabine
5-FU
Vinblastine
Vincristine
Cisplatin
Carboplatin

Fetal/maternal drugconcentration ratio

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Anticancer drugs during pregnancy

While there are some reports indicating that no decrease in cardiac
function was observed with either epirubicin or doxorubicin, there
are also studies indicating that cardiac function disorders wereobserved after idarubicin administration (30–32). Therefore, drug
selection for pregnant cancer patients remains controversial.

Taxanes

Alkylating agentsPlacental transfer of cyclophosphamide has been observed and,
when administered 1 hour before a cesarean section, it can bedetected in the amniotic fluid at a concentration of approximately
25% (37). An increased rate of congenital skeletal malformations
was observed when cyclophosphamide was administered during thefirst trimester, similar to that for the treatment of autoimmune diseases (38–40). However, there are several reports of its use in combination with anthracyclines, and it can be administered relatively
safely from the second trimester onwards (41,42).
There is extremely limited available data regarding the placental
transfer and rate of congenital malformations when using dacarbazine, which is used to treat Hodgkin’s lymphoma and malignant
melanoma. Therefore, caution is required, as there are some reportsof major malformations and IUGR associated with this form oftreatment (43,44).

Antimetabolites
5-FU formulations are used to treat all types of cancer as a monotherapy, or as part of polypharmacy regimens. Rejimens of FAC andFEC (5-FU, epirubicin and cyclophosphamide) are recommended
when selecting anticancer drugs for pregnant breast cancer patientsand are permitted for use as required (3,4). However, if used during
the first trimester, the rate of spontaneous miscarriage increases, inaddition to the issue of teratogenicity. Furthermore, caution must be
exercised even if administered from the second trimester onwards,
as there have been reports of IUGR and IUFD (45,46).
Methotrexate is also indicated for hematological and breast cancer
treatment and its oral version is widely used as an anti-rheumatoid

Vinca alkaloids
Vinca alkaloid formulations have a relatively high plasma proteinbinding rate, suggesting that they may have relatively small effects
on the fetus (5,50). However, there have been several reports ofmajor malformations when it is used in combination with otherdrugs and even as monotherapy; therefore, caution is required (51).
Additionally, the placental transfer rate of vinblastine was found to
be 15% during animal experiments on baboons (9).
Vincristine and vinblastine are used to treat malignant lymphoma. Hodgkin’s lymphoma treatment includes vinblastine as part of
the ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine)
regimen and non-Hodgkin’s lymphoma therapy includes vincristine
as a part of the CHOP (cyclophosphamide, doxorubicin, vincristineand prednisolone) regimen. These treatments have also been shown
to be effective, even during pregnancy (29). Although there havebeen reports of adverse fetal events, use of these regimens is recommended from the second trimester onwards (3).

Platinum agents
The placental transfer of carboplatin was found to be high at 57.5%
during experiments using baboons (10). Moreover, experiments
using mice demonstrated that plasma concentrations above thosefound in the females were observed in the fetuses (11). In addition,
human studies of cisplatin revealed that concentrations of between
31% and 65%, found in the maternal blood, were also measured in
the umbilical cord blood (13). Therefore, platinum-based formulations are assumed to have an extremely high rate of placental transfer. However, compared with other drugs, there are no reports ofobvious increase of congenital malformations or major effects ofplatinum-based formulations on the fetus. Therefore, the administration of carboplatin is recommended for non-small cell lung cancer
or ovarian cancer from the second trimester onwards as well as theadministration of cisplatin for germ cell tumors (3).

Hormonal agentsTamoxifen
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The placental transfer of taxanes, which are important for the chemotherapeutic management of breast cancer and gynecological cancer,
is reported to be low at 1–2%. However, despite the low concentrations, long-term exposure could occur as the drug may remain in the
fetal tissues (10). The results of animal experiments indicate that thedrugs were detected in the fetal tissues even 72 hours after taxanes
had been administered to the dams, which was thought to be due tothe high liposolubility and tissue affinity of taxanes (10). Docetaxel
has a higher tissue affinity than paclitaxel. In addition, CYP3A4, oneof the enzymes that metabolize taxanes, is not expressed in fetal livers(33,34). For this reason, embryotoxicity and fetotoxicity are enhanced,
suggesting an increased likelihood of intrauterine fetal death (IUFD)
and decreased body weight. However, no increase in fetal or maternal
complications was reported despite the use of taxanes during pregnancy, when compared with conventional chemotherapy during acohort study conducted in clinical practice (35).
Compared with anthracyclines, there is less data available for taxanes. Therefore, when clinical treatment of breast cancer is required,weekly paclitaxel has been approved for use from the second trimester
onward (4). Furthermore, in the field of obstetrics and gynecology,
when used together with platinum-based drugs, some consider taxanes as the first choice, even when treating pregnant patients (3,36).

arthritis drug. When patients with rheumatoid arthritis wish to bear achild, a drug cessation period of 3 months is recommended before
conception. Injectable formulations of methotrexate are used to induce
the miscarriage of extrauterine pregnancies, but oral formulations arecontraindicated during pregnancy. In addition, the administration ofdoses of more than 10 mg/week prior to pregnancy may cause aminopterin syndrome, which involves a variety of fetal morphologicalabnormalities (27). Since there is often an alternative drug for any cancer, its use should be avoided unless absolutely necessary (41).
Cytarabine is used to treat acute myeloid leukemia and is a very
important drug. However, it has been reported to cause major malformations, IUGR and stillbirth when administered during pregnancy (27,47). Accordingly, murine experiments have shown thatthe rate of placental transfer is relatively high at 56.7%, and thus
cytarabine may cause a higher rate of stillbirth than other anticancer
drugs (11). However, there are also reports stating that acute myeloid leukemia increases the rate of stillbirth and there is still roomfor discussion regarding the relationship between the rate of adverse
effects with cytarabine (48,49).

Jpn J Clin Oncol, 2016, Vol. 46, No. 9
regarding the effects of tamoxifen during pregnancy, the available
case reports involve recurrent breast cancer, and no obvious tumorshrinking effects were observed due to tamoxifen. Furthermore, progression of the disease during late pregnancy, when estrogen levels
increase, was noted (52).
In addition, regarding safety, since a relationship with congenitalabnormalities (including Goldenhar syndrome, ambiguous genitalia
and Pierre Robin syndrome) has been suggested, tamoxifen should
never be used at any stage during pregnancy (41). If hormone therapy is required, it should be administered during the postpartum
period.

Most monoclonal antibodies (mAbs) have large molecular weights andare hydrophilic. Similar to maternal Immunoglobulins G, the placental
transfer of mAbs actively occurs via a specific receptor-mediated mechanism from gestational Week 16 onwards. Therefore, they are believed
not to cause any major fetal malformations in the first trimester(53,54). On the other hand, tyrosine kinase inhibitors (TKIs) are lowmolecular weight compounds known to cross the placenta during thefirst trimester and have been suggested to cause several disorders, suchas increases in the rate of spontaneous miscarriage.

Human epidermal growth factor receptor Type 2
inhibitors
The human epidermal growth factor receptor Type 2 (HER2) pathway plays an important role in the normal development of the heartand nervous system during fetal organogenesis and may also be
involved during conception and implantation (55,56). Trastuzumab
is an important drug for the treatment of HER2-positive breast cancer overexpressing HER2. It is also used to treat advanced HER2positive gastric cancer.
Compared with non-pregnant patients, one of the pathologicalcharacteristics of breast cancer diagnosed during pregnancy is thatmany cases are found to be hormone receptor-negative (57).
Although there are also reports that the tumors are more often
HER2-positive, this remains controversial (57).
Trastuzumab administration from the second trimester onwards
is known to increase the risk of oligohydramnios (58). The main
hypothesis for this suggests that because HER2 is expressed in the
fetal kidneys, trastuzumab administration affects fetal urine production and amniotic fluid reabsorption (59,60). In addition, theexpression of vascular endothelial growth factor (VEGF), which regulates the production and reabsorption of amniotic fluid by altering
the permeability of the fetal membranes, is also believed to be inhibited by trastuzumab (61,62). The oligohydramnios that occurs dueto these mechanisms increases the risk of premature delivery and, asa result, neonates often present with respiratory and renal failure.
Sarno et al. (53) reported that cases receiving trastuzumab during
pregnancy demonstrated a neonatal mortality rate of 21%, due tomultiorgan failure caused by oligohydramnios. However, oligohydramnios caused by trastuzumab improves when the drug is discontinued, thereby indicating reversibility (58).
Some studies, however, have found that no neonates were bornwith congenital malformations when trastuzumab was inadvertently
administered in cases of unexpected pregnancy during postoperative
adjuvant chemotherapy for breast cancer (63). This may be because
it is difficult for trastuzumab to actively reach the fetus via the placenta during the first trimester. However, data regarding trastuzumab

use during pregnancy are limited; an observational study targeting
pregnant HER2-positive breast cancer patients who received antiHER2 drugs (NCT00833963) is underway and the results are eagerly
anticipated. However, considering the current data and guidelines,
trastuzumab should not be administered during pregnancy.
Other molecular targeted drugs against HER2 include pertuzumab, T-DM1 and the TKI lapatinib. Despite the promise of these
therapies, there is currently no data to verify the safety of any ofthese drugs. Pertuzumab is used in combination with trastuzumab
and T-DM1 is an antibody-drug conjugate that consists of trastuzumab linked to the cytotoxic agent emtansine. Like trastuzumab,
these drugs should not be administered during pregnancy.
Lapatinib, a low-molecular weight compound, is believed to crossthe blood–placenta barrier, beginning in the first trimester. Resultsfrom reports of cases exposed to lapatinib in the first trimester indicate that healthy infants were delivered (64). However, since thesafety of lapatinib is unknown, similar to TKIs in general, it should
not be administered during pregnancy.

Epidermal growth factor receptor inhibitors
The epidermal growth factor receptor (EGFR) pathway is not only
associated with cell proliferation and differentiation but is also
involved in various stages of embryonic development. Experiments
using mice have shown that an inhibited EGFR pathway leads toimpaired maturation of the skin, lungs and gastrointestinal tract epithelium, resulting in increased fetal death (65,66). Similar to the
HER2 pathway, it is also implicated in conception and implantation, as well as fetal renal maturation and the migration and differentiation of cerebral cortical cells (67–69).
Gefitinib and erlotinib, the low-molecular weight EGFR-TKIs,
are important drugs for treating lung cancer patients with EGFR
gene mutations. In animal experiments, when erlotinib was administered during organogenesis and the plasma concentration was comparable to that in humans, no increase in fetal death or miscarriage
rates were reported. However, when the concentration wasincreased by 3-fold, there was an increase in fetal death and miscarriage. In addition, the rate of miscarriage increases when erlotinib isadministered from the first gestational week (70).
To date, there have been only approximately 60 reported casesof lung cancer diagnoses during pregnancy (71). Among these, there
are five reports in which EGFR-TKIs were used; in all cases, delivery
occurred without evidence of congenital malformations(17,18,70,72,73). However, two cases of IUGR due to oligohydramnios were observed, and a reversible increase in hepatic enzymes
was observed in one other case (twin pregnancy) (18,73). Gefitinib
and erlotinib crossed the placenta and reached the fetus; with
reports evaluating their pharmacodynamics indicating that approximately 20% of the maternal plasma concentration of gefitinib wasobserved in the cord blood (17). Similarly, approximately 25% of
the maternal concentration of erlotinib was observed in cord blood(18). According to international guidelines, carboplatin and paclitaxel can be used for the chemotherapeutic management of lungcancer, from the second trimester onwards (3). Moreover, as reports
regarding EGFR-TKIs are also limited, these drugs should not be
administered to pregnant lung cancer patients. However, if the lungcancer prognosis is very poor, it is worth further investigation,
depending on the situation—since the effect of gefitinib or erlotinibon the fetus may be pharmacokinetically limited.
There is no clinical data regarding the use of the anti-EGFR
antibody drugs, such as cetuximab and panitumumab, during

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pregnancy. However, we presume that they are pharmacokineticallysimilar to other mAbs.

Angiogenesis inhibitors

Rituximab
Rituximab is an antibody-based drug against the CD20 antigen, andit dramatically improves the prognosis of malignant B-cell
lymphoma.
Rituximab is known to be actively transferred to the fetus from thesecond trimester onwards. When comparing rituximab concentrations
in mothers and neonates at the time of delivery, the concentrations
measured in the neonates were approximately 1.5–3-fold those measured in the mothers, even 2–3 months after the final administration,
demonstrating that the drug remains present in the fetal blood for along period (15,16). Due to these effects, lymphopenia and B-cell
depletion are observed in many of the neonates born to patients who
received rituximab during pregnancy. However, this effect is reversible, with neonates recovering within a few months, although there arereports stating that no increased risk of pregnancy-related complications and morphological abnormalities were observed (85,86).

Imatinib
Imatinib, the low-molecular weight compound, is a drug that plays
an important role in the treatment of chronic myeloid leukemia(CML) expressing the ‘BCR-ABL’ fusion gene. It is also used to treat
KIT-positive GIST and Philadelphia chromosome-positive acutelymphocytic leukemia.
In animal experiments, administration of doses that wereapproximately equivalent to the clinical doses for humans in theearly stages of a pregnancy affected early embryogenesis by causing
an increased rate of post-implantation mortality and decreased fetal
body weight (87). Furthermore, teratogenicity was observed withcranial defects, such as exencephaly and encephaloceles. The mostcommonly reported morphological abnormalities were defects of theskeletal system (87). It is hypothesized that the morphologicalabnormalities may be caused by the fact that platelet-derived growth
factor receptor α, which plays an important role in organogenesis, isinhibited by imatinib (88).
Imatinib has been shown to undergo placental transfer to thefetus and Ali et al. (19) reported detecting the drug at a concentration approximately 30% that of the maternal concentration in neonatal peripheral blood. In addition, when imatinib was administeredduring the first trimester, the rate of spontaneous abortion was relatively high at 17% (8). Major malformations also occurred in 12%of cases. A report by Pye et al. stated that among the 12 cases inwhich major malformations were observed, the majority had skeletal system abnormalities. A total of eight children were delivered,
one was stillborn and three pregnancies underwent an artificial termination (89). Based on the above findings, imatinib should not be
administered during pregnancy.

Pregnancy during chemotherapy
When patients receive chemotherapy, contraception should be actively
encouraged throughout the treatment period (3). Additionally, contraception for the first 3–6 months following the final administrationof chemotherapy is recommended (3). If the patient is pregnant while
receiving chemotherapy, termination of pregnancy is an option as
there is an increased risk of drug-induced fetal malformations.
Patients with breast cancer sensitive to premenopausal hormones
may miss their opportunity to become pregnant, as the postoperative
administration of tamoxifen may be long term (90). However, if therapy is discontinued early, the risk of recurrence increases, and therefore the patients wishing to bear a child and their clinicians may be
faced with a dilemma. At present, the timing of tamoxifen discontinuation is determined on an individual case basis, once discussed
sufficiently with the patient. Meanwhile, the ongoing POSITIVE trial(NCT02308085) examines the effects of tamoxifen discontinuation
for a maximum of 2 years on the occurrence of pregnancy.
It is difficult for mAbs to pass through the placenta during theearly stages of pregnancy. Moreover, when mAbs are discontinued,
continuing with the pregnancy is an option (54). TKIs, on the other
hand, cross the placenta from the first trimester onwards; imatinib

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The signal transduction pathways that involve VEGF play animportant role in placental angiogenesis and neovascularization, as
well as embryogenesis and normal fetal maturation (74,75). VEGF
also plays an important role in the permeability of fetal membranes,
regulating the volume of amniotic fluid and embryonic implantation, with a suggested relationship to infertility (76). During animal
experiments, the inhibition of the VEGF pathways causes hypertension, proteinuria, glomerular endotheliosis and preeclampsia. This
has a negative impact on normal placenta formation and increases
the risk of IUGR (77,78).
Bevacizumab, the VEGF antibody-based drug, is used to treat an
extensive range of cancer types. Moreover, tumor shrinkage andimprovement in survival time have been noted when this drug is usedin combination with chemotherapy. Experiments using rats havedemonstrated that fetal death, low body weight and skeletal abnormalities are observed at the equivalent concentrations as used inhumans (79). There are no reports of intravenous administration of
bevacizumab during pregnancy. However, there are its post-marketingsurveillance reports that state it has been administered to pregnant
women and that malformations were observed, although the exact
details are unknown (14). In contrast, intravitreous administration of
bevacizumab has been used to treat choroidal angiogenesis and diabetic retinopathy in the field of ophthalmology. Although there arecases in which it has been administered safely (80,81), studies involving primate models have shown that the drug reaches systemic circulation even when it is administered to the vitreous humor (82). In thesestudies, there were also cases of spontaneous miscarriage when the
drug was administered during the first trimester and therefore caution
is required when performing intravitreous administration (83).
Sunitinib is a low-molecular weight multikinase inhibitor used totreat renal cell carcinoma and gastrointestinal stromal tumors(GIST). This drug caused fetal and embryonic developmental disorders resulting in fetal death during animal experiments when administered at doses commonly used in humans (84). However, there
are no such reports in humans.
Thus, inhibitors of angiogenesis should not be administered, as it
is highly likely that they will affect the fetus from embryonic
implantation until late gestation.

Thus, rituximab may be administered during pregnancy if
required. Although the effects of rituximab on the fetus in the firsttrimester are considered to be low, a study of the relationshipbetween pregnancy and rituximab administration reported a spontaneous abortion rate of 21% (15). The drug may cause a latent
increase in the risk of miscarriage. In addition, the fact that neonatal
hematopenia increases the risk of infection must also be considered.

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Jpn J Clin Oncol, 2016, Vol. 46, No. 9

Implantation period

Fetal development period

Organogenesis period

2ndtrimester

1st trimester
1

2

3

4

5

6

7

8

9

16

3rd trimester
32

38

Extremely high risk

Observed in 20%

Relatively high rate of complications in
the mother and fetus (e.g., IUGR)Monoclonal
antibodies

Moderately high risk

Relatively low

High rate of drug-specific complications(e.g., oligohydramnios and lymphopenia)

Tyrosine kinase
inhibitors

Moderately high risk

Potential

Complications may occur in the mother andfetus (insufficient data)

Death of embryo andspontaneous abortioncommonMajor malformation

Functional defects
Minor malformation

Figure 1. Administration risks for each anticancer drug during the stages of pregnancy and their effects on the fetus.

in particular has been shown to increase the rate of fetal morphological abnormalities and abortion. Therefore, patients may miss theopportunity to fall pregnant during these treatments. However,when adult patients with CML have experienced complete molecular remission for 2 years or more, 40% of those cases were able totemporarily discontinue imatinib administration. Moreover, byreadministering imatinib to treat cases of recurrence, complete
molecular remission was demonstrated in all cases (91). In addition,
since there have been no reports of major malformations when usedfrom the second trimester onwards, it may be of value to investigate
whether it is possible to become pregnant by discontinuing or readministering the drug, even when patients are treated with imatinib.
However, there is currently no data available on other TKIs andthus we believe that continuing pregnancy would be at risk.

Discussion
Since the publication of a case report on the use of urethane duringchemotherapy to treat a pregnant CML patient, perspectives regarding the administration of anticancer drugs during pregnancy have
gradually been established (Fig. 1) (92). Additionally, the thresholdfor treating pregnant cancer patients with chemotherapy has become
low. However, there are several points that remain to be elucidated.
For example, with regard to the doses of the anticancer drugs,
there is no evidence-based data regarding whether to calculate thedose based on the current body weight and body surface area during
pregnancy or whether to use pre-pregnancy values. According tointernational recommendations, performing administration based on
the actual body weight is recommended (41).
In addition, the plasma volume and cardiac output in pregnant
women continue to increase until the end of the second trimester,
resulting in physiological changes such as increased glomerular

filtration rate and creatinine clearance (93,94). We presume that thesechanges cause decreased plasma concentrations of anticancer drugs.
In studies of the pharmacokinetics of some small-scale anticancer
drugs when treating pregnant cancer patients, the area under the
curve (AUC) and peak plasma concentration both decreased while
clearance increased (95,96). For paclitaxel in particular a 27.4%
decrease was noted in the AUC. Therefore, we estimate that a dose
increase of 37.8% is required to achieve an AUC equivalent to thatof non-pregnant women (96). Cohort studies have reported no differences in the treatment outcomes of pregnant breast cancer patientscompared with non-pregnant patients (97). However, chemotherapy
in clinical practice may be administered at lower doses. The optimaldose for the administration of anticancer drugs that will achieve maximal effects in the mother must be determined, taking pharmacokinetics into consideration. However, this is extremely difficult due to its
complexity and individual variation. At the very least, pregnancy
should not be the reason for decreasing the dose of anticancer drugs.
Amant et al. (25) conducted a prospective multicenter study
regarding the effects on children whose mothers received cancer
treatment during pregnancy. They found that the cognitive development and physical health outcomes at 1.5 and 3 years of age wereequivalent to those of children born to mothers who did not havecancer. Furthermore, no increase in the rate of reduced cardiac function was reported, although the observation period was short. This
does not necessarily apply to all types of cancer and therapeutics,
but supports the fact that a diagnosis of cancer during pregnancy
should not necessarily be a reason for termination due to potential
effects on the fetus.
However, there have been recent developments in drug treatments, such as the novel molecular targeted drugs and immune
checkpoint inhibitors. The knowledge gained to date using cytotoxic
anticancer drugs often does not apply when these newer drugs areadministered to pregnant women. Decisions can be made based on

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Cytotoxic agents

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Anticancer drugs during pregnancy

the characteristics of mAbs and TKIs; however, there are still many
unclear points. Therefore, treating pregnant cancer patients withthese types of drugs remains a largely unknown territory.

Summary and conclusions

Conflict of interest statement
None declared.

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