Annals of Oncology 16: 18551860, 2005

doi:10.1093/annonc/mdi388
Published online 19 July 2005

Review
Breast cancer and pregnancy
A. E. Ring1,2, I. E. Smith2 & P. A. Ellis1*
1

Guys Hospital; 2Royal Marsden Hospital, London, UK

Received 26 January 2005; revised 16 April 2005; accepted 31 May 2005

Introduction

Diagnosis and staging

It has been estimated that up to 3% of breast cancers may be

diagnosed in pregnant women [1]. Breast cancer associated with
pregnancy presents the clinician with particular challenges. The
diagnosis may be delayed and difficult owing to the physiological changes within the breast and limitations on investigations.
Moreover once a diagnosis has been confirmed and staging
completed, options for treatment will be influenced by the
need to give optimal treatment to the mother whilst minimising
risks to the fetus. The particular challenges faced both in the
initial diagnosis and management of women with pregnancyassociated breast cancer are discussed in this paper.

The physiological changes occurring in the breast during pregnancy may mean that clinical examination becomes more difficult as pregnancy progresses. Contrary to popular belief,
mammography with abdominal shielding can be performed
during pregnancy with minimal risk [2, 3]. It has been estimated
that a standard two-view mammogram of each breast subjects
the fetus to only 0.004 Gy of radiation [2]. However, the increased breast density seen in premenopausal women, together
with the physiological changes within the breast during pregnancy, may mean that mammograms are difficult to interpret
[3]. Small series report mammographic abnormalities in
6387% of patients with pregnancy-associated breast cancer
[46]. On the other hand, ultrasound represents a simple, sensitive alternative to mammography in pregnant and lactating
women, and in two small series has been shown to be more
sensitive than mammography [4, 5]. In our view, therefore,
mammography should rarely be necessary in the investigation
of breast cancer in the pregnant woman.
During pregnancy and lactation atypical cytomorphologic
features are seen in normal breast tissue, and therefore interpretation of samples acquired by fine needle aspiration needs to be
performed with caution [7]. Therefore, core-needle biopsy may
be a more appropriate initial procedure, particularly if (as is
usually the case) a palpable mass is present. With any interventional procedure performed on the breast of a pregnant woman

Methodology
Data for this review were identified by searches of PubMed
using the keywords breast cancer and pregnancy, chemotherapy and pregnancy and radiotherapy and pregnancy. The
period from 1966 to 2004 was used, and searches were restricted to the English language. References from relevant
articles were also selected. Papers were chosen based on their
size and adequacy of design.
*Correspondence to: Dr P. A. Ellis, Department of Medical Oncology,
Thomas Guy House, Guys Hospital, London SE1 9RT, UK.
Tel: +44-20-7188-4237; Fax: +44-20-7403-8381;
E-mail: paul.ellis@gstt.sthames.nhs.uk
2005 European Society for Medical Oncology

Downloaded from annonc.oxfordjournals.org by guest on March 15, 2011

Background: The management of women who have breast cancers diagnosed whilst they are pregnant
is challenging. The aim is to give optimal treatment to the mother to maximise the chances of survival,
whilst minimising the risks of harm to the fetus. However, few breast surgeons or oncologists develop
expertise in this area owing to the rarity of the association.
Design: In this review we evaluate and summarise the current literature regarding the diagnosis,
management and prognosis of pregnancy-associated breast cancer. Data were identified by searches
of Medline, PubMed and references from relevant articles for the period from 1966 to 2004. Papers
were selected based on their size and adequacy of design.
Results: There is a lack of controlled data concerning the management of pregnancy-associated breast
cancer. The data available suggest that diagnosis and surgery may be carried out as for the nonpregnant patient, with some limitations on staging investigations. Radiotherapy is contraindicated
during pregnancy although, in terms of immediate complications, chemotherapy can be used after
the first trimester.
Conclusions: Data from prospective databases that are currently recruiting will provide further important information concerning the management of this condition, and in particular the long-term
sequelae for mother and fetus.
Key words: breast cancer, chemotherapy, pregnancy

1856

Clinical and pathological characteristics

From a number of case series the median maternal age at the
time of diagnosis of breast cancer during pregnancy is 3334
years. The median gestational age at diagnosis is 1725 weeks
[1518]. As in non-pregnant patients, the majority of tumours
are invasive ductal carcinomas, with between 80% and 100% of
patients presenting with tumours of this subtype [15, 16, 18, 19].
Between 40% and 84% of patients present with poorly differentiated tumours [1517, 19], although in a casecontrol
study the rate of poorly differentiated tumours did not exceed

that seen in matched non-pregnant controls [19]. The incidence

of inflammatory tumours probably lies between 1.5% and 4%
[20], although some series report higher rates of inflammatory
tumours in pregnant patients than in non-pregnant controls
[19]. Previous studies have shown that patients with pregnancy-associated breast cancer commonly present with pathological lymph node involvement (5667%), large tumours and
lymphovascular invasion [17, 21]. Studies have shown that pregnant or lactating women may be more likely to present at a more
advanced stage than matched non-pregnant controls [6, 19, 21].
A common finding in series of patients with pregnancyassociated breast cancer is a high frequency of estrogenreceptor (ER)-negative tumours. Between 54% and 80% of
pregnancy-associated breast cancers are ER-negative [15, 17,
19, 22, 23]. ER-negative tumours are recognised to be more
common in younger women anyway, but in casecontrol studies
ER-negative tumours have been found to be more common in
pregnant patients than in age-matched controls [19, 22]. Using
a variety of antibodies and scoring systems HER2 positivity
has been recorded in 28% to 58% of pregnancy-associated
breast cancers [17, 22, 23]. The numbers in these studies are
too small to conclude whether the frequency of HER2 positivity
is higher than that seen in age-matched controls [22, 23].

Treatment options
Surgery
Surgery is usually the first treatment considered for patients with
breast cancer. Limited procedures may be performed under local
anaesthesia, but for the majority of patients a general anaesthetic
is necessary. In women who are pregnant general anaesthesia
is complicated because of increased blood volume and coagulability, decreased lung capacity, slow gastric emptying and
supine positional hypotension. One study described 5405
operations performed on a population of 720 000 pregnant
women and found that pregnant women undergoing surgery
were more likely to have low birth weight infants as a result
of both prematurity and intrauterine growth retardation [24].
There were also increases in neonatal mortality, but no increase
in congenital malformations or stillbirths. It is not possible to
tell whether the adverse outcomes recorded were due to the surgery, anaesthesia or the underlying conditions requiring the procedure to be undertaken. However, small case series suggest that
breast-conserving surgery, mastectomies and axillary surgery
can all be performed safely with no unexpected complications
[15, 16]. The safety of sentinel lymph node biopsy in pregnant
patients is not known.

Radiotherapy
The radiation doses used in cancer therapy are much higher than
those used in diagnostic radiology, exposing the fetus to considerable risk of toxicity. Using careful fetal dose evaluation it may
be possible to irradiate some parts of the mother without significantly irradiating the fetus. In terms of adjuvant breast radiotherapy, fetal dose exposure may be as low as 0.0360.038 Gy

Downloaded from annonc.oxfordjournals.org by guest on March 15, 2011

there is a risk of milk fistula formation, and there are higher rates
of bleeding and infection [8]. These risks can be minimised by
stopping breastfeeding prior to the biopsy, the use of prophylactic antibiotics and paying close attention to haemostasis [8].
Many routine staging investigations used in non-pregnant
women use ionising radiation and therefore involve a potential
risk to the fetus. The consequences of prenatal exposure to
ionising radiation will depend on the dose of radiation, its
distribution and the stage of fetal development at the time of
exposure [9]. Irradiation in the peri-implantation and early
post-implantation period (up to 8 days) may lead to embryonic
death [10]. During organogenesis (up to 8 weeks) the fetus is
at its most sensitive to radiation-induced malformations, which
may occur with exposure to more than 0.05 Gy [10]. Other
risks to the fetus when exposed to ionising radiation during this
period include intrauterine growth delay, microcephaly and
mental retardation. The risk of severe mental retardation is
dose- and age-dependent, with a threshold between 0.060.31
Gy when the fetus is 815 weeks, and of 0.28 Gy when aged
1625 weeks [11]. Theoretically it is also possible that irradiation may predispose to sterility and subsequent cancers in the
child, although long-term follow-up studies would be required
to establish the true incidences of these complications [10].
In general, chest X-rays are regarded as safe during pregnancy
as the expected fetal doses are less than the thresholds described
above [9]. It is reasonable that these be performed, with appropriate shielding, when clinically indicated. It has been estimated
that computed tomography (CT) scans of the liver and the pelvis
may expose the fetus to mean doses of 0.0036 and 0.089 Gy,
respectively [9]. Therefore, CT scans are usually avoided and
metastases are sought using alternative imaging modalities
such as ultrasonography. There are theoretical risks to the fetus
from exposure to the high magnetic fields used to generate a
magnetic resonance image (MRI), and the UK medical devices
agency recommends avoiding MRI scans during the first trimester until more information becomes available [12]. In addition,
the contrast agent gadolinium should be avoided if possible, as
it is has been shown to cross the placenta, and its effects on
the developing fetus are not known [13]. Bone metastases can
be identified using MR of the skeleton, or modified bone scans
[2, 14]. Using such approaches to staging it is possible to minimise the risks to the fetus. Nonetheless, it is important that
such investigations should only be used where a positive result
would alter immediate management.

1857
when completed by the sixth week of gestation [25], but exposure may increase markedly later in pregnancy as the fetus
moves closer to the radiation field [26]. These exposures may
still put the fetus at risk, and therefore adjuvant breast radiotherapy is usually delayed until after delivery. Unfortunately,
delays in delivering adjuvant radiotherapy exceeding 8 weeks in
women not receiving systemic therapy may impact on maternal
outcome [27]. Under these circumstances this issue will need
to be discussed with the patient. However, practically, the need
to delay adjuvant radiotherapy until after delivery is rarely an
issue as the young age of the patients and high incidence of adverse prognostic features means that adjuvant chemotherapy is
often offered in the interim.

Chemotherapy

Fetal effects of chemotherapy. The effects of cytotoxic chemotherapy on nucleic acid synthesis and microtubule function, and
the rapid rate of cell division occurring in the fetus mean that it
is likely to be particularly susceptible to the effects of chemotherapy. All drugs have the potential to cross the placenta, but
the extent of transfer depends considerably on the physical
and chemical properties of the agent. Methotrexate and 5fluorouracil are distributed widely in tissues and fluid spaces,
and certainly appear to have the potential to enter the amniotic
fluid [2931]. In contrast, in one study doxorubicin was not
detected in amniotic fluid collected 4 and 16 h after drug
administration in a woman who was 20 weeks pregnant [32].
Furthermore, in vitro perfusion studies using term placentae
have shown only very low levels of transplacental transfer of
epirubicin [33]. There are minimal data concerning the transplacental transfer of taxanes. However, it is worth noting that
P-glycoprotein is expressed in the human placenta, and its presence may reduce fetal exposure to several antineoplastic agents
including paclitaxel [34].
First trimester. When chemotherapy is given in the first few
weeks of pregnancy there is a significant risk of spontaneous
abortion [29]. Over the rest of the first trimester, the fetus
remains at risk of spontaneous abortion and there is the additional risk of fetal malformations as a result of exposure to
chemotherapy. The estimated risk of fetal malformations when
chemotherapy is given during the first trimester is up to 17%
[2931]. This risk is thought to increase when combination therapy is used, and when chemotherapy is given in conjunction
with radiotherapy [31]. There also appear to be differences

Second and third trimesters. Chemotherapy has been more

widely used in the second and third trimesters, as organogenesis
is complete and fetal malformations are therefore unlikely to
occur. The only prospective series is from the M.D. Anderson
Cancer Center [15]. In this study 24 women with primary or recurrent breast cancer were treated with doxorubicin 50 mg/m2 as
a continuous infusion over 72 h, cyclophosphamide 500 mg/m2
on day 1 and bolus 5-fluorouracil 500 mg/m2 on days 1 and 4,
all administered every 34 weeks. There were no detectable
congenital anomalies and no maternal or fetal deaths. In a retrospective series of 28 pregnant patients treated with chemotherapy for breast cancer at London teaching hospitals there were
also no deaths or congenital malformations when chemotherapy
was given after the first trimester [16].
Pre-term delivery (under 37 weeks gestation) was recorded in
nine children in the London series; in one case this was due to
spontaneous onset of labour, but in the remainder it was due to
physician intervention [16]. Spontaneous onset of labour and
other pregnancy complications such as pre-eclampsia have both
been reported previously when pregnant women receive chemotherapy [15, 36]. However, it is not known whether the incidences of these complications are in excess of those in the normal
population, and what the contribution of chemotherapy is relative to the effects of the underlying disease. Transient leukopenias have also been described in neonates born to mothers
receiving chemotherapy [15, 18]. Myelosuppression occurring
around the time of delivery may put both mother and baby at risk
of sepsis and haemorrhage, and it is therefore recommended that
chemotherapy should be avoided for at least 3 weeks prior to
delivery in order that maternal blood counts are optimal [18].
Children exposed to chemotherapy in utero might be expected
to be at risk of intrauterine growth retardation. The incidence of
this is likely to be underestimated in retrospective series; nonetheless, none of the infants in the London hospitals series and
only one of those in the M.D. Anderson series had birth weight
below the 10th percentile for gestational age [15, 16].
The relative toxicities of different agents are difficult to assess
on the basis of the existing data. All of the patients in the M.D.
Anderson series and 16 of those in the London series received
anthracycline-based treatment [15, 16]. In terms of peri-partum
complications and immediate fetal outcome it appears that these
agents can be safely administered to women during the second
and third trimesters [15, 16]. This conclusion was also made by
Germann et al. [37] in their review of 160 patients who had
received anthracyclines during pregnancy. However, the use of
other cytotoxic agents also seems possible during the second and
third trimesters. Vinorelbine in combination with 5-fluorouracil
has been given to three patients in the second and third trimesters with no immediate fetal or maternal complications [38].
Paclitaxel has been shown to be toxic to the fetus in animal

Downloaded from annonc.oxfordjournals.org by guest on March 15, 2011

Maternal effects of chemotherapy. The physiological changes

observed in pregnancy may alter the pharmacokinetics and
pharmacodynamics of chemotherapy in the mother. In the pregnant woman there are alterations in hepatic metabolism, renal
plasma flow and plasma protein binding, all of which may affect
drug clearance [28]. The amniotic fluid may also act as a pharmacological third space and delay elimination of agents such
as methotrexate. These effects make it difficult to predict the
appropriate dose to be administered, and may increase the
chances of both maternal and fetal toxicity.

between agents in terms of their potential teratogenicity with

antimetabolites and alkylating agents more likely to be associated with miscarriage and malformations [30, 35]. Given the
significant risks to the fetus of first trimester exposure to chemotherapy, treatment during this stage of pregnancy is usually
avoided.

1858
studies but has been used in combination with cisplatin from
28 weeks of pregnancy and in combination with epirubicin from
14 weeks with no unexpected maternal or fetal complications
[39, 40]. Docetaxel is also toxic to the fetus in animal studies, but
the one report of its use to treat metastatic breast cancer between
the 23rd and 32nd weeks of pregnancy showed no specific complications [41].

Growth factors
Growth factors are sometimes needed for haematological support,
particularly when dose-dense chemotherapy is used; anecdotal
reports describe the use of granulocyte colony-stimulating factor
during pregnancy without immediate complications [16, 44].

Targeted therapy
Studies have shown relatively high rates of HER2-positive
tumours in pregnant women, and therefore treatment with
trastuzumab may be considered [17, 22, 23]. However, HER2
expression is also high in embryonic tissues, suggesting a role
in embryonic development, and placental transfer of the monoclonal antibody trastuzumab has been observed in animal studies (personal communication from Roche Pharmaceuticals,
Welwyn Garden City, UK). Therefore, the use of the trastuzumab during pregnancy cannot currently be recommended.

There is evidence from animal studies that the selective ER

modulator tamoxifen may potentially be teratogenic [45]. Data
from 50 pregnancies in which the mother took tamoxifen
revealed 10 fetal abnormalities, including two craniofacial
defects [46]. Other rare fetal abnormalities, including Goldenhars syndrome (oculoauriculovertebral dysplasia) and ambiguous genitalia, have also been described [47, 48]. Therefore, the
use of tamoxifen is usually delayed until the end of pregnancy.

Bisphosphonates
Bisphosphonates are frequently used in the management of
skeletal complications from metastatic breast cancer and have
an emerging role in the adjuvant setting. Two reports describe
the use of pamidronate to treat malignant hypercalcaemia during
the third trimester of pregnancy [49, 50]. Post-partum, both
neonates suffered from hypocalcaemia, but have subsequently
undergone normal development. It is possible that the transient hypocalcaemia occurred as a result of parathyroid suppression in the neonate caused by maternal hypercalcaemia, rather
than as a direct effect of pamidronate on the fetus [49, 50].
Nonetheless, the authors recommend that in the rare instances
where bisphosphonates are used in pregnant patients neonatal
calcium should be carefully monitored [49]. The long-term
effects of pamidronate on bone growth and development in the
neonate are not known.

Termination of pregnancy
Termination of pregnancy is an option sometimes considered by
pregnant women who are diagnosed with breast cancer. In the
past this option was recommended in the belief that the hormonal changes of pregnancy promoted the growth of breast
cancer. In historical series no significant reduction in relapse
rate or improvement in survival has been seen with termination
of pregnancy [1, 20], but it is possible that any potential benefit
from termination was masked by a tendency for women with
worse prognoses to opt for this, or by a high rate of hormone
receptor-negative tumours. It may still be reasonable to discuss
termination if the fetus is likely to be exposed to significant risk
of harm by potentially curative treatment given to the mother. In
addition, some women with metastatic or high-risk cancer may
not want to carry on with the pregnancy. Patients and their
relatives must be provided with adequate counselling in order
that they can make an informed rational decision in these very
difficult circumstances.

Prognosis of pregnancy-associated
breast cancer
Pregnancy-associated breast cancer has long been regarded as
having a poor prognosis, with the earliest reports describing 5year survival rates of <20% [1]. However, in a more recent study

Downloaded from annonc.oxfordjournals.org by guest on March 15, 2011

Long-term effects of chemotherapy exposure. The M.D.

Anderson Cancer Center prospective study, the French National
Survey and the London hospitals series suggest that in the shortterm chemotherapy can be safely administered to women within
the second and third trimesters of pregnancy [15, 16, 18]. Whilst
this is true for the pre-partum and immediate peri-partum
periods, little is known about the long-term effects on the fetus
of in utero chemotherapy exposure. One could postulate that
fetal exposure to chemotherapy may lead to gonadal damage and
later problems with fertility, germ cell damage, and higher rates
of malignancy and teratogenicity in subsequent generations.
Similarly, damage to organs such as the heart, kidneys or central
nervous system may not manifest itself as physical or neurological impairment until later in life. In reality, there are very few
reports documenting the long-term follow-up of children exposed to chemotherapy in utero. Aviles and Neri [42] described
a cohort of 84 children born to mothers who were treated with
combination chemotherapy during pregnancy for haematological malignancies. The childrens ages ranged from 6 to 29 years
(median 18.7) at the time of assessment, and 12 secondgeneration children were included in the analysis. Normal
physical, neurological and psychological development was
observed in all children and there were no reports of malignancies in this cohort. Reports such as this are reassuring but large
prospective studies such as that initiated by the German Breast
Group [43] and recently extended by the Breast International
Group (BIG 2-03) are needed to provide further information
regarding the sequelae of treatment.

Endocrine therapy

1859
overall survival of patients with stage II and III disease was
found to be 75% (at a median of 40 months), suggesting that
with modern multimodality therapy outcome may not be as poor
as was previously thought [15]. The previously observed poor
prognosis was thought to be partly explained by a tendency for
pregnant patients to present at a more advanced stage than nonpregnant women, possibly reflecting delay in diagnosis [6, 19].
However, late stage at diagnosis may not be the only explanation
for the poor prognosis observed; it has been proposed that pregnancy itself may be an independent predictor of worse survival
[19]. Many of the earlier studies that documented poor survival
rates failed to adjust for age, stage, pathological features, treatment effect and other established prognostic variables. Where
casecontrol studies have been carried out, most suggest little
difference in survival between pregnancy-associated and nonpregnancy associated breast cancer [21, 22].

Women who are diagnosed with breast cancer during pregnancy

require a tailored approach to management with careful consideration given at all stages to the needs of the mother and risks to
the fetus. Data concerning the long-term risks of surgery, radiotherapy and systemic anticancer treatment are limited. Management is critically influenced by the stage of the pregnancy. In
particular, during the first trimester there may be significant risks
of fetal damage, and options both in terms of investigations and
treatment may be limited. However, current data concerning the
short-term safety of surgery and chemotherapy administered
during the second and third trimesters are reassuring. At all
stages the management of the patient should be decided by
a multidisciplinary team, incorporating not only breast surgeon,
medical and clinical oncologists, but also obstetricians, neonatologists and specialist nursing staff in order to ensure the
best possible outcome for both mother and infant.

References
1. White TT. Carcinoma of the breast and pregnancy; analysis of 920
cases collected from the literature and 22 new cases. Ann Surg 1954;
139: 918.
2. Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer
patient. Semin Oncol 2000; 27: 623632.
3. Hogge JP, De Paredes ES, Magnant CM, Lage J. Imaging and management of breast masses during pregnancy and lactation. Breast J
1999; 5: 272283.
4. Liberman L, Giess CS, Dershaw DD et al. Imaging of pregnancyassociated breast cancer. Radiology 1994; 191: 245248.
5. Ahn BY, Kim HH, Moon WK et al. Pregnancy- and lactation-associated
breast cancer: mammographic and sonographic findings. J Ultrasound
Med 2003; 22: 491497.
6. Ishida T, Yokoe T, Kasumi F et al. Clinicopathologic characteristics
and prognosis of breast cancer patients associated with pregnancy
and lactation: analysis of casecontrol study in Japan. Jpn J Cancer Res
1992; 83: 11431149.
7. Novotny DB, Maygarden SJ, Shermer RW, Frable WJ. Fine needle
aspiration of benign and malignant breast masses associated with pregnancy. Acta Cytol 1991; 35: 676686.

Downloaded from annonc.oxfordjournals.org by guest on March 15, 2011

Conclusions

8. Petrek JA. Breast cancer during pregnancy. Cancer 1994; 74 (1 Suppl):

518527.
9. Osei EK, Faulkner K. Fetal doses from radiological examinations.
Br J Radiol 1999; 72: 773780.
10. Greskovich JF Jr, Macklis RM. Radiation therapy in pregnancy: risk
calculation and risk minimization. Semin Oncol 2000; 27: 633645.
11. Otake M, Schull WJ, Lee S. Threshold for radiation-related severe
mental retardation in prenatally exposed A-bomb survivors: a reanalysis. Int J Radiat Biol 1996; 70: 755763.
12. Medical Devices Agency, UK. Pregnancy and MR exposure. In
Guidelines for Magnetic Resonance Equipment in Clinical Use 2002;
2223.
13. Shellock FG, Kanal E. Safety of magnetic resonance imaging contrast
agents. J Magn Reson Imaging 1999; 10: 477484.
14. Baker J, Ali A, Groch MW et al. Bone scanning in pregnant patients
with breast carcinoma. Clin Nucl Med 1987; 12: 519524.
15. Berry DL, Theriault RL, Holmes FA et al. Management of breast
cancer during pregnancy using a standardized protocol. J Clin Oncol
1999; 17: 855861.
16. Ring AE, Smith IE, Jones A et al. Chemotherapy for breast cancer
during pregnancy: an 18 year experience from five London teaching
hospitals. J Clin Oncol 2005; 23: 41924197.
17. Middleton LP, Amin M, Gwyn K et al. Breast carcinoma in pregnant
women: assessment of clinicopathologic and immunohistochemical
features. Cancer 2003; 98: 10551060.
18. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy: A French national survey. Cancer 1999; 86:
22662272.
19. Bonnier P, Romain S, Dilhuydy JM et al. Influence of pregnancy on
the outcome of breast cancer: a casecontrol study. Societe Francaise
de Senologie et de Pathologie Mammaire Study Group. Int J Cancer
1997; 72: 720727.
20. Clark RM, Chua T. Breast cancer and pregnancy: the ultimate challenge. Clin Oncol (R Coll Radiol) 1989; 1: 1118.
21. Zemlickis D, Lishner M, Degendorfer P et al. Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 1992;
166: 781787.
22. Aziz S, Pervez S, Khan S et al. Case control study of novel prognostic
markers and disease outcome in pregnancy/lactation-associated breast
carcinoma. Pathol Res Pract 2003; 199: 1521.
23. Elledge RM, Ciocca DR, Langone G, McGuire WL. Estrogen receptor,
progesterone receptor, and HER-2/neu protein in breast cancers from
pregnant patients. Cancer 1993; 71: 24992506.
24. Mazze RI, Kallen B. Reproductive outcome after anaesthesia and
operation during pregnancy: a registry study of 5405 cases. Am J Obstet
Gynecol 1989; 161: 11781185.
25. Antypas C, Sandilos P, Kouvaris J et al. Fetal dose evaluation during
breast cancer radiotherapy. Int J Radiat Oncol Biol Phys 1998; 40:
995999.
26. Mayr NA, Wen BC, Saw CB. Radiation therapy during pregnancy.
Obstet Gynecol Clin North Am 1998; 25: 301321.
27. Ruo Redda MG, Verna R, Guarneri A, Sannazzari GL. Timing of
radiotherapy in breast cancer conserving treatment. Cancer Treat Rev
2002; 28: 510.
28. Redmond GP. Physiological changes during pregnancy and their
implications for pharmacological treatment. Clin Invest Med 1985;
8: 317322.
29. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and pregnancy. Semin Oncol 1989; 16: 337346.
30. Schapira DV, Chudley AE. Successful pregnancy following continuous
treatment with combination chemotherapy before conception and
throughout pregnancy. Cancer 1984; 54: 800803.

1860
42. Aviles A, Neri N. Hematological malignancies and pregnancy: a
final report of 84 children who received chemotherapy in utero.
Clin Lymphoma 2001; 2: 173177.
43. German Breast Group. GBG-29: Breast cancer in pregnancy. Prospective register study for the diagnosis and treatment of breast cancer in
pregnancy. www.germanbreastgroup.de/pregnancy (22 December
2004, date last accessed).
44. Losch A, Lahodny J, Petru E. Possible influence of granulocyte colonystimulating factor and recombinant human erythropoietin on human
chorionic gonadotropin secretion during chemotherapy for choriocarcinoma. Gynecol Oncol 2001; 83: 165166.
45. Furr BJ, Valcaccia B, Challis JR. The effects of Nolvadex (tamoxifen
citrate; ICI 46,474) on pregnancy in rabbits. J Reprod Fertil 1976; 48:
367369.
46. Saunders CM. Breast cancer in pregnancy. In Shaugn OBrien P,
MacLean A (eds): Hormones and Cancer. London: Royal College of
Obstetricians and Gynaecologists Press 1999: 312321.
47. Tewari K, Bonebrake RG, Asrat T, Shanberg AM. Ambiguous genitalia
in infant exposed to tamoxifen in utero. Lancet 1997; 350: 183.
48. Cullins SL, Pridjian G, Sutherland CM. Goldenhars syndrome associated with tamoxifen given to the mother during gestation. JAMA 1994;
271: 19051906.
49. Dunlop DJ, Soukop M, McEwan HP. Antenatal administration of
aminopropylidene diphosphonate. Ann Rheum Dis 1990; 49: 955.
50. Illidge TM, Hussey M, Godden CW. Malignant hypercalcaemia in
pregnancy and antenatal administration of intravenous pamidronate.
Clin Oncol (R Coll Radiol) 1996; 8: 257258.

Downloaded from annonc.oxfordjournals.org by guest on March 15, 2011

31. Espie M, Cuvier C. Treating breast cancer during pregnancy. What can
be taken safely? Drug Safety 1998; 18: 135142.
32. Roboz J, Gleicher N, Wu K et al. Does doxorubicin cross the placenta?
Lancet 1979; 2: 13821383.
33. Gaillard B, Leng JJ, Grellet J et al. Transplacental passage of doxorubicin. J Gynecol Obstet Biol Reprod (Paris) 1995; 24: 6368.
34. Smit JW, Huisman MT, van Tellingen O et al. Absence of pharmacological blocking of placental P-glycoprotein profoundly increases fetal
drug exposure. J Clin Invest 1999; 104: 14411447.
35. Glantz JC. Reproductive toxicology of alkylating agents. Obstet
Gynecol Surv 1994; 49: 709715.
36. Muller T, Hofmann J, Steck T. Eclampsia after polychemotherapy for
nodal-positive breast cancer during pregnancy. Eur J Obstet Gynecol
Reprod Biol 1996; 67: 197198.
37. Germann N, Goffinet F, Goldwasser F. Anthracyclines during pregnancy:
embryo-fetal outcome in 160 patients. Ann Oncol 2004; 15: 146150.
38. Cuvier C, Espie M, Extra JM, Marty M. Vinorelbine in pregnancy.
Eur J Cancer 1997; 33: 168169.
39. Sood AK, Shahin MS, Sorosky JI. Paclitaxel and platinum chemotherapy for ovarian carcinoma during pregnancy. Gynecol Oncol 2001;
83: 599600.
40. Gadducci A, Cosio S, Fanucchi A et al. Chemotherapy with epirubicin
and paclitaxel for breast cancer during pregnancy: case report and
review of the literature. Anticancer Res 2003; 23: 52255230.
41. De Santis M, Lucchese A, De Carolis S et al. Metastatic breast cancer
in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer
Care (Engl) 2000; 9: 235237.