Cance Du ing P egnancy: How o
Handle he Bioe hical Dilemmas?—A
Scoping Re iew Wi h Pa adigma ic
Cases-Based Analysis
Diogo Alpuim Cos a
1,2
*, Jose
´Guilhe me Nob e
3
, Susana Bap is a de Almeida
4
,
Ma isa Ho a Fe ei a
5
, Ine
ˆs Gonc¸al es
6
,Sofia B aga
1,2,4
and Diogo Pais
7
1
CUF Oncologia, Haema ology and Oncology Depa men , Lisbon, Po ugal,
2
NOVA Medical School, Faculdade de
Cie
ˆncias Me
´dicas, Lisbon, Po ugal,
3
Uni e sidade de Lisboa, Faculdade de Medicina, Lisbon, Po ugal,
4
Hospi al P o esso
Dou o Fe nando Fonseca EPE, Oncology Depa men , Amado a, Po ugal,
5
Uni e sidade da Bei a In e io , Faculdade de
Cie
ˆncias da Sau
´de, Co ilhã, Po ugal,
6
Hospi al CUF Almada, Eme gency Depa men , Almada, Po ugal,
7
E hics
Depa men , NOVA Medical School, Faculdade de Cie
ˆncias Me
´dicas, Lisbon, Po ugal
E hical issues ha a ise du ing he ca e o a p egnan woman wi h cance a e challenging
o physicians, policymake s, lawye s, and he bioe hics communi y. The main pu pose o
his scoping e iew is o summa ize exis ing li e a u e ega ding he bioe hical dilemmas
when a conflic a ises in he ma e nal- e us dyad, like he one ela ed o cance and
p egnancy ou comes. Mo eo e , we illus a e he decision-making p ocess o eal-li e
case epo s. Published da a we e sea ched h ough he PubMed and Google Schola
da abases, as well as in g ey li e a u e, using app op ia e con olled keywo ds in English
and Po uguese. A e iden ifica ion, sc eening, eligibili y and da a ex ac ion om he
a icles, a o al o 50 was selec ed. The e a e se e al es ablished e hical amewo ks o
conflic esolu ion and decision-making. P agma ic heo e ical app oaches include case-
based analysis, he e hics o ca e, eminis heo y, and adi ional e hical p inciplism ha
sc u inizes he amewo k o au onomy, jus ice, beneficence, and non-maleficence. In
addi ion, socie y and p ac i ione alues could media e his complex e hical in e play. The
physician mus balance au onomy and beneficence-based obliga ions o he p egnan
woman wi h cance , along wi h beneficence-based obliga ions o he e us. E hical
challenges ha e ecei ed less a en ion in he li e a u e, pa icula ly be o e he hi d
imes e o p egnancy. Bes , unbiased and balanced in o ma ion mus be g an ed bo h
o he pa ien and o he amily, ega ding he benefi s and ha ms o he woman he sel as
well as o he e al ou come. Based on a p e iously alida ed me hod o analyzing and
wo king up clinical e hical p oblems, we sugges an adap a ion o an algo i hm o
biomedical decision-making in cance du ing p egnancy, including ecommenda ions
ha can acili a e counseling and help educe he su e ing o he pa ien and he amily.
Keywo ds: e hics, e hical, ca cinoma, cance , neoplasm, p egnancy, p egnan , ges a ion
F on ie s in Oncology | www. on ie sin.o g Decembe 2020 | Volume 10 | A icle 5985081
Edi ed by:
Ma eo Lambe ini,
Uni e si y o Genoa, I aly
Re iewed by:
Alma Linke iciu e,
Eu opean Ins i u e o Oncology, I aly
F ancesca Poggio,
San Ma ino Hospi al (IRCCS), I aly
*Co espondence:
Diogo Alpuim Cos a
[email p o ec ed];
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
Women's Cance ,
a sec ion o he jou nal
F on ie s in Oncology
Recei ed: 24 Augus 2020
Accep ed: 17 No embe 2020
Published: 23 Decembe 2020
Ci a ion:
Alpuim Cos a D, Nob e JG,
de Almeida SB, Fe ei a MH,
Gonc¸al es I, B aga S and Pais D
(2020) Cance Du ing P egnancy:
How o Handle he Bioe hical
Dilemmas?—A Scoping Re iew
Wi h Pa adigma ic
Cases-Based Analysis.
F on . Oncol. 10:598508.
doi: 10.3389/ onc.2020.598508
REVIEW
published: 23 Decembe 2020
doi: 10.3389/ onc.2020.598508
BACKGROUND
Cance is he second and fi s mos common cause o dea h in
women aged 25–34 and 35–65 yea s, espec i ely (1). Howe e ,
cance ha occu s du ing p egnancy is a ela i ely a e e en ,
wi h an es ima e be ween 0.03 and 0.1% o all p egnancies. The
incidence is expec ed o upsu ge wi h la e childbea ing age and
unplanned p egnancies. In Eu ope, 3,000–5,000 pa ien s a e
diagnosed yea ly wi h cance du ing p egnancy, whe eas 3,500
cases a e epo ed in he USA (2–5). The mos common
neoplasms ha occu du ing p egnancy a e b eas cance ,
hy oid, ce ical, o a ian and melanoma (2–5), bu he
cu en ly a ailable da a is mainly limi ed o hose a eas o
Wes e n/Cen al Eu ope and No h Ame ica (6,7). Some
ecen da a indica e ha o he cance s may be mo e p e alen
in p egnan women in pa icula egions, as mo e cases o
melanoma in Scandina ia (8) and gas oin es inal cance in
Asia (9).
The p oblema ics o how o handle cance du ing p egnancy
hasbeenalong- e mma e o deba ein hemedical
communi y. The many e hical issues ha a ise in he ca e o
p egnan women in ol e many s akeholde s—such as amily,
physicians, legisla o s, ju isdic ion and he bioe hics communi y
- and i s bounda ies a e impe ec since many con ex s in e sec .
In he ca e o p egnan cance women, i is impo an o conside
he s a us o wo biologically- ela ed pa ien s, bu indi idually
iable. Howe e , cance du ing p egnancy ep esen s a dilemma
gi en ha ea men should be di ec ed o keep wo li es: ma e nal
and e al. Despi e his complex e hical in e play, i should
be emphasized, wi h he excep ion o special ci cums ances,
ha he pa ien has he final wo d in he decision-making
p ocess and ha he emaining s akeholde s con ibu e wi h a
a iable ole and weigh depending on each specificcase
and scena io.
This a icle ocuses on he discussion o he clinical/
pha macological backg ound and e hical issues ha eme ge
om he medical managemen , especially be o e he hi d
imes e , o a p egnan woman wi h cance , which occu s
whene e he he apy oxici y c ea es a conflic o in e es ha
unbalances cance and p egnancy ou comes. Fu he mo e, in
o de o pe mi a be e aming o his p oblema ic, we desc ibe
eal-li e pa adigma ic cases ha allow us o highligh he
idiosync asies ela ed o he e hical app oach o cance du ing
p egnancy. Finally, we sugges an adap a ion o an algo i hm o
biomedical decision-making in cance du ing p egnancy,
including some ecommenda ions ha can acili a e counseling
and help educe he su e ing o he pa ien and he amily.
METHODS
Assessing easons o a gumen s p esen ed in he no ma i e
bioe hics’li e a u e can be a icky ask, as iden i ying any
ele an da a on a gi en opic in bioe hics can be ime-
consuming and no always possible due o he high bu den o
g ey li e a u e, including books, edi ed book olumes and e en
p eda o y magazines, some o hem wi h dubious con en .
The e o e, some au ho s a gue ha , e en i he sys ema ic
sea ch should be main ained in bioe hics esea ch, he ype o
me hodology will depend on he esea ch ques ion. In some
cases, iden i ying all he li e a u e on a gi en ques ion may no be
easible and, e en i i is, he ime spen will no add significan
alue o he esea ch (10,11).
Tha is why some ad oca e a u n o c i ical in e p e a i e
e iews which migh be e se e bioe hics esea ch pu poses
(11). Based on ha , we chose he scoping e iew as he bes
me hodology o ou esea ch objec i es, which we e o apidly
map he exis ing li e a u e (including he one no indexed in
majo da abases, such as he g ey li e a u e), cha da a om he
s udies, and cla i y concep s. We we e no in e es ed in asking a
single o p ecise ques ion, bu mo e ocused on he iden ifica ion
o ce ain concep s in pape s o s udies, and in he mapping,
epo ing o discussion o he da a collec ed. Ou aim wi h his
e iew is o summa ize and cla i y he exis ing published
li e a u e on he e hical dilemmas in e wo en in o he
dimension o p egnan women wi h cance , pa icula ly be o e
he hi d imes e . Mo eo e , we pu in pe spec i e he po en ial
e hical p oblems and amewo ks ega ding he mo e
app op ia e app oach o specific and ep esen a i e case epo s.
We de eloped an a p io i p o ocol o define ou esea ch
objec i e, and me hods, which in o med ou selec ion o
da a ex ac ion.
On Oc obe 8-9
h
, published li e a u e was sea ched be ween
2010 and 2020 h ough he PubMed, using app op ia e
con olled keywo ds: [“e hics”(MeSH) OR “e hical”(MeSH)]
AND [“ca cinoma”(MeSH) OR “cance ”(MeSH) OR
“neoplasm”(MeSH)] AND [“p egnancy”(MeSH) OR
“p egnan ”(MeSH) OR “ges a ion”(MeSH)]. Re e ences om
he selec ed a icles we e scanned in o de o iden i y
o he pape s.
By he au ho ’s decision, o he ele an a icles beyond his
scope, including g ey li e a u e, ha e been included. Fo ha
pu pose, we used Google Schola sea ch engine wi h he
con olled wo ds in English and Po uguese (“e hics”AND
“cance ”AND “p egnancy”)OR(“e ica”AND “canc o”AND
“g a idez”), espec i ely.
Using Co idence (Co idence.o g), we inpu ed ou inclusion/
exclusion c i e ia and selec ed he a icles independen ly by wo
e iewe s (DAC, JGN).
The inclusion c i e ia defined included: 1) pa ien s who a e
p egnan ; 2) pa ien s who ha e ac i e cance ; 3) a icles add essing
he p oblem o he iad: e hics, cance and p egnancy; 4) a icles
including an e hical pe spec i e du ing p egnancy; 5) a icles and
expe mee ing epo ing clinical p ac ice guidelines o
ecommenda ions o cance managemen du ing p egnancy; 6)
s udy based on he oxici y o an ineoplas ic ea men du ing
Abb e ia ions: AFP, Alpha- e op o ein; AMH, An i-Mülle ian ho mone; ATRA,
All- ans- e inoic acid; Bc -Abl, B eakpoin clus e egion p o ein-Abelson
mu ine leukaemia i al oncogene homolog 1; CA, Ca bohyd a e an igen; G-
CSF, G anulocy e colony-s imula ing ac o ; GM-CSF, G anulocy e colony-
s imula ion ac o ; HE-4, Human epididymis p o ein-4; I-131, Radioac i e
iodine; LDH, Lac a e dehyd ogenase; mGy, mili G ay uni s; PD-1, P og ammed
cell dea h p o ein-1; PD-L1, P og ammed cell dea h p o ein-ligand 1; SCC,
Squamous cell ca cinoma; US, Ul asonog aphy; USA, Uni ed S a es o Ame ica.
Alpium Cos a e al. Cance , P egnancy, and Bioe hical Dilemmas
F on ie s in Oncology | www. on ie sin.o g Decembe 2020 | Volume 10 | A icle 5985082
p egnancy ha includes one o he ollowing: chemo-, ho mone-,
a ge ed-, immuno-, and adio- he apy; 7) s udy based on he
oxici y o suppo i e medica ion du ing p egnancy; 8) a icle
language in English o Po uguese; 9) a icles mus be a ailable
wi h ull- ex .
The exclusion c i e ia we e: 1) p emenopausal women and
e ili y issues; 2) cance isk exclusi ely a e p egnancy; 3) cance
isk and ho mone eplacemen he apy; 4) ac i e cance and
b eas eeding; 5) a icles discussing cance he apeu ics exclusi ely;
6) a icles no men ioning p egnancy, cance , and e hics a all.
Da a ex ac ion was conduc ed in Mic oso Excel e sion 16.41
(20091302) using a da a cha ing o m de eloped o ou p o ocol.
RESULTS
Resul s we e mos ly es ic ed o e iew a icles, e hical
pe spec i es, clinical p ac ice guidelines and case-based
eaching guides (only a ailable English and Po uguese ex ).
A e wa ds, he sc eening and selec ion o a icles, quali y
assessmen , and da a ex ac ion we e pe o med independen ly
by wo e iewe s (DAC, JGN), acco ding o he p e-planned
inclusion and exclusion c i e ia. Conflic s we e esol ed by a
hi d pa y (IG) when a consensus was no eached.
Fo he pe iod be ween 2010 and 2020, he ini ial sea ch in
English yielded 633 publica ions a e he possible combina ions
o keywo ds in PubMed. Excluding he 292 duplica es, he
numbe was educed o 341. Ti le sc een educed he selec ion
o 75 pape s o e iewing abs ac s and 61 ulfilled he c i e ia
o eading he ull- ex . In he final selec ion, 12 a icles we e
chosen o be included in his e iew (Figu e 1).
The ini ial sea ch in Google Schola wi h he English
keywo ds (“e hics”AND “cance ”AND “p egnancy”) esul ed
in 330.000 publica ions. By limi ing he sea ch be ween 2010 and
2020, 81.200 a icles we e e ie ed. Fu he mo e, when
sea ching o he Po uguese keywo ds (“e ica”AND “canc o”
AND “g a idez”), 3,150 pape s we e ound. By limi ing he
sea ch be ween 2010 and 2020, 2.680 publica ions we e e ie ed.
Twen y-nine addi ional a icles in English and Po uguese,
also indexed in PubMed, we e included in his e iew and se ed
as a e e ence o some o he p e iously sea ched a icles. This
second subg oup o a icles included pionee ing and ele an
a icles published in e e ence jou nals, as well as clinical ials
and in e na ional guidelines/consensus.
Finally, a hi d subg oup o 10 publica ions was conside ed,
which, despi e no being indexed in da abases, added alue o he
li e a u e e iew. This g oup o a icles was he e ogeneous, wi h
ex s co esponding o in e na ional guidelines o o a heal h
FIGURE 1 | Flowcha explaining he a icle selec ion s a egy (adap ed om PRISMA, 2009).
Alpium Cos a e al. Cance , P egnancy, and Bioe hical Dilemmas
F on ie s in Oncology | www. on ie sin.o g Decembe 2020 | Volume 10 | A icle 5985083
p o ec ion agency, book chap e s o magazine sec ions (English
and Po uguese), and case-based eaching guides.
DISCUSSION
Abou Cance Du ing P egnancy
The knowledge abou he e ec o cance du ing p egnancy and
he e ec o cance p og ession in p egnancy is o c ucial
impo ance o he success o he mo he ’s ea men and
a o able ou come o he e us. The e a e con adic o y
epo s ha ha e been published ega ding he ou comes o
hese pa ien s.
In 1880, Samuel G oss s a ed ha b eas cance du ing
p egnancy would beha e like a apidly g owing disease,
including wi h an “excessi ely malignan ”clinical cou se (12).
In 1943, a e ea ing 20 pa ien s wi h b eas cance , a g oup a
Columbia Uni e si y P esby e ian Hospi al concluded ha
p egnancy “made he disease inope able”(13). Ten yea s la e ,
i was consensual ha abo ion was linked o imp o ed pa ien
su i al (12). A popula ion-based coho s udy o 15,721 women
diagnosed wi h b eas cance , o whom 1,110 (7%) had cance
du ing o wi hin 2 yea s a e p egnancy, e ealed ha his subse
o pa ien s had a wo se p ognosis, alida ing p e ious da a (14).
Con e sely, a mul icen ic egis y con aining 447 women wi h
b eas cance du ing p egnancy and 865 non-p egnan
coun e pa s, showed simila o e all-su i al in bo h g oups,
a e adjus ing o known p ognos ic ac o s (15). None heless, a
ca e ul in e p e a ion o hese s udies should be aken, gi en he
he e ogenei y o he pa ien popula ions and ea men s
p esc ibed (16).
So a , he e is no consolida ed expe opinion on whe he
p egnancy can induce he occu ence o elapse o cance and i
i co ela es only wi h ma e nal o also wi h o he ex e nal o
endogenous isk ac o s.
Complemen a y Diagnos ic Exams and
T imes e Conside a ions
Du ing he las decades, imaging o he p egnan pa ien has been
pe o med wi h adiog aphy, compu ed omog aphy, magne ic
esonance imaging, scin ig aphy, posi on emission omog aphy
scan, and ul asonog aphy (US). US imaging has eme ged as he
p ima y imaging modali y because i p o ides eal- ime images
wi hou he use o ionising adia ion (16).
A clea link be ween he se e i y o e us impai men ,
ges a ional s age, and cumula i e adia ion dose ecei ed has
al eady been es ablished (16). Fo ins ance, du ing he
o ganogenesis, he e is a highe likelihood o majo induc ion
mal o ma ions and he h eshold dose is abo e 100 mGy. The e
a e also o he issues besides ionising adia ion. The adioac i e
iodine (I-131) c osses he placen a and has he abili y o a ec
e al hy oid and gadolinium e a ogenic in animal s udies. Mo e
in asi e imaging es s should only be pe o med i he diagnosis
and/o s aging is expec ed o con ibu e decisi ely o he
p ognosis o he mo he o e us and ha he isks and benefi s
a e pe ec ly cla ified and unde s ood by he mo he (16,17).
Al hough he e us is unsca hed by labo a o y es s, ou main
conce n will be he influence ha p egnancy will ha e on
diagnosis, s aging and ollow-up, due o he ac ha he se um
bioma ke s lack sensi i i y and specifici y du ing his pe iod.
The e a e umo bioma ke s ha may be inc eased, such as CA
15-3, SCC, CA 125, and AFP, and o he s ha a e no so much,
such as he example o CEA, CA 19-9, LDH, AMH, and HE-4.
Inhibin B and LDH inc eased in he las imes e may be a
labo a o y sign o hype ensi e abno mali ies linked o
p egnancy (4).
T ea men Op ions and T imes e
Conside a ions
The main challenge while managing cance in p egnancy is
balancing he apeu ic egimen and e us wel a e. In addi ion,
as an es ima ed 50% o p egnancies a e unplanned, many women
a e exposed o e a ogens be o e ealising hey a e p egnan (13).
This condi ion demands a en ion and ca e ul p o ocols.
App oxima ely 0.5% o all bi hs occu be o e he hi d
imes e o p egnancy and he majo i y o hese e y ea ly
deli e ies esul in neona al dea hs and mo e han 40% in
in an dea hs. The deli e y be o e 23 weeks o ges a ion,
usually leads o neona al dea h (5%–6% su i al), and among
a e su i o s emains significan mo bidi y (98%–100%). When
deli e y is an icipa ed nea he limi o iabili y, he pa ien ,
amilies and heal hca e eams a e aced wi h complex and
e hically challenging decisions (18,19). Fo mos cy o oxic and
a ge ed he apies, he e is a lack o da a ega ding he isk o
e a ogenesis, based on case epo s and e ospec i e se ies. The
po en ial mu agenic, e a ogenic and ca cinogenic e ec s o
ionising adia ion and cy o oxic agen s in he emb yo a e well
known and depend on he dose, na u e o he compound,
ea men field and ges a ional s age. Some au ho s ad oca e
ha , i p egnancy occu s while he pa ien is unde endoc ine
ea men (e.g., amoxi en) o chemo he apy, a p egnancy
e mina ion should be ecommended i i is done in he
fi s imes e .
Su ge y
In gene al, su ge y can be pe o med du ing any s age o
p egnancy wi h obus e idence demons a ing he sa e y o
su gical p ocedu es and mos anaes he ic agen s seem o be
sa e o he e us. Howe e , he isk o misca iage is sligh ly
inc emen ed (1%–2%), especially in he fi s imes e . In
addi ion, he e is a highe isk o low bi h weigh and
p ema u e deli e y (1.5–2 imes ela i e isk), an inc eased a e
o complica ions and highe mo bidi y in majo abdominal and
pel ic p ocedu es. Rela i ely o anaes he ic d ugs, he e is a
eco d o good sa e y and none o hem s ands in he d ug lis
o p o en e a ogens. Gi en he ac ha he e is a minimal isk
o he e us and po en ial benefi s o he ea men , he e should
no be any delay on he su ge y, i indica ed (2–4,16).
Radio he apy
The emb yo- e al isk can also be influenced by adio he apy co-
ea men and doses highe han 50–100 mGy should be a oided.
Below hese doses, he e is a low isk o s ochas ic biological
Alpium Cos a e al. Cance , P egnancy, and Bioe hical Dilemmas
F on ie s in Oncology | www. on ie sin.o g Decembe 2020 | Volume 10 | A icle 5985084
e ec s (mu a ions), and non-s ochas ic e ec s (mal o ma ions,
de elopmen al diso de s) a e as equen as in gene al
popula ion (3%–5%) (2,4,20). In ce ain cases, i is necessa y
o use adio he apy in he umo , so he clinician mus use i , in
he pe iod ha i is leas ha m ul o he e us. F om 2 o 12 weeks,
he use o adia ion has he isk o e a ogenesis and g ow h
e a da ion. Un il 20 weeks, he e us can p esen men al and
g ow h e a da ion, mic ocephaly, eye, pala e and geni al
de o mi ies and beyond ha , he e is an inc eased isk o
s e ili y, malignancies, and gene ic de ec s (2–4,16).
Chemo he apy
The mos sensi i e and c i ical pe iod o d ug exposu e is
o ganogenesis, which occu s oughly 2–8weekspos -
concep ion (17), especially du ing he gas ula ion pe iod when
issues a e di e en ia ing apidly, and damage becomes as and
i epa able (21). The e o e, du ing he fi s imes e , he isk o
spon aneous abo ions, e al dea h and majo congeni al
mal o ma ions a e inc eased, eaching 10%–20% and decline o
abou 6% when ola e an agonis s like me ho exa e a e excluded.
The e ec s o an ineoplas ic agen s du ing he second imes e
a e ela ed o in au e ine g ow h es ic ion, low bi h weigh ,
misca iage, and p ema u e bi h (20%–40%) (2–4). Du ing he
pe ina al pe iod, he e ec s a e ela ed o ma e nal/ e al
myelosupp ession, in ec ions, and haemo hage. Long- e m
ou comes o child en exposed o chemo he apeu ic agen s in
u e o a e no well examined. I is known ha i is sa e o gi e
some d ugs du ing he hi d imes e wi hou causing long- e m
damage o he baby, o example, o Hodgkin´s disease o b eas
cance (22).
Endoc ine T ea men
In con as o non-p egnan coun e pa s, p egnancy-associa ed
b eas cance is mo e likely o de elop highe s age umo s,
mo e poo ly di e en ia ed, and less common oes ogen
o p oges e one- ecep o posi i i y. These esul s we e
co obo a ed by p e ious s udies. Ne e heless, he e is s ill a
significan ac ion o ho mone- ecep o s posi i e b eas
cance (23).
Howe e , many o he physiological changes du ing
p egnancy a e ho mone-d i en. Fu he mo e, he blockade o
oes ogen (e.g., wi h amoxi en), which is equen ly used in
ho mone-posi i e b eas cance , migh in e e e wi h hese
physiological modifica ions and can be e a ogenic and
associa ed wi h e al dea h and bi h de ec s, mainly
c anio acial anomalies (p eau icula skin ags, mic o ia,
hemi acial mic osomia), ambiguous geni alia (cli o omegaly,
labial usion), and ace abula and sac al dysplasia. Tamoxi en
is also associa ed wi h aginal bleeding and misca iage.
Mo eo e , amoxi en is no ecommended du ing he lac a ion
pe iod, as i delays milk p oduc ion, and he e a e limi ed sa e y
da a ega ding i s exc e ion in human milk. Impo an ly, he
decision o pos pone he amoxi en o allow lac a ion should be
based on indi idual isk and include a balanced discussion
be ween isk and benefi (3,4,16,20,24). Howe e , he
amoxi en e ec s on he e us and he cou se o p egnancy a e
no ye ully unde s ood (24).
Ta ge ed Agen s
Mos o hese a ge ed agen s commonly used in b eas cance ,
such as as uzumab, pe uzumab, be acizumab, among
o he s, should no be used because hey p esen some
undesi able ad e se e ec s, bu also due o he ac ha he e is
missing much in o ma ion ye . In gene al, human epide mal
g ow h ac o ecep o 2 agen s a e sa e du ing he fi s
imes e , al hough du ing he second and hi d imes e s
oligohyd amnios, p e- e m deli e y and neona al dea hs may
be p esen . Ri uximab, an an i-CD20, ima inib, an an i-Bc -Abl
y osine kinase, and ATRA, a ans- e inoic acid, can be used
wi h cau ion, e en hough hey c oss he placen a. Ri uximab is
sa e in he fi s imes e , bu in he coming imes e s, i causes
cy openia and B cell deple ion, e e sible a bi h, while ima inib
is sa e in he second and hi d imes e s, wi h he isk o causing
majo mal o ma ions in he fi s imes e . ATRA is mainly
dange ous in he fi s imes e due o he isk o abo ion. The
only a ge ed agen sa e h oughou p egnancy is in e e on-a(3,
4,16,20,25,26).
Immuno he apy
A ple ho a o immuno he apy op ions is being used in he
in es iga ion and ac i e ea men o se e al malignancies. As
i is a mo e ecen ea men , he e is no much in o ma ion
ega ding he secu i y o hese d ugs du ing human p egnancy.
Howe e , as we all know, mo he and e us a e no gene ically
iden ical. The e o e, an immunological ole ance om he
mo he owa ds he e usisnecessa yino de o he
p egnancy o de elop success ully (26).
Immune checkpoin s, such as p og ammed cell dea h
p o ein-1 (PD-1), PD-1 ligand (PD-L1), and cy o oxic T-
lymphocy e–associa ed p o ein 4, play a c ucial ole in he
p ocess a o enamed. Consequen ly, he e us can be ha med by
an agg essi e immune esponse a e he inhibi ion o hese
immune checkpoin s. Fu he mo e, he d ugs ha can inhibi
he checkpoin s a e immunoglobulins G4 an ibodies ha ha e
he abili y o c oss he placen a and cause oxici y di ec ly o he
e us. In animal models, hese d ugs demons a ed ha hei use
could inc ease abo ion a es, s illbi hs, p ema u e deli e y and
highe incidence o in an mo ali y, namely in he hi d
imes e . Howe e , he e was no an inc ease in e us
mal o ma ions. In summa y, since hese d ugs a e so ecen
and ha e so li le in o ma ion ega ding hei secu i y among
p egnan women, immune checkpoin inhibi o s a e no
ecommended (26).
Suppo i e Medica ion
Ou conce n abou p egnancy in women wi h cance should no
only ocus on an ineoplas ic agen s, bu e en on non-
an ineoplas ic agen s used in clinical cance p ac ice, such as
bisphosphona es, g anulocy e colony-s imula ing ac o (G-CSF)
o g anulocy e-mac ophage colony-s imula ing ac o (GM-
CSF), an ieme ics, analgesics, and an i-inflamma o ies (2–4,16,
20,26).
Because bisphosphona es inhibi bone eso p ion, hey a e
used in he ea men o hype calcemia, os eopo osis, me as a ic
bone disease, and Page disease. The bisphosphona es inhibi
Alpium Cos a e al. Cance , P egnancy, and Bioe hical Dilemmas
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os eoclas ic bone eso p ion ia a mechanism ha di e s om
ha o o he an i eso p i e agen s. In addi ion o hei inhibi o y
e ec on os eoclas s, bisphosphona es appea o ha e a beneficial
e ec on os eoblas s. These biological e ec s can lead o a
educ ion in se um calcium in he ma e nal blood and i s
a ailabili y o he e us, which migh induce skele al
mal o ma ions, educed bone g ow h and low bi h weigh . I
can, inclusi ely, a ec pa u i ion ad e sely by educing u e ine
con ac ions. The e o e, i is con aindica ed du ing p egnancy
(3,20).
G-CSFs/GM-CSFs a e ecommended in cases o se e e
neu opoenia o as p ima y/seconda y p ophylaxis du ing
ea men wi h some chemo he apy egimens. I s sa e y du ing
he p egnancy pe iod is s ill unknown. In animal s udies, i seems
o c oss he placen a and inc ease he a e o spon aneous
abo ion and low bi h weigh (2,3). Howe e , G-CSFs ha e
al eady been used du ing p egnancy, wi hou complica ions.
Thus, hese agen s may also be conside ed du ing p egnancy i
a high isk o neu opoenia is o wa ed (2,3,16,26).
An ieme ics (me oclop amide, cyclizine, meclozine, alizap ide,
ondanse on, and ap epi an ) can be sa ely used du ing he fi s
imes e o p egnancy. The sa e y o co icos e oids is a iable, wi h
he use o hyd oco isone and p ednisolone being p e e ed o
dexame hasone o be ame hasone, as hey a e ex ensi ely
me abolized in he placen a and ela i ely li le de ec ed in he
e al compa men . Repea ed adminis a ions o be ame hasone a e
associa ed wi h a en ion p oblems and ce eb al palsy. Analgesics
(pa ace amol, opioids, an i-inflamma o y agen s), wi h he
excep ion o he fi s imes e , did no gene a e side e ec s, bu
he e is some isk o espi a o y dep ession and e al duc us
a e iosus closu e (3,4,16).
The E hical Issue: Balancing In e es s
P egnancy appea s as an excep ional ci cums ance in medical
e hics as he p ima y medical p inciple P imum non noce e can
be ques ioned, as he access o he e us occu s exclusi ely
h ough in e en ion on he p egnan mo he and ea ing he
mo he may imply ha ming he e us. This is a unique si ua ion
since he wel a e o bo h mo he and e us mus be conside ed on
any ea men planning.
When a conflic a ises in he ma e nal- e us dyad, ca egi e s
mus unde s and he p egnan woman´s mindse , b oad social
ne wo k, alues, cul u al, and eligious belie s, as his may impac
hei decisions (27). Consequen ly, i is impe a i e o p omo e
he au onomy and physical in eg i y o he p egnan woman,
ensu ing ha all a ailable in o ma ion on p egnancy and cance
ou comes is p o ided in o de o allow o a ully in o med
consen consis en wi h he alues (28)since hewoman’s
decision is absolu e and unlimi ed. The e o e, in cases when
he woman’s decision may ha m he e us (e.g., ea men o
cance du ing he fi s imes e ) coe cion o o ce ea men is
ne e jus ified.
To da e, he e is no da a sys ema ically collec ed epo ing he
decision-making p ocess o women who had cance and
p egnancy a he same ime. Al hough, he e a e wo s udies
conduc ed in he Uni ed Kingdom epo ing pa ien expe iences
wi h pa icipa ion in ORACLE (29) (e alua e he possibili y ha
ea men wi h an ibio ics p olongs labo and imp o es neona al
ou comes in women who a e less han 37 weeks p egnan and
expe iencing ei he p e- e m labo o p ema u e up u e o
memb anes) and in he Magpie T ial (30) (p ophylac ic use o
an icon ulsan s o women wi h se e e p eeclampsia). In hese
s udies, he majo mo i a ing ac o s we e iden ified as sel -
benefi (i can help ea mo he condi ion), benefi o you child
(i can minimize he associa ed isks o he e us) and al uism
(pa icipa ion can help u u e women o is i o he sake o
medical science). I was also shown ha , al hough some women
seek he opinion o amily and iends, hey ha e li le
in ol emen o influence in women’s decisions. The pa ne s
played a ole in p o iding a second opinion o many women,
bu s udy pa icipan s ejec ed he idea ha hei ela i es o
iends we e in a posi ion o influence hei decision. In pa allel,
i may be easonable o conside , in he u u e, he op ion o
o e ing p egnan women wi h cance he possibili y o
pa icipa ing in clinical ials and/o en olling in egis ies,
inc easing he mo i a ion and he expec a ion o benefi s o
hem and he e us.
In he child- o-be pe spec i e, he e a e ex a laye s o e hical
complexi y o add ess, because he an ineoplas ic ea men
ypically a ec s no only he p egnan woman bu also he
e us. The de eloping e us clea ly has no capaci y o
au onomous choice, and he e is no o mula o balancing he
in e es s and mo al claims o he e us wi h hose o he mo he .
Fu he mo e, he wel a e o he e us is ypically no independen
o he in e es s o i s mo he (31).
When a conflic a ises in he ma e nal- e us dyad, such as
cance ea men and he isk o e al demise, a ange o e hical
amewo ks may be use ul in he decision-making p ocess. I is
clea ha he physician has beneficence-based and au onomy-
based obliga ion o he p egnan cance pa ien (32). Because o
an imma u e cen al ne ous sys em, he e us canno
meaning ully be said o possess alues and belie s, al hough
his is emendously a guable.
Hence, scien ifically he e canno be au onomy-based
obliga ions o any e us, al hough women’s belie s may has en
he o judge di e en ly (32). Howe e , he physician can ha e
beneficence-based obliga ions o he e us, i he e us is
conside ed as a pa ien (33). The p egnan woman is ee o
wi hhold pa ien s a us, con e pa ien s a us, o , a e con e ing
i , wi hd aw i om he p e- iable e us (32). The e us has no
claim o pa ien s a us independen ly o he p egnan woman’s
au onomy. When he woman is unce ain abou o is no able o
con e he s a us, he e us can be p o isionally ega ded as a
pa ien (32,33). Howe e , hese app oaches ha e been c i icized
o hei endency o emphasize he di e gen a he han sha ed
in e es s o he p egnan woman and he e us. In ac , in mos
cases, he in e es s o he p egnan woman and e us ac ually
con e ge (28).
Whene e a p egnan woman is p esen ed wi h a cance
diagnosis, se e al e hical conce ns add essing echnicali ies
mus be app oached, while keeping in mind he su ounding
emo ional issues.
Alpium Cos a e al. Cance , P egnancy, and Bioe hical Dilemmas
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The e is no es ablished modus ope andi o he physician,
which aises pe inen ques ions: i) should he pa ien be
included in he decision-making o he bes o he abili ies in a
limi ed way, o should pa e nalis ic decision-making ake o e ?
ii) Should a p oxy decision-make decide based on he pe cei ed
pa ien ’s bes in e es ? (20) These a e que ies ha can be ca e ully
g asped by sol ing eal-li e cases, in pa allel hose ha will be
p esen ed la e .
To allow o an in o med decision, he pa ien mus be well
awa e o mul iple medical ac s, such as cance p ognosis, he
possibili ies o an ineoplas ic he apy, i s main oxici ies and i s
aim, namely: whe he cu a i e o pallia i e, i i will imp o e quali y
o li e, o o e all and p og ession- ee-su i al, i he e is a isk o
p e- e m deli e y o i pe ipa um complica ions a e expec ed.
The iming o ea men mus also be conside ed—is he
mo he symp oma ic and needs o ini ia e ea men quickly o is
i possible o delay i un il he hi d imes e , when he e is no
significan isk o e al de ec s in a sho and long- e m? Besides
echnical issues, be o e s a ing he ea men , he physician mus
conside emo ional issues, such as he possibili y o he child- o-
be mee ing i s mo he .
The e a e se e al es ablished e hical amewo ks o conflic
esolu ion and decision-making. P agma ic heo e ical
app oaches include case-based analysis, he e hics o ca e,
eminis heo y, and adi ional e hical p inciplism ha
sc u inizes he amewo k o au onomy, jus ice, beneficence,
and non-maleficence. In addi ion, socie y and p ac i ione
alues could benefi his complex p ocess.
Illus a i e Cases o Bioe hical Dilemmas
and a P oposed Algo i hm o E hical
Decision-Making
Fo ins ance, he 1987 pa adigma ic case o a p egnan woman in
he la e 20s, who had a la e lung elapse 15 yea s a e Ewing´s
sa coma diagnosis b ough hese issues o ahead. Al hough ully
commi ed o sa ing he li e, a he end o he second imes e , i
became clea ha he pa ien was dying. The Medical Cen e
ied o insis upon an ea ly Cesa ean sec ion deli e y in o de o
sa e he e us. She e used he in e en ion wi h he suppo o
he amily, knowing i would almos ce ainly kill he , bu he
hospi al o ced he deli e y h ough a cou o de . Bo h he
pa ien and he ex emely p ema u e baby su i ed o only a
sho while a e he su ge y. In 1990, he Cou o Appeals
pos humously aca ed he cou -o de ed Cesa ean sec ion,
holding ha he pa ien is o ally au onomous o make
heal hca e decisions o he sel and he e us and ha only in
he mos excep ional ci cums ances should a p egnan woman’s
igh o e use in e en ions be called in o ques ion (34). Despi e
he media exposu e o his case, o he s wi h simila e hical issues
we e a om being elucida ed (35–37).
This fi s case is an example o wha should no be done in
e hical e ms when app oaching such a complex and sensi i e
con ex . I was no iceable ha he e was no mul idisciplina y
managemen and s a egy o a balanced app oach o ou line
cance and p egnancy ac s o he case and he non-medical
issues o achie e he bes e hical possible scena io (Figu e 2).
I is possible o in e ha he woman would be in men al
condi ions o ake a posi ion. Hence, all he bes possible
in o ma ion, a ha momen , namely he cance and
p egnancy ou comes o he woman, e idence-based ea men
op ions and a ailable suppo i e measu es o he si ua ion,
should ha e been p esen ed o he pa ien . Fu he mo e, he
compa ison wi h p e ious simila e hical scena ios and he
consul a ion o guidelines should ha e been assessed and
discussed, in a mul idisciplina y ga he ing, comp ising he
whole medical speciali ies ela ed o his subjec (e.g., Medical
Oncology, Obs e ics, among o he s), a ep esen a i e o he
e hics commi ee, all he s akeholde s (such as he pa ien ’s
amily and he e us’ a he ) and he pa ien i sel . Finally, he
pa ien ’sfinal decision, in collusion wi h he au onomy e hic’s
p inciple, should ha e been espec ed.
In 2016, on Feb ua y 20, a 17-week-p egnan woman in he
la e 30s, collapsed a e an in ace eb al haemo hage, p obably
ela ed o a la e ecu ence o kidney cance diagnosed 10 yea s
ea lie (40). Soon a e physicians decla ed he b ain dead (41).
The hospi al e hics commi ee and he amily we e enqui ed. I
was explained o bo h pa ies - mo he ’s amily and he e us’
a he — ha , o allow o he e us su i al, he woman should be
kep on li e-sus aining ea men o each a leas i s 32 weeks,
he ea lies da e doc o s el ha a success ul Cesa ean deli e y
would be possible (40). This emphasizes he ole o he “mo he ’s
body as a cada e ic incuba o ”,“mo he as he o gan dono and
e us as he ecipien ”, and he conce n o “possible damages o
he e us”(42–44). Some p o essionals belie e ha i is no
e hically accep able o main ain he mo he ’s body a e b ain
dead o use i as a “ e al con aine .”Such a decision should no be
assumed, bu i mus be deba ed. I he mo he is o be conside ed
a“cada e ic incuba o ”wi h no au onomous igh s, he igh s o
he e us should legally p e ail. Ano he a gumen claims ha he
con inued soma ic suppo i sel is ac ually o gan dona ion wi h
he e us as he ecipien (42–44). The amily s ongly exp essed
ha he mo he would ha e wan ed he li e p ese ed in o de o
gi e he e us a chance o su i al. The e hics commi ee equa ed
he e us li e o a child a isk and allowed he suppo o he
b ain-dead mo he . The decision was aken in a mee ing o he
neu osu gical, c i ical ca e, obs e ics, neona al, ansplan and
e hical s a , along wi h he pa ien ’s amily. One hund ed se en
days la e , he baby was bo n heal hy, and he li e-sus aining
machines we e u ned o (40,41).
Abou 10 yea s ea lie , a woman o he same age and
ges a ional s age as in he p e ious case su e ed a s oke
seconda y o he b ain p og ession o melanoma. Soon a e ,
he doc o s decla ed b ain dead. He amily also decided o keep
he ali e o gi e he e us a chance. I became a ace be ween he
e us’de elopmen and cance ha was a aging he pa ien ’s
body. The baby was bo n abou 2 mon hs p ema u ely, and
agically did no su i e. A ha ime, he case was also
conside ed o be no able because he e was no con o e sy (43).
Pu in o pe spec i e, he wo a o emen ioned cases ha e
analogous e hical issues, howe e , wi h di e en endings.
Ne e heless, bo h hese si ua ions ollow he bes e hical possible
scena io app oach (Figu e 2). Since bo h pa ien s we e decla ed
Alpium Cos a e al. Cance , P egnancy, and Bioe hical Dilemmas
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b aindead,noneo hemwouldbemen allysui able o akea
posi ion. Thus, he pa ien ’s amilyand he e us’ a he should be
esponsible o he decisions ega ding equally he pa ien and he
e us wel a e. As obse ed, in hese ci cums ances, all o he
s akeholde s had ecei ed he bes in o ma ion possible is-à- is
he cance and p egnancy ou comes, he e idence-based ea men
op ions o ollow p egnancy and suppo i e measu es o
main enance o “cada e ic incuba o ”, wi h he aim o he
su i al o he e us. All he decisions we e engaged wi h a
mul idisciplina y eam, aking in o conside a ion p e ious
compa able clinical cases, and espec ing he pa ien ’s amilyand
e us’ a he au onomy. Since he numbe o cases desc ibing he
managemen o ex ended ma e nal soma ic suppo a e b ain
dea h is limi ed, e e y case should be con inuously eassessed and
adap ed along wi h he inc easing expe ience and knowledge
(42–44).
In hese di ficul cases, mainly be o e he hi d imes e , he
so e eign decision should be aken a e ho ough discussion
be ween mo he (o legal subs i u e) and he ea ing physician
(42–46). While espec ing he p inciple o au onomy, ano he
final e hical issue is he igh o he physicians o conscien iously
objec o ce ain ea men op ions.
As s a ed be o e, physicians should no bias wi h hei
ecommenda ions and should p esen o conside h ee
scena ios: i) ea men du ing p egnancy, wi h close moni o ing
o side e ec s and econside a ion o e mina ion be o e iabili y;
ii) ea men wi h e mina ion o he p egnancy; and iii)
ea men delay un il e al lung ma u i y, when i ’s easonably
sa e o deli e he baby (34,47).
All o e Eu ope, he e a e di e ences be ween coun ies
ega ding a ailabili y, condi ions and ges a ional limi . In
Po ugal, since 2007, and a e a Na ional Re e endum, he
olun a y e mina ion o p egnancy un il 10 weeks o ges a ion
was legalized (law n°16/2007). In ha same legal documen , i is
s a ed ha in case o dange o dea h o physical and/o psychic
inju y, he possibili y o in e up ing he p egnancy un il 12
weeks o ges a ion is allowed (48).
The a ailable in e na ional guidelines ecommend ha
ma e nal e al medicine consul a ion should include counseling
on main aining o e mina ing a p egnancy, including a e iew
o he ea men op ions. These guidelines suppo a amewo k
o sha ed decision-making in he con ex o ma e nal- e al
conflic o p o ide guidance o compassiona e conflic
esolu ion. An e hics consul a ion may be help ul o media e
conflic esolu ion. In e en ion by he cou s is a ely
app op ia e o indica ed and should be a oided (27,47,49).
Based on a alida ed me hod o analysing and wo king up
clinical e hical p oblems, we sugges an adap a ion o an
algo i hm o biomedical decision-making in p egnancy-
associa ed cance (Figu e 2).
The fi s ask in his e hical decision-making p ocess is o
es ablish he medical and p egnancy ac s o he case. The second
FIGURE 2 | Algo i hm o biomedical e hical decision-making (adap ed om Schenck (38) and Bo ha e al. (39)).
Alpium Cos a e al. Cance , P egnancy, and Bioe hical Dilemmas
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s ep is o de e mine pe inen non-medical issues, which is mo e
challenging. These s eps a e ollowed by an assessmen o he
goods ele an in he case. The immedia e conce n is clea ly wha
is sui able o he woman medically, bu ha is ollowed closely
by an a emp o unde s and he pa ien ’s o e all good—e.g.,
psychological good, good in e ms o amily and ela ions,
spi i ual good, and good in e ms o he pa ien ’s p eceding li e
his o y and alues. While ensu ing he good o he woman is he
p ima y aim, his is insu ficien in i sel , as he goods o e us and
o he s mus also be conside ed (38).
The p inciples ha apply in he case a hand a e hen e alua ed,
speci ying wha a gi en p inciple means in his case and balancing i
agains he mo al claims o each o he o he s. In hemsel es,
p inciples can become me e abs ac ions, pe haps e en s e ile
nos ums o dealing wi h hese complex e hical dilemmas.
The e o e, i ue e hics, ano he bioe hical app oach ha has
ecei ed inc eased a en ion in ecen yea s, add esses he na u e
o he ela ionship be ween pa ien and heale , wi h pa icula
a en ion o he cha ac e o he physician (38). Pelleg ino and
Thomasma ha e p esen ed a de ailed analysis o how hey in e p e
he i ues ha a e essen ial o medical p ac ice. These i ues
include ph onesis, compassion, fideli y, us , in eg i y, sel -
e acemen , jus ice, o i ude, and empe ance (50).
In any case, a conside a ion o he i ues and p inciples on
he one hand, and guidelines ecommenda ions and p io simila
cases analysis on he o he , p o ide mo e guidance o a igh
answe o bioe hical dilemmas.
Finally, he guidelines ecommenda ions should be
accompanied by se e al s eps ha mus ake place in he “bes
e hical possible scena io”, in o de o enhance he quali y o he
counseling and emo ional suppo ha a e an essen ial pa o
managemen (Figu e 2):
•Assess he men al s a e o he pa ien ;
•Ensu e p i acy;
•Sui medical language o he pa ien and he o he
in e locu o s;
•Be ealis ic and accu a e abou cance and p egnancy ou comes;
•Ensu e an uncondi ional a ailabili y o he discussion and e-
discussion o each dough o cla ifica ion.
•Encou age pa icipa ion in he decision-making p ocess o he
pa ne and he closes amily membe s;
•In o m ha medical managemen is no he esponsibili y o a
single p o essional, bu o a mul idisciplina y eam wi h a
holis ic app oach;
•P o ide e idence-based ea men op ions;
•In o m abou o he suppo i e measu es;
•In o m ha he pa ien has he final wo d in he decision-
making p ocess;
•P o ide he necessa y ime o he in o ma ion p ocessing
phases acco ding o Küble -Ross model (denial, ange ,
ba gaining, dep ession, accep ance);
•Ne e ake hope om he pa ien .
CONCLUSIONS
Scien ific and clinical da a add essing he isks and he e ficacy o
ea ing a p egnan woman wi h cance ha e al eady been
explo ed in he li e a u e. Howe e , he imb ica ed e hical
challenges ha e ecei ed less a en ion, pa icula ly be o e he
hi d imes e o p egnancy.
A p egnan woman wi h cance aces he choice be ween bes
an ineoplas ic ea men e sus maximal e al wel a e. Bes ,
unbiased and balanced in o ma ion abou he benefi s and
ha ms o he woman he sel as well as o e al ou come mus
be g an ed bo h o he pa ien and o he amily.
Hal ing, in his scoping e iew, he au ho s iden ified ce ain
concep s and discussed he he e ogeneous da a collec ed
ega ding bioe hical decisions on cance du ing p egnancy.
Ne e heless, he e a e s ill some unsol ed que ies, ha mus
be discussed in mul idisciplina y g oups, and pe sonalized o
each unique scena io. Each new decision should be included in
an upda ed sha ed and anonymous da abase o pu in pe spec i e
wha should be done in a pa icula cance si ua ion ha a ec s
wo unique li es (ma e nal and e al), allowing o ga he a i udes
and expe iences ha fill a knowledge gap needed o de elop
e hical ca e guidelines.
AUTHOR CONTRIBUTIONS
All au ho s ha e ead he submission and ag eed o submi his
manusc ip . The p esen manusc ip is he esul o o iginal wo k by
he co-au ho s. Concep ion and design: DAC, JN. De elopmen o
me hodology: DAC, JN. Acquisi ion, analysis, and in e p e a ion o
da a: DAC, JN, IG. W i ing, e iew, and/o e ision o he
manusc ip :DAC,JN,SD,MF,IG.Manusc ip supe ision:SB,DP.
ACKNOWLEDGMENTS
CUF Oncologia.
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F on ie s in Oncology | www. on ie sin.o g Decembe 2020 | Volume 10 | A icle 5985089