Management of Cancer During PregnancyDonald C. Doll, MD; Q. Scott Ringenberg, MD; John W. Yarbro, MD, PhD

\s=b\Although cancer during pregnancy is Infrequent, its man-agement is difficult for patients, their families, and theirphysicians. When termination of the pregnancy is unaccept-able, decisions regarding the use of Irradiation and chemo-therapy are complicated by the well-known high risks ofabortion and fetal malformation. This risk is concentrated inthe first trimester and varies with the choice of chemothera-peutic agents or combinations of agents. There is only minimalevidence of increased risk of malformation or abortion in thesecond or third trimester. Recent progress in cancer therapyhas made cure a reasonable goal, and for some malignantneoplasms, cure is still possible even when initial therapy ismodified or delayed. When cure is a reasonable goal, curativetherapy should not be compromised by modification or delay.When treatment for cure or significant palliation is not possi-ble, however, the goal should shift to protection of the fetusfrom damage by the injudicious use of teratogenic cancer

therapy. This report will review the available data that mayassist in these difficult decisions.

(Arch Intern Med 1988;148:2058-2064)

fiancer is a leading cause of death in women of childbear-^ ing age,1 but its simultaneous occurrence with preg¬nancy is uncommon, with a reported incidence of 0.07% to0.1%.2·3 The malignant neoplasms complicating pregnancyare those most frequently seen in young women: lym¬phoma, leukemia, melanoma, and cancers of the breast,cervix, ovary, thyroid, and colon.4-7 There is no evidence ofan increased incidence of malignant neoplasms in pregnantpatients. In the past, pregnancy has been thought to havea deleterious effect on some cancers, but except for delayin diagnosis, no convincing data exist that pregnancy perse adversely influences the prognosis or biology of maternalcancer, including breast cancer. No firm data exist thatthere is a greater likelihood of reactivation of cancer duringpregnancy. Conversely, there are only a few reports indi¬cating that cancer per se adversely affects pregnancy.Metastasis to the placenta and fetus is rare, with 44 cases

reported and only 12 infants with cancer at birth (sevenmelanoma, two leukemia, two lymphoma, and one ethmoidcarcinoma); two with melanoma had regressions, and theother infants died.8·9 The immediate and delayed effects ofdiagnostic and therapeutic interventions, however, are

potentially deleterious to the fetus and mother.It is well established that irradiation and cytotoxic drugs

during pregnancy are associated with a significant risk ofabortion and teratogenesis. Similarly, delay or modificationof cancer therapy to ensure the birth of a healthy infantmay adversely affect maternal prognosis. Hence, the deci¬sion to initiate therapy in a pregnant patient is usually adifficult one for all concerned and may be complicated byheightened emotions, ethical issues, and religious beliefs.

Accepted for publication March 30, 1988.From the Division of Hematology/Medical Oncology, Department of

Medicine, Harry S Truman Memorial Veterans Hospital (Dr Doll) and theUniversity of Missouri\p=m-\Columbia(Drs Doll, Ringenberg, and Yarbro).

Reprint requests to Department of Medicine, Harry S Truman MemorialVeterans Hospital, Columbia, MO 65201 (Dr Doll).

This article discusses the effects of cancer diagnosis andtreatment on the fetus and makes recommendations re¬

garding management.DRUG METABOLISM DURING PREGNANCY

Drug metabolism is altered by the physiologic changesof pregnancy. The stomach empties more slowly,1011 whichmay affect the rate of drug absorption. Plasma volumeincreases by approximately 50%,12 resulting in a largerspace for drug dilution. Albumin concentration decreaseswhile plasma protein levels increase, which alters plasmaunbound drug concentration.13 Hepatic oxidation by themixed function oxidase system is enhanced and renalplasma flow and glomerular filtration rate are increased.14Changes in drug distribution volume, peak drug concen¬

tration, renal and hepatic excretion, and half-life alter theconcentration and time relationship that is so importantfor chemotherapeutic drugs.15 The possibility exists thatthese changes alter the efficacy of cancer chemotherapyregimens, although there are no data on this question (toour knowledge). Whether the amniotic fluid functions as a

pharmacologie third space is not reported, but this wouldbe especially relevant to methotrexate, where distributioninto a third space such as ascitic fluid or pleural effusiondelays elimination and increases toxicity.16

Drug characteristics that enhance entry into the fetusacross the placenta are low molecular weight, high lipidsolubility, nonionization, and loose binding to plasma pro¬tein.1314 Multiple drugs, including most antineoplasticagents, possess these qualities. The immature fetal liverand kidney are functional to a variable degree as the fetusdevelops, and chemotherapeutic agents may be excretedvia bile and urine. Since the fetus ingests amniotic fluid,agents excreted in active form may have their activityenhanced.

ADVERSE EFFECTS OF ANTINEOPLASTICAGENTS ON THE FETUS AND NEONATE

The timing of exposure to cytotoxic agents is critical,since their effects are different during each trimester.During the first trimester, when organogénesis occurs,drugs can produce congenital malformation or abortion.17After the first trimester, drugs rarely cause congenitalmalformations but can impair fetal growth and functionaldevelopment, particularly that of the brain. The back¬ground incidence of major congenital malformations isabout 3% of all births,18 and radiation treatment andchemotherapeutic drugs increase this incidence. The ter¬atogenic and mutagenic potentials of chemotherapeuticagents have been clearly demonstrated in animals,19-21 butextrapolation to humans is tenuous.22 Many drugs thatproduce defects in animals seem to be harmless to thehuman embryo, eg, aspirin. Conversely, the absence ofteratogenicity in animals is no guarantee of safety inhumans, eg, thalidomide.

The probability of teratogenesis is influenced by thetrimester of exposure, drug dose, frequency of administra¬tion, and duration of treatment. To be teratogenic it seems

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Table 1.—Chemotherapy During First Trimester of Pregnancy

Class

No. ofExposed Patients/

No. ofFetal Malformations Reference No.

Alkylating agentsBusulfanChlorambucilCyclophosphamideMechlorethamine

hydrochlorideTriethylenemelamineTotal (%)

AntimetabolitesAminopterinMethotrexateMercaptopurineCytarabineFluorouracilTotal (%)

Plant alkaloidsVinblastine

sulfateAntibiotics

Daunorubicinhydrochloride

MiscellaneousProcarbazine

hydrochlorideAmsacrineCisplatinTotal (%)

TotalCombinations (%)

22/25/17/3

6/04/0

44/6 (14)

52/103/3

20/01/11/1

77/15 (19)

14/1

1/0

1/11/11/0

18/3 (17)139/24 (17)30/7 (23)

30,32,34-3849-52,9330,32,53,54,94

30,32,52,56-5812,30,59,60

30,32,61-69,72-7470-72

30-32,73-818485

25,30,32,86-89

90

913192

25,96-109

that the required drug dose lies within a narrow rangebetween that which causes death of the fetus and thatwhich has no discernible effect.23 Synergistic teratogenicinteractions may occur with combination chemotherapy,24·25different drugs given sequentially,25·26 and the combinationof chemotherapy and radiotherapy.26-28 Individual and ge¬netic susceptibility may be important but have not beenclearly defined.19

There are many reports of chemotherapy during preg¬nancy.2494 Table 1 shows drug-associated fetal malforma¬tions during the first trimester. In several reported cases,the mothers were also treated with radiation,26·27·53·85 whichis well recognized as a potent teratogen.95 The apparentrate of fetal malformation from combinations of drugs96-109is only slightly higher than that observed with singleagents: six (25%) of 24 cases vs 24 (17%) of 139 cases. Ifone excludes the folate antagonists and those cases involv¬ing the concomitant use of irradiation, however, the inci¬dence for single agents declines to 6%.

In contrast, no evidence of an increased risk of terato-genicity in the second and third trimesters exists (Table2).* In 110 cases, one report of trisomy C was notedfollowing cytarabine and thioguanine administration,126 oneinfant had multiple anomalies following third-trimesterexposure to busulfan,126 and one neonate had adherence ofthe iris to the cornea after combination chemotherapy inthe last trimester.94 One should not assume that suchexposure is safe, however, because there may be delayedeffects. Nonteratogenic effects of antineoplastic agentsinclude low birth weight, intrauterine growth retardation,spontaneous abortion, premature birth, and myocardial

*References 24-30, 94, 100-108, 112-142.

Table 2.—Chemotherapy During Second and Third Trimesterof Pregnancy

No. ofExposed Patients/

No. ofClass Fetal Malformations Reference No.

Alkylating agents 26/1 30,32,126-128Antimetabolites 38/0 30,32,75Antibiotics 1/0 110Plant alkaloids 6/0 25,32,89,94,112,113Combinations 60/1* 25,31,94,104-107,

111-142Total (%) 131/2 (1.5)

*One case of trlsomy C following cytarabine and thioguanine was reported.Autopsy revealed no congenital malformation.

Table 3.—Estimated Average Fetal Dose

Procedure Dose to Fetus, mllliradExtremity 1Shoulder 1Cervical spine 2Skull 4Chest roentgenogram 8Pelvis 40Cholecystography 200Lumbar spine 275Abdomen 290Hip 300Intravenous pyelogram 400Upper gastrointestinal series 560Barium enema 800Lymphangiogram 1100Computed tomography abdomen 1000-5000

toxicity.17·26·30-33·143 Regarding biologic response modifiers,we are not familiar with any data concerning their use inpregnancy.

Little is known about the delayed effects of exposure toantineoplastic agents in utero, but several—impairedmental and physical development, infertility, carcinogen¬esis, and second-generation teratogenesis—have been sug¬gested.17·31-33·144 Transplacental carcinogenesis is well doc¬umented in animals, with the time of greatest susceptibilitynear the end of gestation.146 Second malignant neoplasmsare well-recognized delayed complications of antineoplasticagents in humans,146 but clear evidence of carcinogenesisfrom chemotherapy in utero is lacking. In utero exposureto diethylstilbestrol has been linked to the late develop¬ment of clear-cell vaginal carcinoma in young women,147though the validity of this association has been ques¬tioned.148 Reynoso et al94 recently reported the case of aninfant exposed to cyclophosphamide and prednisonethroughout gestation who developed neuroblastoma at age14 years and thyroid cancer at age 16 years.

ADVERSE EFFECTS OF RADIATION EXPOSUREON THE FETUS AND NEONATE

Radiation effects are related to dose, dose rate, fieldsize, energy of the radiation, and gestational age. Theincidence of malformation is greatest during the period oforganogénesis from the second to the eighth week. Growthretardation, microcephaly, and eye abnormalities have beenthe predominant manifestations. The major unresolvedquestion with radiation is the maximum safe dose. Severalstudies have demonstrated no increase in abortion, growthretardation, or congenital malformations from diagnosticexposures below 0.05 Gy delivered at any time duringgestation.18·149·150 As given in Table 3, the estimated fetal

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dose from many commonly used radiologie diagnosticprocedures is less than 0.01 Gy.161 However, proceduressuch as lymphangiography and computed tomography ofthe pelvis and abdomen may expose the fetus to muchhigher doses (up to 0.05 to 0.1 Gy), and low doses ofradiation potentially could be associated with deleteriouslong-term effects.95 Since diagnostic ultrasound and mag¬netic resonance imaging are not associated with ionizingradiation, these procedures are relatively safe duringpregnancy. However, subdiaphragmatic therapeutic radia¬tion exposure is associated with severe toxic effects to thefetus. The minimal lethal dose increases from approxi¬mately 0.1 Gy at day 1 to greater than 1 Gy after the firsttrimester.161 During the second and third trimesters, thechance of abortion and congenital abnormalities declines,but damage to the central nervous system can occur.

Dekaban152 correlated gestational age with dose and fetaldamage in 26 infants. At 2.5 Gy, more than 50% of theinfants exposed between the third and tenth week ofgestation developed mental retardation, microcephaly, cat¬aracts, retinal degeneration, low birth weight, and skeletaland genital abnormalities. Radiation exposure between 12and 20 weeks was associated with stunted growth, mentalretardation, and microcephaly. Radiation exposure after20 weeks was not associated with any gross malformation,but some infants had evidence of radiation-exposure dam¬age, including erythema, epilation, and hématologie de¬pression. Epidemiologie studies from the Nagasaki andHiroshima (Japan) atomic bombings reported congenitalabnormalities in 28 of 205 infants exposed during the first20 weeks of gestation.153 Abnormalities were not observedbelow an estimated in utero dose of 0.5 Gy in Hiroshima154and 1.5 Gy in Nagasaki.156

In experimental animals, 0.1 to 0.2 Gy does not increasethe incidence of microcephaly.156 To our knowledge, a "safe"dose has not been established, but a commonly repeatedrule is that therapeutic abortion should be considered if adose of 0.1 Gy is exceeded during the first trimester.157 Adose of 0.5 Gy has been associated with a strong possibilityof fetal damage.96

With supradiaphragmatic radiation, substantial scatterto the fetus can occur.60168159 Much of the scatter is internal,but abdominal shielding can reduce the fetal dose signifi¬cantly160 and it may be safe to administer localized radiationto the neck or axilla during the first trimester if absolutelynecessary.60 There are reports of normal infants after full-mantle radiotherapy,96 but one patient with Hodgkin'sdisease had a spontaneous abortion in the first trimesterafter 44 Gy to the chest.50 It is difficult to generalize aboutsafe doses because the size of the uterus varies duringpregnancy and thus its distance from the field of radiationvaries. Sharma et al,160 using a "phantom," validated Clark-son's method of calculating scatter and measured thefraction of mediastinal dose delivered to the uterus atvarious levels below the lower border of the mediastinalportal with and without shielding. They found values of1,2% at 11 cm, 0.6% at 18 cm, and 0.3% at 28 cm whenshielding was used. Thus, the delivery of therapeutic levelsto the mediastinum, ie, 35 to 44 Gy, should scatter lessthan 0.5 Gy to the fetus. In two patients treated withmantle irradiation, fetal doses were measured as 0.04 Gyat the level of the cervix and 0.1 Gy at the level of thefundus at 16 weeks' gestation and 0.08 Gy and 0.3 Gy,respectively, at 25 weeks' gestation.96

The long-term sequelae of fetal radiation exposure areunknown. Chromosomal aberrations have been docu¬mented,161 but to our knowledge, no conclusive data existlinking in utero irradiation to any human mutation or tofuture infertility. The data on carcinogenesis are conflictingwith both positive162165 and negative studies.166167

ADVERSE EFFECTS OF SURGERY ONTHE FETUS AND NEONATE

Of the primary treatment modalities for cancer duringpregnancy, surgery is the type least associated with fetalsequelae. Needle or excision biopsy and surgery underlocal anesthesia are essentially without risk to the fetus.Moreover, if indicated, the ovaries may be safely removedduring the second trimester, since placental progesteroneproduction begins at seven weeks and completely replacesthe corpus luteum by 12 weeks.168 However, pelvic surgeryand cervical conization during the first trimester increasethe risk of abortion.169

Striking physiologic and anatomic changes in manyorgans occur during gestation,170 and such changes may berelevant to the operative management of pregnant patients.For instance, the supine position during late pregnancycauses the uterus to compress the aorta and vena cava171;this may lead to a reduction in uteroplacental perfusionand thus may potentially cause fetal hypoxemia. Since thefetus is sensitive to hypotension and hypoxia, pregnantpatients should not be supine for prolonged periods afterthe first trimester. Also, certain anesthetic drugs andtechniques may compromise blood pressure and cardiacoutput in the gravid patient.170 Knowledge of the variousalterations associated with pregnancy is mandatory for theoptimal management of these patients, and a recent reviewhas discussed this problem in depth.170

ADVERSE EFFECTS OF PREMATURE BIRTH

The risks ofprematurity172 decline rapidly after 28 weeks;in expert neonatal units, the risk of neonatal death forinfants after 32 weeks may not exceed the risk of thoseborn at term.172 Low-birth-weight (^2500 g) infants, andparticularly very-low-birth-weight (<1500 g) infants, areat an increased risk of neonatal death, congenital anoma¬lies, pulmonary complications, and subsequent neurode-velopmental handicaps.173·174 Approximately 90% of theseinfants survive at 1500 g, 80% survive at 1250 g, 60% to75% survive at 1000 g, and 50% survive at 800 to 900 g.174

MANAGEMENT RECOMMENDATIONS

The treatment of cancer occurring during pregnancy iscomplicated, and therapeutic decisions must be individu¬alized. These decisions might best be facilitated by a

multidisciplinary team, including the patient's obstetrician/gynecologist, family physician, oncologist, pediatrician,neonatologist, and other ancillary consultants. Such inter¬action should begin when the patient is initially diagnosedas having cancer. Considerations must be given to theimmediate health of the mother and fetus and to the long-term health of infants exposed to potentially teratogenicand carcinogenic drugs and radiation.

When there is inadvertent chemotherapy or radiationexposure in excess of 0.1 Gy to the uterus during the firsttrimester, the most conservative recommendation is ther¬apeutic abortion. The degree of risk if the pregnancy isnot terminated can be estimated from the data reviewedherein. If the decision is to continue the pregnancy, thenthe question of further therapy should be evaluated as

carefully as if initiating a new therapeutic regimen.If intensive cancer therapy is anticipated early in preg¬

nancy, the conservative approach is to consider therapeuticabortion because of the hazard to the fetus. If the preg¬nancy is to continue and cure is a realistic goal, therapyshould not be modified or delayed to compromise that goal.However, when there is no hope for cure or even significantpalliation, the primary goal should become protection ofthe fetus from the potential harmful effects of chemother-

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apy or irradiation. The most difficult cases are the majorityin which the issues are not so obvious.

When cancer is diagnosed during the first trimester, adecision must be made as to whether treatment can besafely postponed until the second trimester or later. Fortumors encountered after 20 weeks when abortion is notpossible (except as part of the surgical management ofsome tumors), delay of therapy should be considered whenit will not adversely affect maternal prognosis. Earlydelivery may allow a compromise between risk to motherand risk to child by permitting earlier cancer treatment.Ultrasound and laboratory analysis of amniotic fluid canbe helpful in determining the timing and mode of deliveryof a viable fetus.176

When chemotherapy must be given, one should selectdrugs to minimize fetal damage without compromisingtherapeutic benefit to the mother. During the first trimes¬ter, folate antagonists should never be given. At present,methotrexate is not part of any curative regimen for whicha therapeutic equivalent is lacking. This is fortunate sincethe folie acid antagonists, more than any other agents,have been associated with fetal abnormalities when givenduring the first trimester.61-69·72-74 A syndrome of congenitalanomalies has been recognized, the "aminopterin syn¬drome," with the most consistent anomaly being cranialdysostosis.72 Other antimetabolites have rarely been asso¬ciated with fetal malformations. An isolated case of fluo-rouracil-associated congenital abnormality also occurredin a fetus who had received radiotherapy.86 Of 20 patientsexposed to mercaptopurine alone, no fetal anomalies weredocumented.30·32·77-83

There are only two cases of malformation in 44 patientswho received alkylating agents in the first trimester (whenpatients who also received radiotherapy are excluded), so

alkylating agents given alone may be relatively safe. Thereare two potentially curative or significantly palliativeregimens using single alkylating agents: melphalan inovarian cancer176 and the adjuvant breast cancer regimenusing cyclophosphamide reported by Nissen-Meyer et al.177

Although vinblastine sulfate is highly teratogenic inanimal models,178 there has been only one reported abnor¬mality observed in the offspring of 14 women treated withvinblastine in the first trimester.25·30·32·86-89 Therefore, theuse of vinblastine in the first trimester may be relativelysafe. Used alone this agent is only palliative, but it mightbe considered in the patient with Hodgkin's disease whentemporizing chemotherapy is necessary until a curativeregimen becomes safer for the fetus. We found no data onthe closely related vinca alkaloid, vincristine sulfate.

Regarding combination chemotherapy, four of the sevenmalformations seen with combination regimens were inpatients who had received procarbazine hydrochloride.The popular MOPP (mechlorethamine [Mustargen] hydro¬chloride, vincristine sulfate [Oncovin], procarbazine, andprednisone) regimen, one of two regimens curative inHodgkin's disease, contains this drug. The other popularcurative regimen is ABVD (doxorubicin hydrochloride[Adriamycin], bleomycin sulfate, vinblastine, and dacar-bazine), and although no data concerning the use of thisregimen during pregnancy are available (to our knowledge),the drugs in this combination, used singly, have rarely beenassociated with fetal malformations. Insufficient data areavailable to evaluate the CHOP (cyclophosphamide, doxo¬rubicin [Adriamycin], vincristine [Oncovin], and predni¬sone) and BACOP (bleomycin, doxorubicin [Adriamycin],cyclophosphamide, vincristine [Oncovin], and prednisone)regimens curative in intermediate and high-grade lympho¬mas and the PVB (cisplatin [Platinol], vinblastine, andbleomycin) regimen curative in germ cell tumors, but thedrugs in these regimens, used singly, are not unusually

teratogenic based on the human data in Table 1.Single and combination chemotherapy may be adminis¬

tered in the second and third trimester, with a low risk ofteratogenicity. Nevertheless, the least potentially terato¬genic regimen should be selected. The mother and familyshould be informed of the possible early and delayed effectsof cancer therapy.

There are several tumors seen during pregnancy in whichchemotherapy may increase the cure rate: breast cancer,acute leukemia, intermediate and high-grade lymphomas,Hodgkin's disease, and ovarian cancer. Other tumors inwhich radiation therapy may be curative are: carcinoma ofthe cervix, Hodgkin's disease, non-Hodgkin's lymphoma,epithelial and germ cell tumors of the ovary. Surgery maybe curative in melanoma and carcinomas of the breast,cervix, ovary, large bowel, vagina, thyroid.

Breast cancer is best managed surgically rather thanwith the newer breast-sparing procedures that requireirradiation. Patients in this age group are likely to havehormone-receptor-negative, lymph-node-positive diseaseand thus have a poorer prognosis. Survival can be improvedby 20% to 30% in such patients by the use of adjuvantchemotherapy,179 but such therapy is not effective if de¬layed. If adjuvant chemotherapy for breast cancer is usedin the first trimester, the CMF (cyclophosphamide, meth¬otrexate, and fluorouracil) regimen is not the regimen ofchoice. One might consider the CAF (cyclophosphamide,doxorubicin [Adriamycin], and fluorouracil) regimen oreven the regimen of Nissen-Meyer et al177 that utilizes onlycyclophosphamide. In the second or third trimester, CMFmay be utilized.

Acute leukemia requires immediate, intensive, and pro¬longed chemotherapy that may produce fetal damage ifgiven during the first trimester. Delay in therapy willeliminate the very real possibility of cure. During the firsttrimester, if abortion is refused, the therapy may produceabortion or fetal malformation. During the second andthird trimester, despite the intensity of therapy, there arenumerous reports of normal infants.24·94·114115 Because acuteleukemia is potentially curable, particularly in youngerpatients, the best available regimen should be used.

Approximately half the cases of leukemia diagnosedduring pregnancy are chronic myelogenous leukemia.180Often it is possible to observe these patients, withoutprescribing therapy, after the diagnosis is made. If thewhite blood cell count rises to the level where vascularevents are likely, over 250 109/L, or if splenomegalybecomes a problem, leukapheresis may be useful in reduc¬ing the count and decreasing the size of the spleen.181

Lymphoma presents a more complex dilemma. Delayuntil after delivery is almost certainly the best choice innon-Hodgkin lymphoma of the low-grade variety, but thisis uncommon in pregnancy. In the intermediate and high-grade forms, intensive chemotherapeutic regimens are

required to achieve a potential cure rate of about 33% to70%, but delay from the first to the second trimester oruntil after delivery may compromise such results. Inconsidering delay, it should be remembered that withintermediate and high-grade non-Hodgkin's lymphoma,there are no curative salvage regimens, except perhapsintensive chemotherapy coupled with bone marrow trans¬plantation. If therapy is to be given, a first-line regimensuch as CHOP, or one of the newer combination regimens,182should be selected to maximize the possibility of cure.

For Hodgkin's disease, it is probably not possible todeliver full-mantle radiation or one of the curative chemo¬therapy regimens early in pregnancy without a high prob¬ability of fetal damage. Delay, at least until the secondtrimester, seems indicated, and the availability of severalcurative approaches makes delay more reasonable in this

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instance that in high-grade non-Hodgkin's lymphoma. Iftreatment becomes necessary due to disease progressionduring the first trimester, it is reasonable to temporizewith limited radiation to supradiaphragmatic areas andsingle-drug therapy with vinblastine. After the first tri¬mester, it is probably reasonable to begin radiotherapyabove the diaphragm with modification of field and doseand appropriate abdominal shielding. Calculation of esti¬mated fetal dose should be performed. Curative combina¬tion chemotherapy, such as MOPP or ABVD, may be givenduring the second or third trimester with little teratogenicrisk to the fetus. If the disease permits, delay of definitivetherapy until after delivery is an alternative with even lessfetal risk. Staging Hodgkin's disease during pregnancymay be a problem; some have suggested a single 24-hourlymphangiogram as producing the maximum informationfor the least fetal exposure.96 Ultrasound and magneticresonance imaging may be useful and do not expose thefetus to ionizing radiation. If definitive therapy is delayed,staging should also be delayed until after delivery.

Ovarian cancer may be cured by salpingo-oophorectomyalone in stage IA or IB, whether of epithelial183 or germcell184 origin, but more extensive disease requires chemo¬therapy for cure. Because of a high risk of inducingabortion, surgical exploration of an asymptomatic ovarianmass should be delayed until the second trimester unlessthe mass is very large, over 6 cm186 or over 10 cm.186Extensive investigation with multiple biopsy specimens isnecessary. If cure is to be achieved by subsequent chemo¬therapy in cancer of epithelial origin, the usually recom¬mended surgery is total hysterectomy and bilateral sal¬pingo-oophorectomy with omentectomy and debulking ofperitoneal implants over 1 cm in size. In such cases, thequestion of chemotherapy damage to the fetus will notarise. On the other hand, tumors of germ cell origin mayconstitute up to one third of ovarian cancers in pregnancy187;even in the absence of debulking surgery, these seem to becurable with radiation therapy or with intensive chemo¬therapy with PVB,188 with the latter being the treatmentof choice.

Colposcopy should be used to follow up suspicious cer¬vical cytologie specimens; if carcinoma in situ is discovered,careful observation is necessary until after delivery. Ifcolposcopy is unsatisfactory, cone biopsy may be necessary,but this carries substantial risk to the pregnancy. Coniza-tion should be performed during the second trimester, ifpossible.168 When invasive cervical cancer is diagnosed, itmay be possible to delay definitive therapy until afterdelivery; if rapid progression of the disease is observed,however, the best treatment is probably hysterectomy,with appropriate dissection based on stage. Radiotherapygives comparable survival, and the products of conceptionare generally passed after three to six weeks.189 Hysterot-omy or cesarean delivery may precede surgery or radiationafter 20 weeks' gestation in the rare patient in whom delayuntil delivery is not possible. This question has beenextensively reviewed elsewhere.168

Melanoma and cancers of the thyroid, colon, and vaginaare best managed surgically as in the nonpregnant patientexcept that irradiation and radioactive iodine are not used.In none of these cancers—melanoma, thyroid, colon, va¬

gina—does chemotherapy offer sufficient benefit to themother to warrant the risk to the fetus.

If chemotherapy has been given, delivery should beinduced or cesarean section performed as near to term as

possible when maternal blood cell counts are not compro¬mised due to cancer therapy.144 Neonatal cytopenias havebeen noted after exposure to cancer chemotherapy,108 so a

complete blood cell count should be obtained on the new¬born. Antineoplastic agents administered systemically

may reach significant levels in milk,190 and cyclophospha¬mide has produced neutropenia and thrombocytopenia ina breast-fed infant191; therefore, breast-feeding is contra¬indicated if the mother is receiving chemotherapy. A carefulexamination should be made for congenital malformationsand organ dysfunction, and long-term follow-up of theinfant is essential.

Michael C. Perry, MD, Alfred Llorens, MD, and Jerry Murrell, MD,reviewed the manuscript, and Susan E. Brown gave secretarial assistance.

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