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MD Consult: Books: Goldman: Cecil Medicine: Chapter 258 – MANAGEMENT OF NEOPLASTIC DISEASES DURING PREGNANCY

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 258 – MANAGEMENT OF NEOPLASTIC DISEASES DURING PREGNANCY

Edward C. Grendys Jr.

Epidemiology

Although cancer is uncommon in a relative sense, it remains a leading cause of death in women of reproductive age ( Table 258-1 ). Overall cancer-related deaths account for 13% of mortality in women between the ages of 15 and 34 years and 38% in women aged 35 to 54 years. It is estimated that 1 in 1000 to 1 in 1500 live births is complicated by maternal malignant disease. However, it has been suggested that as women continue to delay childbearing, this incidence may rise in concordance with the direct relationship of age and cancer incidence ( Fig. 258-1 ).


TABLE 258-1   — 
REPORTED DEATHS IN U.S. WOMEN AGED 15 TO 54 YEARS

Cause No. of Cases/Year
Cancer 34,361
Cardiac disease 13,900
Trauma 12,154

Data from Landis SH, Murray T, Bolden S, Wingo PA: Cancer statistics, 1998. CA Cancer J Clin 1998;48:6–29.

FIGURE 258-1  Incidence of common malignant neoplasms in pregnancy.  (Data from Landis SH, Murray T, Bolden S, Wingo PA: Cancer statistics, 1998. CA Cancer J Clin 1998;48:6-29.)

Given these statistics, it is imperative that physicians involved in the care of pregnant women be knowledgeable about and attentive to current screening recommendations, especially regarding the cervix, colon, and breast malignant neoplasms. Subtle signs of malignancy can occasionally be mistaken for side effects of pregnancy, thus possibly leading to diagnostic and treatment delay.

Treatment Planning

The diagnosis of cancer in pregnancy presents a unique management dilemma that ultimately affects two patients. The decision process is complicated by the significant risks to the fetus in terms of developmental abnormalities and preterm delivery and to the mother in terms of the malignant process itself. Multiple social, ethical, moral, and religious issues also play an important part in the decision tree.

The treatment of these patients should remain unbiased, well researched, and above all multidisciplinary. Basic aspects of cancer screening must be maintained even during pregnancy, and signs and symptoms of serious neoplastic processes must not be overlooked.

When a cancer occurs in a gravid woman, it obviously carries with it enormous pressures on both the patient and her family as well as on the treating team of physicians. Treatment decisions are complicated by multiple issues including medical (risk versus benefit to mother and fetus), ethical, cultural, and religious.

The approach to a pregnant patient diagnosed with a concomitant malignant process requires a concerted multidisciplinary approach. This team should include, at a minimum, obstetricians with experience in high-risk pregnancies and oncologists with a keen understanding of the potential teratogenic risk in fetal development and maturation. Also, significant input from psychosocial, religious, and even legal personnel can be invaluable to maximize the outcome of mother, fetus, and family. An integrated care plan should be formulated, and communication between all team members must be encouraged. The medical and psychological sequelae of this process are complex and not to be taken lightly. Decisions regarding pregnancy preservation, type and timing of diagnostic and therapeutic interventions, use of antepartum lung-maturing corticosteroids, and timing and mode of delivery must be carefully planned and executed.

When pregnancy is complicated by a diagnosis of malignancy, timing in terms of treatment becomes critical. Risks versus benefits of potential life-saving therapeutic intervention and early delivery with subsequent fetal immaturity must be weighed carefully. It must also be understood that certain interventions, including radiographic imaging, surgery, and cytotoxic chemotherapy, are safe during pregnancy if they are performed in an appropriate manner. Impetuous and biased decisions in terms of pregnancy termination or delivery must be avoided. Recent data suggest that a delay in delivery for even a few weeks may have a dramatic impact on fetal well-being (see later).

Two fundamental issues must be contemplated when one approaches the care of a gravid patient diagnosed with a malignant process. The impact of the disease on the patient is obviously of paramount importance, and therefore an understanding of the natural history of the disease is critical. Treatment options, success rates, and risk of treatment modifications or delays must be considered. Equally important are the maternal and paternal desires of pregnancy preservation and the risk of the chosen treatment regimens on fetal health, including sequelae resulting from elective early delivery or potential for in utero fetal harm from toxic side effects of therapy. Patients need to be presented with unbiased information about risks to both mother and fetus and with all potential options of intervention, including pregnancy termination if it is required and desired. Most likely, these management issues are best left to a tertiary care center with a high-risk neonatal nursery (level III) that can adequately manage a preterm yet viable infant if it is necessary.

Fetal Development

Physicians involved with the treatment of cancer in the pregnant patient must possess an in-depth understanding of embryonic development as well as of the disease process and the available therapeutic options. The terminology adopted by embryologists and clinical obstetricians also must be understood.

Fetal age is the most critical concept in terms of prediction of fetal survival and subsequent morbidity. In clinical obstetrics, estimated gestational age (EGA) is defined as the time from the last day of the last menstrual period ( Fig. 258-2 ). Embryonic age from a developmental biologist’s viewpoint begins at fertilization and is thus 2 weeks shorter in duration. This 2-week differential is critical and potentially legally important in considering fetal viability and age at which termination (abortion) can be performed. Ovulation and subsequent fertilization do not occur until approximately 2 weeks after the last menstrual period. Thus, the normal gestation is 40 weeks; clinical viability generally has been defined as an EGA of more than 25 weeks. For accurate clinical communication, fetal age should be documented in terms of EGA (in weeks). Gestation is further subdivided into 14-week trimesters, as shown in Figure 258-2 . In most states, abortion can legally be performed in the first trimester, whereas some states allow termination until 24 weeks (late abortion).

FIGURE 258-2  Fetal development. EGA = estimated gestational age; LMP = last menstrual period.

The most vulnerable portion of development, in terms of teratogenicity, is believed to be during the embryonic period (see Fig. 258-2 ). During this time, major organ systems are forming (organogenesis), and it appears that the conceptus is susceptible to outside teratogenic influences. For this reason, most clinicians believe that therapeutic intervention is best delayed until after this period to lessen fetal risk in a patient desirous of preserving her pregnancy.

After the embryonic period, fetal development is focused on organ growth and maturation. Certain basic physical and metabolic capabilities appear to be required to maintain extrauterine life. Most commonly, viability is defined as 25 weeks of EGA, although fetal survival before this age has been reported. Subsequent fetal morbidity and mortality are linearly correlated with gestational age and weight (Tables 258-2 and 258-3 [2] [3]). Obviously, preterm infants require care in a specific neonatal unit prepared for such complicated management (level III nurseries). Significant literature supports the concept of maximizing in utero fetal life to decrease fetal morbidity, mortality, and long-term developmental delay.


TABLE 258-2   — 
SURVIVAL STATISTICS IN RELATION TO FETAL WEIGHT

Weight (g) % Survival
401–500 11
501–600 29
601–700 62
701–800 75
801–900 88

TABLE 258-3   — 
SURVIVAL STATISTICS IN RELATION TO ESTIMATED GESTATIONAL AGE (EGA)

EGA (weeks) % Survival
25 75
26 80
27 90
28 92
29 95
30 97

Although the short-term major risk to the fetus appears to be secondary to poor lung development, subsequent development of hyaline membrane disease, and bronchopulmonary dysplasia, reports are confirming increased risk of intraventricular hemorrhage and significant long-term motor and neurologic sequelae associated with survival of a preterm delivery. Infants weighing less than 1500 g at birth appear to suffer from significant long-term deficiencies in intelligence quotient, visual-motor integration, and reading performance. Similar data reveal significant neurologic impairment in infants documented with intraventricular hemorrhage. In one study, only 26% of low-birthweight children with subsequent intraventricular hemorrhage had normal developmental abilities at the time of preschool testing. Predelivery use of corticosteroids (at an EGA of 24 to 34 weeks) decreases the risk of pulmonary complications as well as intraventricular hemorrhage. It is important for parents to understand the potential ramifications of early delivery for their child and to realize that survival can be associated with significant long-term morbidity.

Diagnostic and Therapeutic Procedures in the Pregnant Patient with Cancer

Commonly accepted practices of diagnostic imaging, surgery, therapeutic radiation therapy, and chemotherapy have profoundly different implications in the pregnant versus nonpregnant patient. The risk-benefit profiles of each modality must be carefully considered before implementation.

Radiation Therapy

It appears that ionizing radiation poses significantly more risk to fetal development than do the environmental sources of both ionizing and nonionizing radiation to which one is constantly exposed. Ionizing radiation can cause both direct and indirect intracellular damage and is typically expressed in terms of radiation absorbed dose or relative biologic equivalent. Direct radiation damage is believed to be a relatively minor component of these detrimental effects. Rather, the large amount of intracellular water that undergoes radiation-induced ionization leads to free radical formation with subsequent chemical intracellular reaction and damage. In vitro studies indicate that dividing cells, specifically near the mitotic phase, appear to be most vulnerable.

At therapeutic doses, radiation does not significantly directly damage cellular microstructures, membranes, or metabolic processes. The primary toxic effects appear to result primarily from free radical–induced damage at the DNA level. The damage is most likely secondary to double-stranded breaks in DNA leading to replication errors, which are presumably lethal and potentially teratogenic.

At doses of radiation less than 100 cGy, cell death results from direct inhibition of cell division and is most prevalent in cells undergoing active division. Radiation-induced mutations increase as a linear function of single doses of 400 to 600 cGy. Because of the acute toxicity to cells, radiation is considered a weak teratogen. Clinical retrospective studies suggest some association of spontaneous abortion with early fetal irradiation.

The fetal effects of radiation appear to be related to the gestational age at the time of exposure as well as to total dose received. An analysis of children exposed in utero to atomic bomb–produced radiation revealed that most long-term neurologic sequelae occurred in children exposed between an EGA of 8 and 15 weeks, with no cases reported in children exposed before 8 weeks. Exposure at an earlier gestational age most likely resulted in miscarriage.

Fetal exposure to radiation between 11 and 16 weeks of gestation appears to result in an increased risk of microcephaly and mental retardation. Exposure in the third trimester may be associated with longer term developmental abnormalities (Tables 258-4 and 258-5 [4] [5]). In general, third-trimester fetal doses should not exceed 100 cGy.


TABLE 258-4   — 
CRITICAL PERIODS FOR FETAL IRRADIATION

  Radiation Dose
Disorder or Problem 100–500 cGy 500–1000 cGy
Embryonic death   0–1 week
Malformation 1–8 weeks 1–8 weeks
Microcephaly 1–15 weeks 1–15 weeks
Mental retardation 8–15 weeks 8–25 weeks
Growth retardation 1–15 weeks 1–25 weeks
Late-onset cancer ? 1–39 weeks
Genetic aberrations ? ?

TABLE 258-5   — 
ESTIMATED TOTAL RADIATION EXPOSURE RESULTING IN MAJOR ABNORMALITIES

Gestation (months) Radiation Dose (cGy)
1 40
2 90
3 140
4 200
5 250
6 350
7 No published data
8 500
9 600

Typical sources of medically indicated ionizing radiation are both diagnostic and therapeutic. The fetal exposure during most diagnostic radiographic imaging modalities is relatively small and generally exaggerated by both clinicians and patients, leading to unwarranted fear. In the appropriate setting, the procedures are thought to be safe if they are clinically indicated. Estimated fetal radiation exposures for standard radiographic procedures are listed in Table 258-6 . A risk-benefit assessment must be performed before any radiographic evaluation is undertaken in a pregnant patient.


TABLE 258-6   — 
ESTIMATED FETAL DOSE FROM COMMON DIAGNOSTIC RADIOGRAPHIC PROCEDURES

Examination Fetal Dose (cGy)
Chest (posteroanterior, lateral) 0.006
Abdomen 0.15–0.26
Lumbar spine 0.65
Pelvis 0.2–0.35
Hip 0.13–0.2
Intravenous pyelography 0.47–0.82
Upper gastrointestinal tract 0.17–0.48
Barium enema 0.82–1.14
Mammography Undetectable
Ventilation-perfusion scan 0.35
CT of abdomen (early pregnancy) 0.4
CT of pelvis 2.5
99mTc-MDP bone scan 0.15
Spiral CT pulmonary angiography 0.2

CT = computed tomography.

Because of the relatively high fetal exposure associated with pelvic-abdominal computed tomography, it is not recommended in early pregnancy. However, pulmonary imaging with contrast enhancement to evaluate for possibly life-threatening pulmonary emboli is associated with minimal fetal exposure, as are ventilation-perfusion scans.

Mammography (see Table 258-6 ) presents essentially no risk to the developing fetus. Therefore, its use as a diagnostic modality in the patient with a clinically suspicious breast lesion is recommended.

Perhaps the most commonly employed imaging procedure in the pregnant patient is real-time ultrasonography. Its use in fetal anatomic observation and age determination has been well studied and is considered safe throughout the gestational period.

Ultrasonography can also be an important instrument for maternal evaluation of suspected renal, abdominal, pelvic, hepatic, cardiac, vascular, and breast tissues. Hepatic ultrasonographic evaluation can detect occult liver metastasis with a sensitivity of 76% without fetal risk. Breast ultrasonography is a useful adjunct in characterizing breast lesion architecture noted on physical examination or mammography (see section on breast cancer).

Magnetic resonance imaging, because of its lack of ionizing radiation, is believed to be acceptable in pregnancy. No adverse fetal or maternal sequelae have been described to date.

The maternal effects of radiation are well documented. Direct ovarian exposures of 1000 cGy are associated with permanent sterilization in more than 90% of women. Lower doses also result in sterility but appear to be dependent on the patient’s age and menstrual and reproductive history. Ovarian suppression with oral contraceptives or gonadotropin hormone antagonists may help preserve ovarian function and subsequent reproductive potential, especially in the adolescent woman, although randomized trials are lacking. This effect appears to be less pronounced as age increases. Therapeutic megavoltage radiation therapy has a pivotal role in the management of many malignant neoplasms, such as breast and cervical cancer and lymphoma. Its use in pregnancy must be regarded as a completely separate entity from diagnostic radiographic procedures. Depending on the specific anatomic area to be treated, the fetal exposure can range from minimal to substantial ( Table 258-7 ).


TABLE 258-7   — 
ESTIMATED FETAL DOSES FROM EXTRAPELVIC AND EXTRA-ABDOMINAL MATERNAL IRRADIATION

Radiation Site/Prescribed Dose Estimated Gestational Age Fetal Dose (cGy)
Tibia sarcoma/50 Gy 25 weeks 1.5
Brain glioblastoma/60 Gy 13 weeks 3.9
Hodgkin’s disease (mantle fields)/38 Gy 34 weeks 42
Hodgkin’s disease with mediastinum/neck/40 Gy 18–31 weeks 20
Breast cancer/50 Gy Ovarian dose 9

Data from Greer BE, Goof BA, Kuh W, et al: Cancer in the pregnant patient. In Hoskins WJ, Perez CA, Young RC (eds): Principles and Practice of Gynecologic Oncology, 2nd ed. Philadelphia, Lippincott-Raven, 1997, pp 463–485.

Surgical Therapy

Most common solid tumor cancers affecting the pregnant patient are treatable; many are curable by a surgical approach. Fetal risk appears to be most dependent on the anatomic location of the neoplasm and the risk of subsequent stimulation of preterm labor, which is most affected by timing of the procedure. Pelvic and abdominal radical procedures can be safely undertaken with appropriate planning.

Surgical approaches to breast, ovarian, gastrointestinal, thyroid, melanoma, neurologic, and vulvar cancer have been well described, along with a multitude of benign surgical conditions. The current anesthetic agents in common use are believed to be without risk of fetal teratogenicity, and certainly minor procedures with local or regional analgesia (epidural, spinal, nerve block) are essentially without risk. Exclusive of cesarean section, it has been estimated that approximately 35,000 pregnant women undergo some surgical procedure each year.

An issue that should be considered by the surgeon and anesthesiol-ogist is the critical nature of the uteroplacental unit, which is susceptible to blood pressure changes and intravascular volume depletion. Major changes in blood flow to the placenta can lead to subsequent fetal hypoxia and potentially precipitate neurologic sequelae. Therefore, the supine position is best avoided in the gravid patient (especially after an EGA of 20 weeks) owing to decreased cardiac return associated with uterine compression on the inferior vena cava. Patients are best maintained in the left lateral decubitus position (30 degrees) to decrease this compressive effect. Diagnostic procedures including fine-needle aspiration, core biopsy, and surgical removal of suspicious lesions should rarely if ever be deferred because of pregnancy.

Equally critical is the increased thrombogenic state associated with pregnancy as brought about by decreases in plasma fibrinolytic activity, increases in coagulation factors, and increased pelvic and lower extremity stasis. These factors combine for a five- to six-fold increased risk of thromboembolic phenomena in the pregnant patient, and thus appropriate thromboprophylaxis should be undertaken. Current acceptable techniques include subcutaneous heparin (5000 units three times a day), low-molecular-weight heparin (enoxaparin, 40 mg/day), and inflatable compression stockings. Non–custom fit elastic stockings (e.g., TED hose) have no role in thromboprophylaxis.

Medical Therapy

 

Chemotherapy

Chemotherapy, by definition, is the use of chemical agents to treat or to control disease. Therefore, any medication from acetaminophen to zinc has the potential to cause fetal effects, both beneficial and harmful. The U.S. Food and Drug Administration has established labeling of prescription drugs to provide information about potential fetal risks. These five categories (A, B, C, D, and X) indicate risk of fetal teratogenicity ( Table 258-8 ). A similar classification system has been adopted by the Australian Drug Evaluation Committee as well as by the German Health Care Administration. From a practical standpoint, drugs in Food and Drug Administration categories A, B, and C are prescribed with impunity.


TABLE 258-8   — 
U.S. FOOD AND DRUG ADMINISTRATION PREGNANCY CATEGORY DEFINITIONS

Category Definition
A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester, and the possibility of fetal harm appears remote.
B Animal studies do not indicate a risk to the fetus, and there are no controlled human studies. Animal studies do show an adverse effect on the fetus, but well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.
C Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
D Positive evidence of human fetal risk exists, but benefits in certain situations may make use of the drug acceptable.
X Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, and the risk of drug administration clearly outweighs any possible benefit.

Chemotherapy specifically as an antineoplastic agent has an integral role in the management of many of the cancers encountered during pregnancy. Some agents are used as adjuvant therapy after primary surgery (e.g., breast cancer), whereas others are the primary treatment modality (e.g., Hodgkin’s disease). The potential toxicity to the developing fetus must be considered in discussing potential treatment regimens in the pregnant patient.

All chemotherapeutic agents, by virtue of their mechanism of action, have the ability to be both mutagenic and teratogenic to the actively dividing cells of the embryo and fetus. Most of these agents are considered category D or X. Unfortunately, controlled data on their effects on the developing fetus are limited. Most information has come from retrospective reviews, clinical observation, and laboratory experiments on gravid animals.

It appears that the first trimester is the most susceptible to deleterious chemotherapy influences. Overall, it appears that approximately 20% of fetuses exposed to cytotoxic agents in the first trimester will manifest major anomalies, compared with 3% in an unexposed population.

Chemotherapeutic agents primarily act by interrupting various portions of vital cell processes. This reproductive cell cycle is divided into five phases, each with specific actions leading to cell duplication ( Table 258-9 ). Cancer cells are thought to replicate at a higher rate and therefore should be more susceptible to the cytotoxic or cytostatic effects of chemotherapy. Specific chemotherapeutic agents are often categorized by their interaction within the cell cycle and are traditionally classified into alkylating agents, antitumor antibiotics, antimetabolites, vinca alkaloids, biologic response modifiers, hormones, and taxanes. Specific agents and their actions are listed in Table 258-10 .


TABLE 258-9   — 
CELL CYCLE

Cell Phase Approximate Time Activity
G1 (gap 1) Variable RNA manufacture, preparation for DNA synthesis
S (synthesis) 8 hours DNA duplication
G2 (gap 2) 3 hours Spindle apparatus formation
M (mitosis) 1 hour Mitosis
G0 (gap 0)   Resting (quiescent)

TABLE 258-10   — 
SPECIFIC CHEMOTHERAPEUTIC AGENTS AND THEIR ACTIONS

Agent Cell Cycle Action Potential Fetal Toxicity
Alkylating agent: cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, cisplatin Nonspecific 14% fetal malformations in first trimester; chlorambucil syndrome of renal aplasia, cleft palate, skeletal anomalies
Antitumor antibiotics: dactinomycin, mitomycin C, bleomycin, doxorubicin Variable None reported
Antimetabolites: 5-fluorouracil, methotrexate, cytarabine Cell cycle specific Multiple defects: cranial dysostosis, hypertelorism, micrognathia, cleft palate; contraindicated in pregnancy
Taxanes: paclitaxel Cell cycle specific No data in pregnancy
Biologic response modifiers: interleukins, interferons Nonspecific Contraindicated in pregnancy
Hormones: tamoxifen, megestrol Nonspecific Contraindicated in pregnancy

The timing of chemotherapy administration in relationship to anticipated delivery must be carefully planned to avoid delivery around the time of the maternal hematopoietic nadir. Hematopoietic suppression (anemia, leukopenia, and thrombocytopenia) may occur in the fetus as a result of transplacental passage of cytotoxic agents from the mother to the fetus, and the neonatology team should be advised accordingly.

Taxanes (paclitaxel and docetaxel) have significant activity in many solid tumor malignant neoplasms. Case reports describing safe administration of paclitaxel (Taxol) have been published, but great caution must still be exercised. Appropriate consent must be obtained before administration, and careful risk-versus-benefit analysis must be undertaken. Given its activity of microtubular assembly, concern for its effect on fetal development is significant.

Breast-feeding is contraindicated during chemotherapeutic administration. These systemically administered antineoplastic agents may reach significant levels in breast milk.

   SPECIFIC MALIGNANT NEOPLASMS IN PREGNANCY

The most common malignant neoplasms encountered during pregnancy are uterine and cervical cancer, breast cancer, melanoma, ovarian cancer, thyroid cancer, leukemia, lymphoma, and colorectal cancer ( Table 258-11 ). Specific reviews of these common malignant neoplasms encountered in this population are presented here, along with various strategies employed in their management.


TABLE 258-11   — 
INCIDENCE OF CANCER IN PREGNANCY

Site and Type Estimated Incidence per 1000 Pregnancies
Cervix uteri
  Noninvasive 1.3
Invasive 1.0
Breast 0.33
Colorectal 0.2
Melanoma 0.14
Ovary 0.10
Leukemia 0.1
Lymphoma 0.1

From Allen HH, Nisker JA (eds): Cancer in Pregnancy: Therapeutic Guidelines. Mt. Kisco, NY, Futura, 1986.

   Cervical Cancer

Epidemiology

Cervical cancer remains the most common malignant neoplasm encountered during pregnancy. It occurs with an incidence of approximately 1.2 cases per 10,000 pregnancies. With the expanded knowledge of the natural history of this disease, the majority of patients with early cervical carcinoma can be managed with fetal preservation (if desired) without undue maternal morbidity or mortality.

Diagnosis

Initial prenatal evaluation should routinely include a Papanicolaou (Pap) smear. This simple, inexpensive, and extremely effective screening procedure has significantly decreased the incidence of invasive squamous cell carcinoma of the cervix in the United States. In countries where this procedure is not widely practiced, cervical cancer remains one of the leading causes of death. After intense investigation and numerous clinical observations, the natural progression from a preinvasive dysplastic lesion to overt invasive cervical carcinoma is well understood. The success of Pap smear screening has been in its ability to diagnose dysplastic lesions, thus allowing simple ablative and curative measures.

All clinicians who practice Pap smear screening should have an understanding of the Bethesda system of Pap smear interpretation as well as diagnostic and treatment algorithms. The in utero presence of a fetus should not dramatically change the initial diagnostic approaches to an abnormal Pap smear.

Cytologic evidence of squamous intraepithelial lesions is most commonly evaluated with cervical colposcopy. Colposcopy during pregnancy is safe and effective and in the majority of cases (>90%) provides adequate diagnostic information. As in the nonpregnant patient, any area of gross abnormality, even in the presence of a normal Pap smear, requires biopsy, which again is safe in pregnancy if it is performed by experienced personnel.

Treatment

Given the knowledge of the natural history of cervical dysplasia, observational strategies have been developed to allow the pregnancy to continue without need for intervention. Even in the patient with biopsy-proven carcinoma in situ, excision or cervical ablation can most commonly be deferred until after delivery. Importantly, a diagnosis of cervical dysplasia is not an indication for cesarean delivery because there has been no demonstrable increased risk to mother or fetus with vaginal delivery.

Locally advanced cervical carcinoma not amenable to surgical resection requires treatment with radical radiation therapy. The standard external high-energy teletherapy radiation often exceeds 4500 cGy and is not compatible with fetal life. Again, decisions regarding fetal age, risk of early delivery versus waiting, and parental desires must be weighed, given the curability of this disease. With most lesions confined to the cervix, careful observation with expedited delivery after fetal maturation followed by radical treatment appears reasonable.

   Ovarian Neoplasms

Epidemiology

The incidence of adnexal masses associated with pregnancy has been reported to range from 1 in 81 to 1 in 2500. With the use of ultrasonography for routine fetal surveillance, the detection of previously unrecognized adnexal masses in both early and late gestation is likely to increase.

The lifetime risk of ovarian carcinoma for an American woman is approximately 1 in 70, with an age-adjusted annual incidence of approximately 13.7 cases per 100,000 women. This results in approximately 24,000 new cases of ovarian cancer and 14,500 deaths per annum.

These malignant neoplasms can occur at any age, including infancy and childhood; however, the overall age-specific incidence increases dramatically with age. In women 40 years of age, there are approximately 10 cases per 100,000, increasing to a peak incidence of approximately 45 cases per 100,000 women between the ages of 60 and 65 years. Given this age distribution, the discovery of ovarian carcinoma in pregnancy is still distinctly uncommon.

Pathobiology

Of the adnexal masses noticed in pregnancy, approximately 50% are smaller than 5 cm in diameter, whereas 25% are between 5 and 10 cm and 25% are larger than 10 cm at the time of discovery. Ninety-five percent of these also are unilateral.

Unilateral, mobile, noncomplex masses smaller than 5 cm, noticed in the first trimester, will resolve in more than 90% of cases. It therefore is reasonable to observe nonsuspicious masses conservatively with repeated ultrasonography into the second trimester (when elective surgical intervention is safest) to document spontaneous resolution.

A subgroup of patients undergoing assisted reproductive therapy with various ovulation-inducing medications presents a unique situation. Because of the induced ovarian hyperstimulation and increased ultrasonographic surveillance, these patients commonly have ovarian cysts noted in the first trimester. Spontaneous resolution of benign-appearing ovarian cysts can be expected in more than 90% of patients who have undergone ovulation induction. Reports of possible associations between ovulation induction and an increased incidence of ovarian neoplasms should be kept in mind, however, although this is considered most likely to occur after the pregnancy.

Diagnosis

Adnexal masses can originate from multiple sources, and the differential diagnosis is complex, including multiple gynecologic and nongynecologic entities. Fortunately, modern pelvic imaging, especially ultrasonography, aids greatly in differentiating the primary origins of these masses. The common types of neoplastic and non-neoplastic ovarian masses noticed during pregnancy are described in Tables 258-12 and 258-13 [12] [13]. Most ovarian tumors occurring during early pregnancy are benign; the most common neoplastic ovarian mass is a benign cystic teratoma.


TABLE 258-12   — 
DIFFERENTIAL DIAGNOSIS OF THE PELVIC MASS

GYNECOLOGIC

   Ovary

   Benign (functional)
   Neoplastic (benign, malignant)
   Fallopian tube

   Hydrosalpinx
   Tubo-ovarian abscess
   Ectopic pregnancy
   Uterine

   Benign (leiomyomas)
   Malignant (sarcoma)
NONGYNECOLOGIC

   Gastrointestinal

   Colon (including stool, diverticular disease)
   Small bowel
   Appendix
   Mesothelial tumors
   Lymphoma
   Retroperitoneal neoplasm
   Pelvic kidney
   Urachal cyst
   Mesenteric cyst
   Metastatic disease
   Sacral meningocele
   Distended bladder

TABLE 258-13   — 
HISTOLOGIC TYPE OF NON-NEOPLASTIC OVARIAN TUMORS IN PREGNANCY

Histologic Type Frequency (%)
Endometriotic 14
Paraovarian 11
Simple cyst 12
Corpus luteal 50
Unknown 6
Miscellaneous
  Luteoma 1
Ovarian edema 1
Thecal lutein 5

Data from Stedman C, Kline R: Intraoperative complications and unexpected pathology at the time of cesarean section. Obstet Gynecol Clin North Am 1988;15:745–769.

Imaging

The key to evaluation of the pelvic or adnexal mass in pregnancy is to attempt to differentiate benign from malignant processes to avoid unnecessary intervention. Other than the acute presentation of abdominal pain associated with ovarian torsion, most commonly between weeks 6 and 14 of gestation, these masses often are clinically inapparent and may be accompanied only with the vague nonspecific abdominal discomfort common to pregnancy. Discovery of a mass in the first trimester in most situations should prompt repeated ultrasonography in the early second trimester to confirm resolution or stability.

Two to 5% of adnexal masses persisting after the first trimester are pathologically confirmed as being malignant, resulting in an overall malignancy rate of 1 in 5000 to 1 in 18,000 women who have live births.

Laboratory Findings

Tumor Markers

The use of CA-125 to differentiate malignant from benign adnexal masses has been well described ( Chapter 190 ). Unfortunately, in the premenopausal woman, the high rate of false-positive serum elevations in CA-125 makes this a relatively poor screening test. It is also commonly elevated because of the pregnancy itself, and therefore its use in the pregnant patient to aid in the differentiation of benign from malignant ovarian neoplasm is not recommended. This same principle applies to assessment of α-fetoprotein and human chorionic gonadotropin, both of which are routinely elevated in pregnancy and are therefore of limited value in attempting to identify a germ cell ovarian neoplasm.

Treatment

Surgical Therapy

The timing of surgical intervention cannot always be controlled, and emergency situations occasionally arise. If laparotomy is required during the first trimester, spontaneous abortion is more likely, possibly because of disruption of the delicate corpus luteum. After 7 to 10 weeks of gestation, the trophoblast is capable of supplying sufficient quantities of specific steroid hormones for the maintenance of the gestation.

Should surgical extirpation of the corpus luteum be required in the first trimester, progestin support is recommended. A daily intramuscular injection of 100 mg of progesterone in oil or a 100-mg transvaginal suppository every 12 hours provides adequate progestin replacement. A mass that is first noted in the third trimester is best managed by awaiting fetal maturity if the clinical suspicion of malignant disease is low.

The optimal timing of elective surgical intervention is during the second trimester. Apparent risk of preterm labor with subsequent fetal morbidity seems to be lessened. Uterine size at this gestational age does not preclude appropriate aortic and upper abdominal surgical exposure. Severe third-trimester complications are associated with failure to remove significant ovarian masses during mid-pregnancy.

   Ovarian Carcinoma

Treatment

Surgery

Although uncommon, there are unfortunate instances in which both epithelial and germ cell carcinomas are diagnosed during pregnancy. The mainstay of management is still surgery, with removal of the neoplasm as well as appropriate surgical staging and debulking as indicated. It is strongly recommended that this procedure be undertaken as a team approach, including both an experienced gynecologic oncologist and a maternal-fetal medicine specialist.

Medical Therapy

After completion of the initial surgical effort, consideration of chemotherapy is warranted, depending on stage of disease, estimated fetal age, and desires of the mother. Chemotherapeutic intervention, most commonly with a platinum-based regimen (cisplatin), has been well described and appears to be safe for both mother and fetus. Taxanes (paclitaxel and docetaxel) have significant activity in many solid tumor malignant neoplasms, including epithelial ovarian cancer. Case reports describing safe administration of paclitaxel (Taxol) have been published, but great caution must still be exercised. Appropriate consent must be obtained before administration, and careful risk-versus-benefit analysis must be undertaken.

   Breast Cancer

Epidemiology

Cancer of the breast during pregnancy or within the first year after delivery is considered pregnancy-associated breast carcinoma. Breast carcinoma remains the second most common malignant neoplasm occurring in the pregnant patient and affects approximately 1 in 3000 pregnancies in the United States ( Chapter 208 ).

Traditionally, pregnancy-associated breast carcinoma has been thought to carry a poorer prognosis, although recent matched controlled data do not support this claim. Women with pregnancy-associated breast carcinoma are, however, more commonly diagnosed with locally advanced node-positive disease at the time of diagnosis (61% vs. 38%). The obvious adverse effect of advanced disease is reflected by a decrease in the 5-year survival rate from 82% in the node-negative group to 47% in the node-positive group. Pregnant patients are also 2.5 times more likely to present with distant metastatic disease at the time of diagnosis, compared with their nonpregnant counterparts.

Diagnosis

Both the patient and the clinician must be continually vigilant to subtle breast changes. Most pregnancy-associated breast carcinomas initially manifest as a painless mass, and more than 90% are detected during the patient’s self-examination of the breast. Similar diagnostic algorithms should be applied in both the pregnant and the nonpregnant patient with a suspicious breast lesion. Fine-needle aspiration, diagnostic mammography, ultrasonography, and open-breast biopsy pose no documented fetal risk. The historical reluctance to aggressively pursue histologic diagnosis of breast masses in pregnancy is unwarranted and perhaps detrimental.

A recent series of 134 breast biopsies performed during pregnancy revealed a 21% incidence of malignancy, thereby confirming the need for aggressive measures. As in nonpregnant women, infiltrating ductal carcinoma continues to be the most common histologic subtype encountered.

Breast ultrasonography is an important adjunct in the evaluation of the palpable or mammographically demonstrated breast lesion. Its ability to differentiate cystic from solid lesions can provide useful information and can guide subsequent diagnostic decisions. On characterization of a breast mass, the most common initial diagnostic modality of choice is the fine-needle aspiration.

Treatment

The initial approach to breast carcinoma is most commonly surgical. Depending on the clinical stage, either breast-conserving lumpectomy or mastectomy, both with axillary lymph node dissection, is classically undertaken.

After surgical resection and lymph node evaluation, a decision about adjuvant therapy must be made. In surgically documented, early-stage disease, a complete metastatic work-up is not warranted, given the low yield. Therefore, decisions regarding the need for adjuvant therapy are usually based on the initial choice of surgical procedure. Again, given the potential harm of radiation therapy to the developing fetus, a radical mastectomy with lymph node dissection is usually the procedure of choice, thereby eliminating the need for postoperative radiation therapy.

Chemotherapeutic intervention has been advocated in cases of locally advanced and advanced carcinoma of the breast. As described previously, it is prudent to avoid chemotherapeutic intervention during the critical period of organogenesis in a desired pregnancy (see section on chemotherapy).

   Melanoma

Epidemiology

The overall incidence of cutaneous melanoma appears to be increasing, and it has been estimated that 1 in 90 persons were diagnosed with this neoplasm in 2000 ( Chapter 214 ). Some literature suggests that the incidence of melanoma complicating pregnancy will exceed that of cervical carcinoma.

Diagnosis

Risk factors documented to increase the risk of melanoma development are outlined in Table 258-14 . Increased awareness among physicians and patients as well as improved screening appears to have led to a tendency toward earlier diagnosis. These lesions tend to occur in sun-exposed areas; however, 17% of melanomas diagnosed in the female population are found on the vulva and perineum. This high incidence provides the basis for aggressive biopsy of suspicious pigmented vulvar lesions.


TABLE 258-14   — 
RISK FACTORS ASSOCIATED WITH DEVELOPMENT OF CUTANEOUS MELANOMA

   Fair complexion
   Tendency toward easy sunburning
   Early age at first sunburn
   Inability to tan
   Familial history of malignant melanoma
   Personal history of melanoma
   Environmental exposure to ultraviolet B irradiation
Treatment

Initial treatment of a melanotic lesion is the same in a pregnant or a nonpregnant patient. Wide local excision with adequate surgical margins remains the procedure of choice. Adjuvant therapy remains controversial in this setting.

The fetal risk of maternal melanoma is not well defined. It remains the most common malignant neoplasm to metastasize to the placenta and fetus. Although overall the incidence appears to be extremely low (approximately 60 cases reported), careful pathologic examination of the placenta is warranted. In documented cases of placental spread, the fetal risk appears to be as high as 40 or 50%. An altered clinical course in the pregnant patient with melanoma has also been suggested. Observational data imply a potential hormonal influence on the melanotic process. Given the well-documented cutaneous manifestations of pregnancy, including increased pigmentation of the vulva, areola, and linea nigra, some investigators have postulated that the increased levels of estrogen, progesterone, adrenocorticotropic hormone, and melanin-stimulating hormone may somehow influence melanoma growth.

   Thyroid Cancer

Epidemiology

Thyroid cancer is the most commonly diagnosed endocrinologic malignant neoplasm, with approximately 16,100 cases noted in 1997, of which about 11,000 were in women ( Chapter 244 ). Of these cases, almost half were documented in reproductive-age women (15 to 44 years); thus, thyroid carcinoma complicating pregnancy is not uncommon. Thyroid nodules are common and are often encountered during initial prenatal evaluation (they represent benign entities in approximately 90% of cases).

Diagnosis

Diagnostic evaluation of a thyroid nodule in a pregnant patient is usually limited to physical examination, laboratory studies, and thyroid ultrasonography followed by fine-needle or excisional biopsy. Specifically, nuclear medicine scintigraphy scans are omitted because of concerns about the effects of radioactive 123I or 131I on the fetal thyroid. Transplacental passage of iodine is well documented.

Treatment

After an appropriate diagnosis, surgical resection remains the primary mode of treatment. The timing of this intervention remains an important decision. A retrospective review suggests equivalent outcomes in patients who undergo thyroidectomy during pregnancy and those who wait until the postpartum state. Radionuclide thyroid ablation is contraindicated during pregnancy.

   Colorectal Cancer

Epidemiology

The lifetime risk of colorectal carcinoma in women is 1 in 17 (6%), with most of these being diagnosed after the age of 50 years ( Chapter 203 ). Only 8% of cases are noted in the reproductive-age group (<40 years). A similar increase in incidence may be noted as childbearing is delayed.

Diagnosis

More than 80% of colorectal carcinomas associated with pregnancy occur in the rectum (commonly below the peritoneal reflection and thus palpable on digital rectal examination). Diagnostic delays are usually attributed to the increased frequency of rectal bleeding episodes common to pregnancy (usually hemorrhoid related) and thus decreased clinical suspicion. Symptoms associated with advanced disease, such as abdominal pain, distention, and constipation, are rarely encountered.

The diagnosis of colorectal carcinoma depends on a detailed history of risk factors, such as history of polyps or family history of carcinoma (including gastrointestinal and breast); complete lymph node survey; digital rectal examination with Hemoccult testing; and sigmoidoscopy or colonoscopy. Determination of a serum marker such as carcinoembryonic antigen is of no value in pregnancy because it is elevated in the normal gestation.

Treatment

Management of colorectal carcinoma is most commonly surgical. Surgical practices similar to those outlined previously are followed.

The prognosis for a woman diagnosed with colorectal carcinoma in pregnancy is similar to that of matched nonpregnant control subjects. Postoperative local adjuvant pelvic radiation therapy is obviously contraindicated in a desired pregnancy.

   Hematologic Malignant Neoplasms

Epidemiology

Hematologic malignant neoplasms complicating pregnancy are rare ( Chapters 196 and 197 ). Hodgkin’s disease, considered a primary lymph node malignant neoplasm, commonly affects young adults and is the most common hematologic malignant neoplasm associated with pregnancy. An incidence of 1 in 5000 live births has been reported.

Diagnosis

More than 70% of patients diagnosed with Hodgkin’s disease initially present with painless lymphadenopathy, commonly noted in the cervical, submaxillary, or axillary chains. Systemic signs often associated with advanced disease include night sweats, fever, weight loss, and fatigue. Diagnosis depends on appropriate lymph node biopsy and documentation of the pathognomonic Reed-Sternberg cell.

Staging modalities include physical examination; computed tomography of chest, abdomen, and pelvis; lymphangiography; and occasional staging laparotomy with splenectomy. Abdominal-pelvic computed tomography is not recommended in pregnant patients, although magnetic resonance imaging can be performed safely. Both the surgeon and the oncologist must carefully consider the risk versus benefit for both fetus and mother in making decisions about staging laparotomy.

Treatment

Chemotherapy can be toxic to ovarian function, and its risk seems to be related to the age of the patient. Commonly used protocols consisting of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) result in amenorrhea in one third of patients; permanent ovarian failure occurs in 75% of patients older than 30 years at the time of treatment. It appears that the doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) regimen is potentially less toxic, with an approximate risk of amenorrhea of 5%. The role of ovarian suppression and subsequent functional preservation has already been described.

   Pheochromocytoma

Although it is only rarely encountered in pregnancy, pheochromocytoma represents a unique neoplastic event with significant morbidity and mortality to both mother and fetus. It most commonly represents a nonmalignant entity, although malignant transformation can occur. Pheochromocytomas are most commonly found within the adrenal medulla, although they can also arise from the chromaffin cell within sympathetic ganglia ( Chapter 246 ).

In pregnancy, the syndrome is manifested by severe episodes of hypertension usually not associated with significant proteinuria. It can be easily confused with an atypical presentation of preeclampsia. Associated signs and symptoms include tachycardia, palpitations, headache, diaphoresis, and anxiety. Given its rarity, the diagnosis is often unsuspected. If the pheochromocytoma is undiagnosed and therefore not treated, maternal and fetal mortality rates exceed 16 and 26%, respectively.

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