The diagnosis of malignancies during pregnancy is infrequent, with approximately 1 of 1000 pregnancies complicated by cancer. The most common tumors occurring during pregnancy are breast cancer, cervical cancer, melanoma, and hematopoietic tumor.1
Ovarian tumors complicate approximately 1 of 10000 pregnancies. Most adnexal masses during pregnancy are functional or benign, with a limited percentage (3%–6%) of malignant lesions.2 The most frequent malignant ovarian tumors in pregnancy are germ-cell tumors, followed by borderline ovarian tumors (BOTs) and epithelial ovarian cancer.3 It has been claimed that pregnancy does not worsen the prognosis of ovarian cancer, but the presence of a viable fetus calls for a balance between the optimal therapy for the mother and the lowest possible fetal toxicity. The occurrence of an adnexal mass during pregnancy poses a number of issues, including the most appropriate diagnostic workup, surgical management, and systemic treatment. As data about patients’ management are scanty and few guidelines are available, each woman should be treated within a multidisciplinary setting, after a thorough discussion of each individual case. Gestational age at diagnosis, stage of the disease, patient’s willingness to keep the pregnancy, and fetal risks secondary to maternal treatments are all factors that should be considered. The aim of this article is to review the available evidence about diagnosis and treatment of ovarian tumors during pregnancy.
All articles published from 1979 until July 2013 regarding ovarian tumors during pregnancy were extracted from Pubmed ( http://www.ncbi.nlm.nih.gov/pubmed) using the search items ovarian tumours, pregnancy; ovarian carcinoma, pregnancy; surgery, pregnancy; or chemotherapy, pregnancy. Potentially eligible articles were identified based on the evaluation of the title and abstract. Seventy-eight articles were identified.
Most pelvic masses diagnosed during pregnancy are discovered during routine fetal ultrasound.4
Ultrasound examination is safe, and an experienced examiner can confidently distinguish between benign and malignant pelvic masses on the basis of gray scale evaluation and color Doppler findings, correctly discriminating them in greater than 90% of all cases.5 The reported sensitivity and specificity for malignancies are 88% and 96%, respectively.
Simple ovarian cysts will resolve spontaneously in most cases, and they are usually treated expectantly, at least if they are not causing any symptoms.
Women with simple adnexal cysts of 5 cm or less in diameter have been managed expectantly also outside pregnancy, without any adverse effects being noted.
Large masses with multiple septa, solid components, nodules, or papillae or symptomatic masses should be further investigated,6 and surgery should be considered.
In a study by Whitecar et al,2 89 of the 91 masses diagnosed as simple cysts were confirmed to be benign at pathologic examination; all 6 malignancies in their series were correctly identified by ultrasound characteristics.
Computed tomography might clarify the extraovarian spread of the disease but exposes the fetus to at least 2 to 4 cGy, and it should be avoided during pregnancy. Magnetic resonance imaging allows accurate evaluation of large masses that are difficult to visualize with ultrasound. It can also determine whether the tumor is widespread in the abdomen and discriminate acute bowel processes, such as appendicitis and inflammatory bowel disease. Using magnetic fields and not ionizing radiation, magnetic resonance imaging is deemed safe during the whole pregnancy.3
The role of serum tumor markers during pregnancy is debated. CA125 levels increase during the first trimester, with concentrations greater than 65 IU/mL in 16% of the patients.
Thus, the usefulness of serum tumors markers during pregnancy should be carefully considered.7
When there is a low probability of malignancy, the option of watchful waiting without surgery might be considered.8 Surgical management of ovarian masses during pregnancy is indicated when the patient is at high risk of an acute abdomen, secondary to ovarian torsion or rupture. Moreover, the persistence of an adnexal mass during the second and third trimesters is considered by many authors an indication for surgery, as up to 10% of persistent ovarian masses will be ultimately diagnosed as malignant tumor s.9,10 Whenever possible, midgestation (12-27 weeks) should be elected for ovarian surgery during pregnancy, but the risk of premature delivery remains quite high, reaching 22% in some series. Surgery can be performed by laparotomy or laparoscopy.9 Laparoscopy drawbacks include possible injury to the pregnant uterus by Verres needle or trocar and the potential fetal acidosis due to carbon dioxide.11 On the other hand, laparoscopy is associated with less postoperative pain, reduced use of narcotics, and shorter hospital stay. Currently, there are no prospective studies comparing laparotomy and laparoscopy during pregnancy. However, multiple observational studies have demonstrated that laparoscopic management of adnexal masses in pregnancy is technically feasible and is associated with a lower risk of pregnancy complications.9 The ideal procedure for a suspicious adnexal mass during pregnancy is peritoneal cytology and unilateral salpingo-oophorectomy of the affected side with frozen-section analysis. Results of the frozen section should guide further surgical management.
Borderline Ovarian Tumor
The BOTs account for 10% to 20% of all ovarian malignancies. They are characterized by younger age distribution, lower stage at diagnosis, and favorable prognosis. When BOT is diagnosed, resection of the neoplasm and all macroscopic diseases is required. The macroscopically normal ovary can be left in place, as bilateral oophorectomy does not improve prognosis.
A recent series of 40 patients with diagnosis of BOT during pregnancy highlights a trend to more aggressive characteristics and higher frequency of advanced stage than in nonpregnant women. This emphasizes the need for accurate inspection of the abdominal surface and biopsy of any suspicious lesion.12
Nonepithelial Ovarian Tumor
Most patients with nonepithelial ovarian tumors (germ-cell and sex-cord stromal tumors) have bulky masses, sometimes measuring up to 30 cm.13 Nonetheless, more than 90% of the patients have stage I disease. In 1 series, 24 of the 27 patients with dysgerminoma during pregnancy were diagnosed at stage IA.13 In another series, all patients with sex-cord tumors were diagnosed at stage I, but 13 of the 36 had tumor capsule rupture during the procedure.14 Because prognosis of stage I nonepithelial tumors is good, fertility-sparing surgery is recommended.
Epithelial Ovarian Cancer
In nonpregnant patients with early-stage epithelial ovarian cancer, standard surgeries are hysterectomy and bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies, and lymph node sampling. Only young patients with early-stage lesions who are interested in subsequent pregnancies may be treated conservatively. Surgery is followed by chemotherapy for all stages except for stages IA and IB and grade 1 tumors.15
During pregnancy, hysterectomy is not possible unless the patient decides to terminate the pregnancy. If the patient chooses to continue her pregnancy, preservation of the uterus with peritoneal staging should be offered as the primary surgical treatment.
In nonpregnant patients with an advanced disease, standard surgical management consists of debulking surgery with a complete resection of all macroscopic diseases.15 In patients with unresectable disease, 3 courses of neoadjuvant chemotherapy followed by interval debulking and 3 more courses of chemotherapy should be discussed.16 During pregnancy, in most reported cases,17 patients with an advanced disease chose to terminate pregnancy, but in some patients, neoadjuvant chemotherapy has been administered.
Outside pregnancy, standard chemotherapy regimens include carboplatin plus paclitaxel with or without bevacizumab for epithelial cancer and bleomycin, cisplatin, and etoposide (BEP) for nonepithelial cancer. Preclinical data indicate that platinum derivatives are mutagenic and teratogenic,17–19 particularly during the first trimester. The risk of congenital malformations is around 10% to 20% in the first trimester but decreases to 1% to 3% thereafter. Chemotherapy administered during the second and third trimesters can be associated with preterm delivery, intrauterine growth restriction, low birth weight, and neonatal blood count reduction.20 It should not be given after the 35th week of gestation to reduce the risk of neonatal neutropenia.21,22
Cisplatin and carboplatin are highly bound to plasma proteins, and only the unbound fraction may cross the placenta. During pregnancy, lower albumin levels are observed; thus, higher levels of unbound cisplatin may be associated with higher risks of maternal and fetal toxicity. Ex vivo studies suggest that carboplatin transfer from the maternal to the fetal circulation remains very limited. In a unique pregnant baboon model, transplacental transfer of carboplatin, paclitaxel, and docetaxel has been studied. The concentration of carboplatin in the fetal plasma was half of that measured in the maternal plasma and was relatively stable. Conversely, platinum concentration in amniotic fluid gradually increased, possibly for the platinum excretion through fetal kidneys.23
Mir et al24 identified 36 articles documenting the use of cisplatin and 7 cases of patients treated with carboplatin during pregnancy: platinum-related maternal toxicity during pregnancy was described equivalent to nonpregnant women. In 1 patient treated with BEP during the second trimester, a cerebral atrophy with ventriculomegaly was reported. Other anomalies included polyhydramnios and intrauterine growth restriction in 4 and 3 cases, respectively. Moreover, neonatal creatinine elevation was reported in 1 case, suggesting that cisplatin may be nephrotoxic in the fetus. In other patients treated with BEP during pregnancy, preterm labor, myelosuppression, and neonatal alopecia were reported.25 Detectable levels of cisplatin or platinum-DNA adducts were reported in 2 newborns who were exposed to cisplatin during the third trimester and in 2 newborns exposed to carboplatin, suggesting a late transplacental transfer of these drugs.26 In 2009, an international consensus on the treatment of gynecologic cancers during pregnancy was published: authors proposed to replace BEP with paclitaxel-carboplatin or cisplatin-vinblastine-bleomycin (PVB).25 The PVB was used in some cases without maternal or fetal complications. Fetal morbidity and the potential high risk of secondary leukemia related to etoposide administration support the use of these alternative regimens in pregnant women with nonepithelial ovarian cancers. Other and more recent data support the safety of platinum analogues in pregnancy; patients were treated with cisplatin or carboplatin for ovarian cancer during pregnancy, with normal neonatal outcome, as shown in Table 1.
Paclitaxel has been used during pregnancy for breast and ovarian cancers, but long-term data are scanty. As taxanes have low molecular weight, they would be expected to easily cross the placenta. In the pregnant baboon model previously cited,23 very low levels of paclitaxel and docetaxel were detected in fetal compartments, with a concentration ratio of 1:100 in fetal and maternal plasmas, respectively. Taxanes are substrates for P-glycoprotein, a placental transporter that highly reduces placental transfer, limiting the drug concentration in fetal tissue.
Cardonick et al27 reported data of 15 women treated with taxanes during pregnancy, 12 with a diagnosis of breast cancer and 3 with a diagnosis of ovarian cancer. In 2 patients, there was a preterm delivery secondary to preeclampsia. Three newborns had a weight at delivery below the 10th percentile, and a hypertrophic pyloric stenosis was diagnosed in 1 infant. Even if the treated patients were few, apparently, there were no statistically significant differences in obstetric and neonatal outcomes in pregnant women treated with taxane-based regimen compared with other chemotherapeutic agents.
Smith et al28 published a case report of a pregnant woman with ovarian cancer treated from the 14th week of gestation with intraperitoneal carboplatin along with systemic paclitaxel. At 32 weeks, the patient developed mild preeclampsia and thrombocytopenia, and at birth, bilateral talipes equinovarus was described.
From these data, it clearly seems that the use of chemotherapy during pregnancy should be thoroughly discussed for the potential risk of fetal damage and potential pregnancy complications.29Table 1 reports a summary of all ovarian cancer patients treated with chemotherapy during pregnancy.
Aviles and Neri18 reported the long-term outcomes of 84 children whose mothers received chemotherapy during gestation. All children reached adequate learning and educational performance in the long-term follow-up. A multicenter study by Amant et al30 showed normal cardiologic and neurologic development in 70 children treated with different chemotherapy regimens in the uterus. Median gestational age at birth was 35.5 weeks, with a birth weight under the 10th percentile in 14 of the 70 children. The incidence of fetal malformations was similar to the general population. Neonatal neurologic examination was normal in 91% of the babies with transient anomalies (hypotonia, contracture). After a median follow-up of 22.3 months, a normal cognitive development was reported for most children, with a prevalence of lower performances mainly in the preterm group. No structural cardiac defect nor conduction abnormalities were detected.
Few data are available about monoclonal antibodies treatment during pregnancy. Bevacizumab, the VEGF-specific monoclonal antibody indicated for advanced epithelial ovarian cancer, is assigned to pregnancy category C by the FDA for its teratogenic effect in animal models. No reports on the use of bevacizumab in pregnant ovarian cancer patients have been published; thus, it should not be administered during pregnancy.31
Ovarian tumors in pregnancy are rare, and a multidisciplinary approach involving oncologists, gynecologists, pathologist, perinatologist, and psychologists is necessary to define the most adequate treatment strategy. Therapeutic choices should consider both maternal and fetal well-being, whenever possible. Surgery can be performed during pregnancy, ideally at midgestation and by a laparoscopic approach. Benign pelvic masses and BOTs are treated by surgery alone. Data suggest that chemotherapy can be administered during the second and third trimesters, but close monitoring of pregnancy course and fetal growth remain mandatory. Carboplatin- and paclitaxel-based regimens should be chosen for epithelial ovarian cancer, whereas BEP, PVB, and carboplatin-paclitaxel can be considered for nonepithelial ovarian cancer.
As malignant ovarian tumors during pregnancy are rare, patients should be referred to centers with specific experience and to cooperative registries ( www.cancerinpregnancy.org).
1. Peccatori FA, Azim HA, Orecchia R, et al. Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 .
2. Whitecar P, Turner S, Higby K. Adnexal masses in pregnancy: a review of 130 cases undergoing surgical management. Am J Obstet Gynecol. 1999; 181: 19–24.
3. Morice P, Uzan C, Gouy S, et al. Gynaecological cancers in pregnancy. Lancet. 2012; 379: 558–569.
4. Yazbek J, Salim R, Woelfer B, et al. The value of ultrasound visualization of the ovaries during the routine 11–14 weeks nuchal translucency scan. Eur J Obstet Gynecol Reprod Biol. 2007; 132: 154–158.
5. Kaijser J, Bourne T, Valentin L, et al. Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumor Analysis (IOTA) studies. Ultrasound Obstet Gynecol. 2013; 41: 9–20.
6. Valentin L, Hagen B, Tingulstad S, et al. Comparison of “pattern recognition” and logistic regression models for discrimination between benign and malignant pelvic masses: a prospective cross validation. Ultrasound Obstet Gynecol. 2001; 18: 357–365.
7. Han SN, Lotgerink A, Gziri MM, et al. Physiologic variations of serum tumor markers in gynaecological malignancies during pregnancy: a systematic review. BMC Med. 2012; 10: 86
8. Schmeler K, Mayo-Smith W, Peipert J, et al. Adnexal masses in pregnancy: surgery compared with observation. Obstet Gynecol. 2005; 105: 1098–1103.
9. Mathevet P, Nessah K, Mellier G. Laparoscopic management of adnexal masses in pregnancy: a case series. Eur J Obstet Gyncol Biol. 2003; 108: 217–222.
10. Sherard GB III, Hodson CA, Williams HJ, et al. Adnexal masses and pregnancy: a 12-year experience. Am J Obstet Gynecol. 2003; 189: 358–362.
11. Whiteside J, Keup H. Laparoscopic management of the ovarian mass: practical approach. Clin Obstet Gynecol. 2009; 53: 327–334.
12. Fauvet R, Brzakowski M, Morice P, et al. Borderline ovarian tumors diagnosed during pregnancy exhibit a high incidence of aggressive features: results of a French multicenter study. Ann Oncol. 2012; 23: 1481–1487.
13. Karlen JR, Akbari A, Cook WA. Dysgerminoma associated with pregnancy. Obstet Gynecol. 1979; 53: 330–335.
14. Young RH, Dudley AG, Scully RE. Granulosa cell, Sertoli-Leydig cell, and unclassified sex cord-stromal tumors associated with pregnancy: a clinicopathological analysis of thirty-six cases. Gynecol Oncol. 1984; 18: 181–205.
15. Colombo N, Peiretti M, Parma G, et al. for the ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010; 21:(suppl 5): v23–v30.
16. Vergote I, Tropé CG, Amant F, et al. for the European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group and NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010; 363: 943–953.
17. Behtash N, Karimi Zarchi M, Modares Gilani M. Ovarian carcinoma associated with pregnancy: a clinicopathologic analysis of 23 cases and review of the literature. BMC Pregnancy Childbirth. 2008; 8: 3
18. Aviles A, Neri N. Haemathological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymphoma. 2001; 2: 173–177.
19. Kai S, Kohmura H, Ishikawa K, et al. Teratogenic effects of carboplatin, an oncostatic drug, administered during the early organogenetic period in rats. J Toxicol Sci. 1989; 14: 115–130.
20. Dekrem J, Van Calsteren K, Amant F. Effects of fetal exposure to maternal chemotherapy. Pedriatr Drugs. 2013; 15: 329–334.
21. Van Calsteren K, Heyns L, De Smet F, et al. Cancer during pregnancy: an analysis of 215 patients emphasizing the obstetrical and the neonatal outcomes. J Clin Oncol. 2010; 28: 683
22. Cardonick E, Usmani A, Ghaffar S. Perinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy: results of an international registry. Am J Clin Oncol. 2010; 33: 221–228.
23. Van Calsteren K, Verbesselt R, Devlieger R, et al. Transplacental transfer of paclitaxel, docetaxel, carboplatin and trastuzumab in a baboon model. Int J Gynecol Cancer. 2010; 20: 1456–1464.
24. Mir O, Berveiller P, Ropert S, et al. Use of platinum derivatives during pregnancy. Cancer. 2008; 11: 3069–3074.
25. Amant F, Van Calsteren K, Halaska MJ, et al. Gynecologic cancers in pregnancy: guidelines of an international consensus meeting. Int J Gynecol Cancer. 2009; 19: S1–S2.
26. Marnitz S, Kohler C, Oppelt P, et al. Cisplatin application in pregnancy: first in vivo analysis of 7 patients. Oncology. 2010; 79: 72–77.
27. Cardonick E, Bhat A, Gilmandyar D, et al. Maternal and fetal outcomes of taxanes chemotherapy in breast and ovarian cancer during pregnancy: case series and review of the literature. Ann Oncol. 2012; 23: 3016–3023.
28. Smith E, Borowsky ME, Dharan Jain V. Intraperitoneal chemotherapy in a pregnant woman with ovarian cancer. Obstet Gynecol. 2013; 122: 481–483.
29. Marret H, Lhommè C, Lecuru F, et al. Guidelines for the management of ovarian cancer during pregnancy. Eur J Obstet Gynecol. 2010; 149: 18–21.
30. Amant F, Van Calsteren K, Halaska MJ, et al. Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. Lancet Oncol. 2012; 13: 256–264.
31. Sarno MA, Mancari R, Azim HA, et al. Are monoclonal antibodies a safe treatment for cancer during pregnancy? Immunotherapy. 2013; 5: 733–741.