European Journal of Obstetrics & Gynecology and Reproductive Biology 186 (2015) 97–105
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Feto-maternal outcomes of pregnancy complicated by epithelial ovarian cancer: a systematic review of literature Erin A. Blake a,1, Michiko Kodama b,1, Mayu Yunokawa c, Malcolm S. Ross d, Yutaka Ueda b, Brendan H. Grubbs e, Koji Matsuo f,g,* a
Department of Obstetrics and Gynecology, University of Colorado, CO, USA Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan d Department of Obstetrics and Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA e Maternal-Fetal Medicine, and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA f Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA g Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA12 b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 September 2014 Received in revised form 31 December 2014 Accepted 13 January 2015
Although cancer diagnosed during pregnancy is rare, epithelial cell type ovarian cancers (EOCs) comprise approximately one quarter to one half of cases of ovarian malignancy diagnosed during pregnancy. The behavior of EOC during pregnancy and its implications for maternal and fetal outcomes is not well understood. In order to better define these outcomes, a systematic literature search was conducted in PubMed/MEDLINE using entry keywords ‘‘pregnancy’’ and ‘‘ovarian cancer’’ for the period from 1955 to 2013. The literature search identified 105 cases eligible for analysis. Clinical characteristics, pregnancy outcome, tumor characteristics, clinical management, and survival outcomes were all evaluated. Serious adverse events were defined as complications related to EOC that resulted in severe morbidity or mortality for the mother and/or fetus. The mean age of cases was 31.6 years. The most common histology was serous (47.6%), followed by mucinous (27.6%) and endometrioid types (10.5%). The most common presenting symptom was abdominal or pelvic pain (26.7%) while incidentally detected tumors accounted for one third of cases. The majority of cases were stage I at diagnosis (63.8%) followed by stage III disease (24.8%), and the median tumor size was 12 cm. Live births occurred in 81.3% of cases, and of the remainder 72.2% were due to elective termination. Intrapartum surgery primarily took place in the second trimester (43%) with fetal conservation in 61.9% of operations. Over half of cases received chemotherapy (55.2%), approximately one third of which received it during the pregnancy (36.2%). Among the 21 cases treated with chemotherapy during pregnancy, there was no association with small for gestational age or fetal malformations. Serious adverse events occurred in 21.9% of cases, of which the most common was tumor rupture during pregnancy (10.5%). Three (2.9%) maternal death following surgery during pregnancy and five (6.4%) neonatal deaths were reported. Gestational age at tumor diagnosis (2-year overall survival rate, 1st trimester 94.6%, 2nd trimester 88.8%, and 3rd trimester 72.9%, p = 0.041) type of histology (serous 88.1%, mucinous 84.6%, endometrioid 89.5%, clear cell 100%, mixed type 75.0%, and undifferentiated 30.0%, p < 0.01), stage (stage I 96.9%, stage II 85.7%, stage III 56.3%, and stage IV 25.0%, p < 0.01), and serious adverse events (yes versus no, 68.1% versus 92.2%, p = 0.041) were significantly related to maternal overall survival in univariate analysis. In multivariate analysis, stage III/ IV disease remained the independent prognostic factor associated with decreased maternal overall survival (stage III, hazard ratio 44.6, p < 0.01; and stage IV, hazard ratio 399, p < 0.01). In conclusion, although the majority of EOC cases during pregnancy resulted in live birth, maternal and neonatal mortality needs to be considered in the counseling and management of these pregnancies. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Epithelial ovarian cancer Ovarian cancer Pregnancy Review
* Corresponding authorat: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California 2020 Zonal Avenue, IRD520, Los Angeles, CA 90033, USA. Tel.: +1 323 226 3416; fax: +1 323 226 3427. E-mail address: [email protected] (K. Matsuo). 1 Authors contributed equally to the work. http://dx.doi.org/10.1016/j.ejogrb.2015.01.010 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
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E.A. Blake et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 186 (2015) 97–105
Contents Introduction . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . Source . . . . . . . . . . . . . . . . Eligibility . . . . . . . . . . . . . . Clinical information . . . . . Definition . . . . . . . . . . . . . Statistical analysis. . . . . . . Results . . . . . . . . . . . . . . . . . . . . . Clinical characteristics . . . Pregnancy outcomes . . . . . Expectant management of Oncologic outcomes . . . . . Survival outcomes. . . . . . . Discussion . . . . . . . . . . . . . . . . . . Source of the study . . . . . . . . . . . Disclosure. . . . . . . . . . . . . . . . . . . Condensation . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
......... ......... ......... ......... ......... ......... ......... ......... ......... ......... pregnancy ......... ......... ......... ......... ......... ......... .........
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Introduction
Materials and methods
Ovarian cancers remain the most deadly type of gynecologic malignancy in the United States [1,2]. While there are multiple histological subtypes of ovarian cancer, epithelial cell types are the most common variant and therefore contribute most to the morbidity and mortality attributed to ovarian malignancy [3]. Serous epithelial tumors have the highest incidence, noted to constitute approximately 70% of tumors of epithelial origin, while other subtypes comprise the remaining cases, most commonly mucinous, endometrioid, and clear cell [4,5]. Demographically, white women have the highest incidence of epithelial ovarian cancers (EOCs), with approximately 16.5 cases per 100,000 women per year being noted via data collected in a populationbased database [3]. Although nearly half of ovarian cancer cases are reported in women greater than 60 years of age, a significant percentage of cases are diagnosed in women of reproductive age [3]. EOC often presents insidiously. Manifestations are typically only noted after advanced disease is present and include pelvic or abdominal pain, bloating, decreased appetite or early satiety, and changes in bowel or bladder habits [6–8]. Cancer during pregnancy is a rare clinical entity, affecting approximately 0.1–0.2% of gravid women [9–11]. Ovarian cancer represents the fifth most common cancer to be diagnosed during pregnancy [12]. Despite the relatively low prevalence of EOC in women of reproductive age, epithelial cell types comprise approximately 25–50% of ovarian malignancies diagnosed in pregnancy [13,14]. Pregnancy is characterized by multiple physiological changes including excess endogenous sex and growth hormones, which can potentially affect the clinical course of a malignancy in unpredictable ways. The management of cancer in pregnancy is complicated by three separate but interacting entities which must be managed simultaneously: the mother, fetus, and malignancy. EOC is a rare complication of pregnancy; however, as it has the potential to be an extremely aggressive malignancy, it is imperative that its optimal management during pregnancy is defined. Questions remain about regarding how physiologic alterations during pregnancy complicate the clinical course and treatment methodologies for EOC. Furthermore, the impact of EOC on fetal outcome has yet to be completely understood. Therefore, we conducted a systematic review of the literature to delineate the characteristics and outcomes of EOC during pregnancy.
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This review was conducted based on MOOSE guideline for systematic reviews by using public search engines PubMed and MEDLINE [15]. The entry keywords used for the search were ‘‘pregnancy’’ and ‘‘ovarian cancer’’. The search was limited to articles published in English between January 1955 and November 2013. Eligibility Inclusion criteria were case reports or case series that had an adequate description for (i) clinical demographics, (ii) pregnancy outcomes, (iii) tumor characteristic, (iv) type of intervention and treatment, and (v) maternal survival outcome. References for each evaluated article were also reviewed, and the corresponding articles that met the inclusion criteria were included in the study. Excluded articles included reviews, and case reports with suboptimal description, or if the diagnoses of ovarian cancer was made either prior to the pregnancy or during the postpartum period. Clinical information Among eligible articles, the following variables were abstracted from the case description: (i) clinical demographics including year and country of publication, age at diagnosis, parity, gestational age at ovarian cancer diagnosis, and presenting symptoms; (ii) pregnancy outcomes including gestational age at delivery, route of delivery, birth weight, Apgar scores, and neonatal complications; (iii) tumor characteristics including histologic subtype, tumor laterality and size/weight, and ovarian cancer stage; (iv) type of intervention and treatment for ovarian cancer including gestational age tumor surgery, type and timing of chemotherapy, and type and timing of radiotherapy; and (v) maternal survival outcomes, including tumor recurrence during pregnancy, and overall survival (OS). Definition If the case report did not specify the exact gestational age, ‘‘early’’ and ‘‘late’’ pregnancy was defined as first and third trimester, respectively. In cases of which gestational age at delivery
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was described as ‘‘term’’, gestational age was defined as 37 week. Small for gestational age (SGA) was defined as less than the 10th percentile in birth weight. The expectant management period was determined by the duration between the initial diagnosis of ovarian cancer during pregnancy and the date of delivery. OS was defined as the time interval between the ovarian cancer diagnosis and the date of death or last follow-up. If case report described the survival time from completion of initial cancer treatment, this was properly recalculated from the initial diagnosis of ovarian cancer. Serious adverse events were defined as: any significant complication either to fetus and/or mother such as tumor rupture or torsion, obstructed labor, metastasis to fetal-placental unit, in-utero fetal demise (IUFD) after surgery, maternal death, and neonatal death or stillbirth. Ovarian cancer stage was properly re-classified based on The International Federation of Gynecology and Obstetrics staging system [16]. Cases treated with chemotherapy were grouped as follows; combination of platinum and taxane, combination of platinum, anthracycline, and cyclophosphamide, or others. The systematic review is exempt from the Institutional Review Board (IRB) approval in our institutions. Statistical analysis The normality of continuous variables were tested by Kolmogorov-Smirnov test, and described as mean (SD) or median (range) as appropriate. Fisher exact test or chi-square test was used for comparison of categorical variables as appropriate described as odds ratio (OR) and 95% confidence interval (CI). For survival analysis, Logrank test was used to determine the statistical significance for univariate analysis. Cox proportional hazard regression test was further used to identify the independent predictor of overall survival in multivariate analysis expressed as hazard ratio (HR) with 95%CI. Survival curves were constructed by the Kaplan–Meier method. Pvalues of less than 0.05 were considered statistically significant (twotailed). All statistical analyses were performed using Statistical Package for Social Scientists software (SPSS, Inc., version 12.0, Chicago, IL, USA). Results Clinical characteristics The screening process was shown in Fig. 1. Of the 3703 articles identified through the database search, 102 articles met our inclusion criteria. Upon further assessment, an additional 43 articles were removed because of an inadequate description of maternal survival outcome, unclear or non-disclosed histology, or non-ovarian primary cancer. Four articles were added after reviewing the references from the eligible articles. Finally, 63 articles including 105 cases were eligible for the study analysis [17–79]. Patient characteristics are shown in Table 1. The median age at diagnosis was 31 years (range, 19–44), and in 12.6% of cases, the patient was 40 years. Over half of the cases were nulliparous (52.9%). The most common histologic subtype was serous (47.6%), followed by mucinous (27.6%) and endometrioid (10.5%). The most common presenting symptom was abdominal or pelvic pain (26.7%) while one third were detected incidentally by physical exam, ultrasound, or at the time of Caesarean section. Pregnancy outcomes Pregnancy outcomes are shown in Table 2. Nearly half of cases were diagnosed during the first trimester (45.3%), and the majority of pregnancies resulted in live birth (81.3%). Elective abortion was the most common reason for non-viable pregnancy (72.2%). More
Fig. 1. Selection criteria of literature search. PubMed/MEDLINE were used to identify the articles with entry keywords ‘‘pregnancy’’ and each type of ovarian malignant germ cell tumor. Abbreviations: LMP, low malignant potential; ref., reference.
than half of cases (57.7%) delivered at term, and the majority of births were via Caesarean section (71.6%). The median birth weight was 2725 g (range, 600–4140) and 26.5% of the neonates were classified as SGA. Among cases that received in-utero chemotherapy (n = 21) (Table 3), there was no statistical association with SGA (chemotherapy versus non-chemotherapy, 19.0% versus 12.9%, OR 1.59, 95%CI 0.35–7.21, p = 0.70). There was one case of fetal ventriculomegaly diagnosed prior to the initiation of in-utero chemotherapy at 20 weeks gestation [61]; however, neonatal malformations related to in-utero chemotherapy were not reported. Serious adverse events occurred in 21.9% cases, with the most common being rupture of the tumor during pregnancy (10.5%). Five (6.4%) neonatal deaths were described with the following causes; three prematurity, one meconium aspiration syndrome, with no description provided in the remaining case [24,27,59,63,65,74]. One stillbirth at 25 weeks gestation was attributed to intrauterine infection one week after surgery. The mother in this case had stage IV poorly differentiated adenocarcinoma and died of severe sepsis 2 weeks after delivery. Furthermore, the tumor had metastasized to the central nervous system and placenta [59]. In total,three (2.9%) maternal deaths during pregnancy were reported. Of those two (both stage III), one died of ileus, infection and respiratory dysfunction 2 weeks after surgery [21], and the other died a week after surgery due to an unspecified cause [63]. Expectant management of pregnancy Pregnancy was managed expectantly in 59 cases (56.2%) with a median duration of 19 weeks (range, 1–33). The proportions of pregnancy undergoing expectant management were 72.1%, 70.8%, and 35.7%, in the first, second, and third trimesters at the time of cancer diagnosis, respectively (p < 0.01). The median duration of expectant management for pregnancy when the mass was
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Table 1 Demographics of pregnancy complicated by epithelial ovarian cancer. Number Year of publication 1955–1979 1980–1999 2000–2013 Area of publication Asia North America Europe Others Age
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Review
Feto-maternal outcomes of pregnancy complicated by epithelial ovarian cancer: a systematic review of literature Erin A. Blake a,1, Michiko Kodama b,1, Mayu Yunokawa c, Malcolm S. Ross d, Yutaka Ueda b, Brendan H. Grubbs e, Koji Matsuo f,g,* a
Department of Obstetrics and Gynecology, University of Colorado, CO, USA Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan d Department of Obstetrics and Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA e Maternal-Fetal Medicine, and Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA f Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA g Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA12 b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 September 2014 Received in revised form 31 December 2014 Accepted 13 January 2015
Although cancer diagnosed during pregnancy is rare, epithelial cell type ovarian cancers (EOCs) comprise approximately one quarter to one half of cases of ovarian malignancy diagnosed during pregnancy. The behavior of EOC during pregnancy and its implications for maternal and fetal outcomes is not well understood. In order to better define these outcomes, a systematic literature search was conducted in PubMed/MEDLINE using entry keywords ‘‘pregnancy’’ and ‘‘ovarian cancer’’ for the period from 1955 to 2013. The literature search identified 105 cases eligible for analysis. Clinical characteristics, pregnancy outcome, tumor characteristics, clinical management, and survival outcomes were all evaluated. Serious adverse events were defined as complications related to EOC that resulted in severe morbidity or mortality for the mother and/or fetus. The mean age of cases was 31.6 years. The most common histology was serous (47.6%), followed by mucinous (27.6%) and endometrioid types (10.5%). The most common presenting symptom was abdominal or pelvic pain (26.7%) while incidentally detected tumors accounted for one third of cases. The majority of cases were stage I at diagnosis (63.8%) followed by stage III disease (24.8%), and the median tumor size was 12 cm. Live births occurred in 81.3% of cases, and of the remainder 72.2% were due to elective termination. Intrapartum surgery primarily took place in the second trimester (43%) with fetal conservation in 61.9% of operations. Over half of cases received chemotherapy (55.2%), approximately one third of which received it during the pregnancy (36.2%). Among the 21 cases treated with chemotherapy during pregnancy, there was no association with small for gestational age or fetal malformations. Serious adverse events occurred in 21.9% of cases, of which the most common was tumor rupture during pregnancy (10.5%). Three (2.9%) maternal death following surgery during pregnancy and five (6.4%) neonatal deaths were reported. Gestational age at tumor diagnosis (2-year overall survival rate, 1st trimester 94.6%, 2nd trimester 88.8%, and 3rd trimester 72.9%, p = 0.041) type of histology (serous 88.1%, mucinous 84.6%, endometrioid 89.5%, clear cell 100%, mixed type 75.0%, and undifferentiated 30.0%, p < 0.01), stage (stage I 96.9%, stage II 85.7%, stage III 56.3%, and stage IV 25.0%, p < 0.01), and serious adverse events (yes versus no, 68.1% versus 92.2%, p = 0.041) were significantly related to maternal overall survival in univariate analysis. In multivariate analysis, stage III/ IV disease remained the independent prognostic factor associated with decreased maternal overall survival (stage III, hazard ratio 44.6, p < 0.01; and stage IV, hazard ratio 399, p < 0.01). In conclusion, although the majority of EOC cases during pregnancy resulted in live birth, maternal and neonatal mortality needs to be considered in the counseling and management of these pregnancies. ß 2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Epithelial ovarian cancer Ovarian cancer Pregnancy Review
* Corresponding authorat: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California 2020 Zonal Avenue, IRD520, Los Angeles, CA 90033, USA. Tel.: +1 323 226 3416; fax: +1 323 226 3427. E-mail address: [email protected] (K. Matsuo). 1 Authors contributed equally to the work. http://dx.doi.org/10.1016/j.ejogrb.2015.01.010 0301-2115/ß 2015 Elsevier Ireland Ltd. All rights reserved.
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E.A. Blake et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 186 (2015) 97–105
Contents Introduction . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . Source . . . . . . . . . . . . . . . . Eligibility . . . . . . . . . . . . . . Clinical information . . . . . Definition . . . . . . . . . . . . . Statistical analysis. . . . . . . Results . . . . . . . . . . . . . . . . . . . . . Clinical characteristics . . . Pregnancy outcomes . . . . . Expectant management of Oncologic outcomes . . . . . Survival outcomes. . . . . . . Discussion . . . . . . . . . . . . . . . . . . Source of the study . . . . . . . . . . . Disclosure. . . . . . . . . . . . . . . . . . . Condensation . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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Introduction
Materials and methods
Ovarian cancers remain the most deadly type of gynecologic malignancy in the United States [1,2]. While there are multiple histological subtypes of ovarian cancer, epithelial cell types are the most common variant and therefore contribute most to the morbidity and mortality attributed to ovarian malignancy [3]. Serous epithelial tumors have the highest incidence, noted to constitute approximately 70% of tumors of epithelial origin, while other subtypes comprise the remaining cases, most commonly mucinous, endometrioid, and clear cell [4,5]. Demographically, white women have the highest incidence of epithelial ovarian cancers (EOCs), with approximately 16.5 cases per 100,000 women per year being noted via data collected in a populationbased database [3]. Although nearly half of ovarian cancer cases are reported in women greater than 60 years of age, a significant percentage of cases are diagnosed in women of reproductive age [3]. EOC often presents insidiously. Manifestations are typically only noted after advanced disease is present and include pelvic or abdominal pain, bloating, decreased appetite or early satiety, and changes in bowel or bladder habits [6–8]. Cancer during pregnancy is a rare clinical entity, affecting approximately 0.1–0.2% of gravid women [9–11]. Ovarian cancer represents the fifth most common cancer to be diagnosed during pregnancy [12]. Despite the relatively low prevalence of EOC in women of reproductive age, epithelial cell types comprise approximately 25–50% of ovarian malignancies diagnosed in pregnancy [13,14]. Pregnancy is characterized by multiple physiological changes including excess endogenous sex and growth hormones, which can potentially affect the clinical course of a malignancy in unpredictable ways. The management of cancer in pregnancy is complicated by three separate but interacting entities which must be managed simultaneously: the mother, fetus, and malignancy. EOC is a rare complication of pregnancy; however, as it has the potential to be an extremely aggressive malignancy, it is imperative that its optimal management during pregnancy is defined. Questions remain about regarding how physiologic alterations during pregnancy complicate the clinical course and treatment methodologies for EOC. Furthermore, the impact of EOC on fetal outcome has yet to be completely understood. Therefore, we conducted a systematic review of the literature to delineate the characteristics and outcomes of EOC during pregnancy.
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This review was conducted based on MOOSE guideline for systematic reviews by using public search engines PubMed and MEDLINE [15]. The entry keywords used for the search were ‘‘pregnancy’’ and ‘‘ovarian cancer’’. The search was limited to articles published in English between January 1955 and November 2013. Eligibility Inclusion criteria were case reports or case series that had an adequate description for (i) clinical demographics, (ii) pregnancy outcomes, (iii) tumor characteristic, (iv) type of intervention and treatment, and (v) maternal survival outcome. References for each evaluated article were also reviewed, and the corresponding articles that met the inclusion criteria were included in the study. Excluded articles included reviews, and case reports with suboptimal description, or if the diagnoses of ovarian cancer was made either prior to the pregnancy or during the postpartum period. Clinical information Among eligible articles, the following variables were abstracted from the case description: (i) clinical demographics including year and country of publication, age at diagnosis, parity, gestational age at ovarian cancer diagnosis, and presenting symptoms; (ii) pregnancy outcomes including gestational age at delivery, route of delivery, birth weight, Apgar scores, and neonatal complications; (iii) tumor characteristics including histologic subtype, tumor laterality and size/weight, and ovarian cancer stage; (iv) type of intervention and treatment for ovarian cancer including gestational age tumor surgery, type and timing of chemotherapy, and type and timing of radiotherapy; and (v) maternal survival outcomes, including tumor recurrence during pregnancy, and overall survival (OS). Definition If the case report did not specify the exact gestational age, ‘‘early’’ and ‘‘late’’ pregnancy was defined as first and third trimester, respectively. In cases of which gestational age at delivery
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was described as ‘‘term’’, gestational age was defined as 37 week. Small for gestational age (SGA) was defined as less than the 10th percentile in birth weight. The expectant management period was determined by the duration between the initial diagnosis of ovarian cancer during pregnancy and the date of delivery. OS was defined as the time interval between the ovarian cancer diagnosis and the date of death or last follow-up. If case report described the survival time from completion of initial cancer treatment, this was properly recalculated from the initial diagnosis of ovarian cancer. Serious adverse events were defined as: any significant complication either to fetus and/or mother such as tumor rupture or torsion, obstructed labor, metastasis to fetal-placental unit, in-utero fetal demise (IUFD) after surgery, maternal death, and neonatal death or stillbirth. Ovarian cancer stage was properly re-classified based on The International Federation of Gynecology and Obstetrics staging system [16]. Cases treated with chemotherapy were grouped as follows; combination of platinum and taxane, combination of platinum, anthracycline, and cyclophosphamide, or others. The systematic review is exempt from the Institutional Review Board (IRB) approval in our institutions. Statistical analysis The normality of continuous variables were tested by Kolmogorov-Smirnov test, and described as mean (SD) or median (range) as appropriate. Fisher exact test or chi-square test was used for comparison of categorical variables as appropriate described as odds ratio (OR) and 95% confidence interval (CI). For survival analysis, Logrank test was used to determine the statistical significance for univariate analysis. Cox proportional hazard regression test was further used to identify the independent predictor of overall survival in multivariate analysis expressed as hazard ratio (HR) with 95%CI. Survival curves were constructed by the Kaplan–Meier method. Pvalues of less than 0.05 were considered statistically significant (twotailed). All statistical analyses were performed using Statistical Package for Social Scientists software (SPSS, Inc., version 12.0, Chicago, IL, USA). Results Clinical characteristics The screening process was shown in Fig. 1. Of the 3703 articles identified through the database search, 102 articles met our inclusion criteria. Upon further assessment, an additional 43 articles were removed because of an inadequate description of maternal survival outcome, unclear or non-disclosed histology, or non-ovarian primary cancer. Four articles were added after reviewing the references from the eligible articles. Finally, 63 articles including 105 cases were eligible for the study analysis [17–79]. Patient characteristics are shown in Table 1. The median age at diagnosis was 31 years (range, 19–44), and in 12.6% of cases, the patient was 40 years. Over half of the cases were nulliparous (52.9%). The most common histologic subtype was serous (47.6%), followed by mucinous (27.6%) and endometrioid (10.5%). The most common presenting symptom was abdominal or pelvic pain (26.7%) while one third were detected incidentally by physical exam, ultrasound, or at the time of Caesarean section. Pregnancy outcomes Pregnancy outcomes are shown in Table 2. Nearly half of cases were diagnosed during the first trimester (45.3%), and the majority of pregnancies resulted in live birth (81.3%). Elective abortion was the most common reason for non-viable pregnancy (72.2%). More
Fig. 1. Selection criteria of literature search. PubMed/MEDLINE were used to identify the articles with entry keywords ‘‘pregnancy’’ and each type of ovarian malignant germ cell tumor. Abbreviations: LMP, low malignant potential; ref., reference.
than half of cases (57.7%) delivered at term, and the majority of births were via Caesarean section (71.6%). The median birth weight was 2725 g (range, 600–4140) and 26.5% of the neonates were classified as SGA. Among cases that received in-utero chemotherapy (n = 21) (Table 3), there was no statistical association with SGA (chemotherapy versus non-chemotherapy, 19.0% versus 12.9%, OR 1.59, 95%CI 0.35–7.21, p = 0.70). There was one case of fetal ventriculomegaly diagnosed prior to the initiation of in-utero chemotherapy at 20 weeks gestation [61]; however, neonatal malformations related to in-utero chemotherapy were not reported. Serious adverse events occurred in 21.9% cases, with the most common being rupture of the tumor during pregnancy (10.5%). Five (6.4%) neonatal deaths were described with the following causes; three prematurity, one meconium aspiration syndrome, with no description provided in the remaining case [24,27,59,63,65,74]. One stillbirth at 25 weeks gestation was attributed to intrauterine infection one week after surgery. The mother in this case had stage IV poorly differentiated adenocarcinoma and died of severe sepsis 2 weeks after delivery. Furthermore, the tumor had metastasized to the central nervous system and placenta [59]. In total,three (2.9%) maternal deaths during pregnancy were reported. Of those two (both stage III), one died of ileus, infection and respiratory dysfunction 2 weeks after surgery [21], and the other died a week after surgery due to an unspecified cause [63]. Expectant management of pregnancy Pregnancy was managed expectantly in 59 cases (56.2%) with a median duration of 19 weeks (range, 1–33). The proportions of pregnancy undergoing expectant management were 72.1%, 70.8%, and 35.7%, in the first, second, and third trimesters at the time of cancer diagnosis, respectively (p < 0.01). The median duration of expectant management for pregnancy when the mass was
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Table 1 Demographics of pregnancy complicated by epithelial ovarian cancer. Number Year of publication 1955–1979 1980–1999 2000–2013 Area of publication Asia North America Europe Others Age
