As more women continue to further delay childbearing, the number of women who experience the diagnosis of cancer before pregnancy is also expected to increase because of the higher rate of cancer diagnosis in advanced maternal age group. The average maternal age at first pregnancy continue to advance in the United States (from 21.4 years in 1970 to 25.4 years in 2010).1,2 It is estimated that approximately 47,000 cases of reproductive cancers occurred annu ally among women younger than 40 years in the United States.3 Higher remission and long-term survival rates are now possible with aggressive chemotherapy, radiotherapy, and radical oncological surgery, but these treatments often cause infertility. Nevertheless, the increasing use of fertility sparing operations and fertility preservation strategies are making possible for many of these women to become pregnant.4,5
A comprehensive review of articles published from 1994 to 2005 found that the fertility outcomes of women survivors of reproductive cancer who received conservative treatment vary by cancer type.4 For ovarian cancer (all histological types), a total of 494 subsequent pregnancies had been reported. Among patients with cervical carcinoma who were treated with radical vaginal trachelectomy, a total of 190 pregnancies had been reported. A total of 50 pregnancies/live births have been reported among patients treated conservatively (i.e., progestins) for endometrial carcinoma. Clearly, there is a growing population of young cancer survivors with preserved fertility, which poses concerns about potential adverse effects of cancer and cancer therapy on infants born to women survivors of reproductive cancers.6
In a previous population-based retrospective cohort study, using linked maternal-newborn data from the state of Florida, we found that pregnant women who had a diagnosis of reproductive cancer had a 24% and 33% elevated risk for low birth weight (LBW) and preterm birth (PTB) infants, respectively, when compared with women without such diagnosis. On the other hand, the literature on the association between maternal reproductive cancers and fetal outcomes have not determined clearly the relationship between specific reproductive cancers and fetal outcomes, particularly LBW, PTB, and small size for gestational age. Thus, the objective of this review was to examine the evidence linking selected adverse fetal outcomes with maternal reproductive cancers.
We searched PubMed and Web of Knowledge to identify peer-reviewed articles published between January 1992 and December 2012, investigating the association between reproductive cancer and adverse birth outcomes. The search was restricted to English language and humans only. Our focus was on the following reproductive cancers: cervix uteri, uterine corpus, ovary, and fallopian tube. We focused on 3 primary adverse live birth outcomes: LBW, PTB, and small size for gestational age. We excluded pregnancy-related cancers, concurrent cancer treated during pregnancy, breast cancer, cervical precancerous lesions, and survivors to nongynecological childhood cancers. We searched the following combination of key terms: (1) ovarian/ovaries OR fallopian tubes/oviducts/uterine tubes/salpinges OR uterine/uterus/endometrial OR vaginal/vagina OR cervical/cervix OR vulvar /vulva; (2) cancer OR malignancy OR neoplasm OR neoplasia; (3) 1 AND 2; (4) birth outcomes OR pregnancy outcome OR fetal outcome OR preterm birth OR low birth weight OR small for gestational age; and finally, (5) 3 AND 4. In the review, we did not search terms related to feto-infant mortality outcomes (such as miscarriage, fetal loss, stillbirth, and neonatal demise), but we noted these outcomes when they were reported as secondary outcomes.
PubMed provided 2871 records, and Web of Knowledge provided 1629. After removing duplicates (584 duplicates), 3916 article titles were screened using recommended procedures with the reference manager software Endnote X6.7 A total of 215 abstracts were reviewed. The majority of the excluded studies were: single case reports, editorials, commentaries, studies on non-malignant tumors, studies on non-reproductive cancers, concurrent gynecological cancers treated during pregnancy, and studies that didn’t include the outcomes of interest in this review. Back references identified 3 studies for full-text review. A total of 49 full-text articles were examined by 2 reviewers independently to assess specifically the exposures and outcomes of interest. The quality of the studies was assessed based on the reliability of the methods used for exposure and outcome measurement (eg, clinical diagnosis of cancer), potential of biases in the study, and evidence for causation using Hills criteria. Differences in selection were resolved by consensus, with a third reviewer available for clarification. This step resulted in a total of 36 articles that were finally retained for the review. Because the reported measure of association and study designs differed across the reviewed studies, it was not feasible to calculate a common measure of effect. Figure 1 depicts the details of the search and selection process.
Among the 36 studies selected for the review, we found 13 cervical cancer studies, 16 ovarian cancer studies, and 7 corpus uteri cancers, which reported a total of 6888 subsequent pregnancies in 477 women. Of these pregnancies, 489 pregnancies reached third trimester (referred as viable pregnancies). Among viable pregnancies, only 416 pregnancies had information on maturity status based on gestational age and/or birth weight (n = 416). For those with cervical cancer, the PTB rate was 48.5%. For those with ovarian cancer, there were no cases of PTB. For those with corpus uteri cancers, the PTB was 7.7%. However, studies have small sample sizes, and there is considerable heterogeneity of results. All the studies were early-stage cancers that received fertility sparing treatments. Additional information about study design features are provided in the supplemental table (Supplement Digital Content 1, available at http://links.lww.com/IGC/A168).
Cervical Cancer and Fetal Outcomes
All the studies on cervical cancer included women who had conservative or radical procedures for early stages of cervical cancer. We included 13 studies that assessed early cervical carcinoma treated with fertility preserving radical trachelectomy.8–20 Table 1 summarizes birth outcomes for cervical cancer. A total of 375 pregnancies occurred in 265 women, resulting in 249 live births (viable pregnancies). There were 120 term and 113 preterm deliveries (calculated PTB rate of 48.5 per 100 live births). Besides preterm delivery, studies included in this review also reported other adverse outcomes including abortion, termination, ectopic pregnancy, and still birth (Table 1). However, we could not report rates of these outcomes as we do not have data on the denominator to calculate the rates. Denominators for these outcomes were not available and rates for these. In addition, 3 studies had ongoing pregnancies at the time of publication.14,18,20 One study20 reported 16 third-trimester deliveries but did not specify the maturity status of the newborns.
Ovarian Cancer and Fetal Outcomes
We found 16 ovarian cancer studies that reported feto-infant morbidity outcomes, which were mainly case series studies.21–36 As a result, the findings of these studies were limited to numbers and/or percentages of the occurrence of adverse events of interest. Table 2 presents information on birth outcome for women who received fertility preserving surgery for ovarian cancer. There were 275 pregnancies in 182 women, resulting in 206 live births. Among those studies that reported viable pregnancies and maturity status, there were 157 term deliveries (no cases of PTB or LBW identified). One study26 did not report on the viability for 14 conceptions. In addition, 5 studies21,23,24,29,30 did not report maturity status for 49 viable pregnancies. In such cases, we could not assess if preterm deliveries occurred (outcomes reported as third-trimester deliveries). Other adverse outcomes such as abortions, ectopic pregnancies, congenital malformations were reported (Table 2). Three studies had ongoing pregnancies at the time of publication.29,30,33
Corpus Uteri Cancer and Fetal Outcomes
We found 7 studies that reported pregnancy outcomes among patients with endometrial carcinoma who received conservative treatment with progestins.37–43 Table 3 summarizes birth outcomes for survivors of uterine cancer who received fertility preserving surgery. In the 7 studies included in the review, a total of 38 pregnancies were reported in 30 women, which resulted in 34 live births (viable pregnancies). Two studies did not report maturity status (cumulative for 8 newborns), for which was not possible to determine preterm deliveries or LBW. Among the 5 studies that reported gestational age (cumulative 26 live births), there were 24 full-term babies and 2 preterm infants. We did not find studies that reported fetal outcomes based on gestational age and birth weight among survivors of fallopian tubes cancers.
Few epidemiological studies examined the effect or reproductive cancers on adverse infant outcomes. We found various studies that reported a number of adverse birth outcomes, which suggest a possible association between reproductive cancer and subsequent adverse fetal outcomes. However, the quality of most studies that examined this relationship is poor, making the evidence inconclusive. Concerns that are common to all studies included small samples with low statistical power (some studies include report outcomes for 2 or 3 cases), possibility of publication bias (possibility that normal outcomes are less likely to be published), misclassification of outcomes (some preterm deliveries mixed with “third-trimester deliveries” in studies that did not report gestational age), and biological plausibility of the association with LBW, preterm, and small for gestational age births.
We decided to limit our review to articles published in the past 20 years in an attempt to avoid studies that relied on old ways of cancer classification, diagnosis, and management. However, studies with no association are less likely to be published, and studies published in languages other than English are not included in this review. Another important limitation of the review was the exclusion of studies that assessed pregnancy outcomes among gynecological cancer survivors that only reported third-trimester live births rates with no information on perinatal morbidity (eg, gestational age, birth weight).
Identification of Reproductive Cancer
Some studies relied on routine ultrasound examination, whereas others used cytological studies. On the other hand, observational studies that used administrative data set relied fully on International Classification of Diseases codes to determine subjects with reproductive cancer.
Almost all of the studies under this review did not explain the biological mechanisms for the effect of reproductive cancer on fetal outcomes. In this context, it is important to note that all patients included in the review received conservative treatments and attempted subsequent conceptions with variable success rate. This situation makes it very difficult to disentangle the effects of either cancer or its treatment on fertility and subsequent pregnancy outcomes. Understanding the exact biological mechanism of how diagnosis of reproductive cancer before pregnancy results in adverse birth outcomes is critical to design strategies that minimize its bearings on fetal outcomes.
Although we found some evidence that suggest a relationship between reproductive cancer treated conservatively and adverse fetal birth outcomes, the existing evidence does not allow precise identification of the different stages of cancers, their timing of diagnosis in relation to the impacted pregnancy, and neither moderator nor confounding effects of underlying risk factors. Available studies are underpowered because of to small samples, which preclude meaningful assessments of potential confounding factors. It is essential that we understand whether these adverse effects are principally due to personal characteristics (maternal age, parity, intrapersonal risk factors) or other factors such as exposure to carcinogens, radiation, chemotherapy, surgical modifications, or combination of all these.
Studies on the same type of cancer also differ by the fetal outcomes (some reporting term deliveries vs preterm, whereas others do not report maturity status). For instance, cervical cancer seems to result in an important proportion of adverse fetal outcomes (namely PTB and others); however, the proportion of adverse outcomes reported may be inflated or underestimated by misclassification (preterm deliveries overlooked, not reported, or lumped into third-trimester delivery together with term deliveries). Although studies of ovarian cancer reported no preterm deliveries, significant number of these studies did not report maturity status. On the other hand, studies of ovarian cancer reported a number of other adverse fetal outcomes, such as abortion and ectopic pregnancies. The lack of studies that looked at the impact of fallopian tube cancer on the fetal outcomes of interest under this study is notable. The relatively smaller number of studies on uterine cancer is likely due to the obvious reason that these cases are most often treated with hysterectomy (a radical, permanent contraceptive method), and fertility sparing operations are less likely to be offered owing to advanced cancer stage at diagnosis.
Owing to the small number of studies identified by cancer type, we were not able to explore dose-response effects of cancer severity and treatments (surgery, chemotherapy, or radiation) on subsequent fertility and adverse birth outcomes. Although our review was very comprehensive, we were not able to verify unique membership to selected cancer registries. However, in the cases of updates of case series, we provided information on the latest article available from the authors.
We suggest several priorities for future research. First, it remains to be confirmed that the effects on birth weights, prematurity, and small for gestational age are causal. Second, the contribution of cancers of diverse degree of severity from different anatomic location within the reproductive system needs to be established. Third, the biological pathways require further clarification. Future studies must also attempt to improve exposure and outcomes measurement in relationship to fetal outcomes. Particularly, future studies must attempt to categorize patients according to the treatment they got when reporting fertility and pregnancy outcomes. Finally, we recommend researchers to adopt a life course perspective44,45 to examine whether early cancer exposure and impaired reproductive outcome have any long-term consequences in later life of women and infant born to them.
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