Although tumor markers are very commonly used in clinical practice, their relevance and reliability is frequently debated. Tumor markers mainly have a supportive function, even for the routine care of non-pregnant patients. The role of tumor markers is limited in cases of cancer during pregnancy, or pregnancy after cancer, mainly due to their low specificity rate. Elevations are not always correlated with the presence of malignancy but are more often associated with normal physiologic changes of pregnancy. Moreover, obstetrical complications can induce even more variations. For example, elevated CA 125 has been associated with imminent miscarriage , and LDH is known to increase in cases of severe preeclampsia and HELLP (hemolysis, elevated liver function tests, low platelets) . Physicians and midwives caring for pregnant women are well aware that the reference ranges of various laboratory values differ during pregnancy [27, 30], and this should also be the case with tumor markers in pregnancy (Table 1). Here, we summarize and explain the physiology of elevated levels during pregnancy for CA 15.3, SCC and CA 125. Inhibin-B, AMH and LDH are not elevated during normal pregnancy.
CA 15-3 is a well-characterized immunoassay that allows the detection of the mucin (MUC)-1 antigen. MUC-1 is part of the family of membrane-bound mucins, large glycoproteins, and their expression is frequently elevated in breast cancer cells. Elevated levels can be found in the serum of over 70% of patients with advanced breast cancer . Conflicting data on the possible fetoplacental origin of CA 15-3 are reported. CA 15-3 concentrations in amniotic fluid and/or umbilical cord blood were analyzed and remained very low throughout pregnancy [32–34]; the authors concluded that the combination of an elevated maternal CA 15-3 and low levels in amniotic fluid and umbilical cord blood indicate that the antigen is not produced by the fetus, placenta or decidual tissue, and therefore, could not be considered as an oncofetal antigen [32–35]. However, MUC-1 has been detected in trophoblastic tissue even very early in pregnancy; placental expression increases as the pregnancy progresses and it is highly expressed throughout the third trimester [36, 37]. Several authors have hypothesized that CA 15-3 elevations in maternal serum may result from the proliferation of maternal mammary gland epithelium late in pregnancy, with enhanced secretion of mucin, as opposed to placental transfer of the mucin [9, 10, 35]. Botsis et al. , and also Ercan et al. , asserted that CA 15-3 is independent of gestation and remains a reliable tumor marker for breast cancer during pregnancy. This statement is not in accordance with most other studies as found in this review. Although the reported values during pregnancy are only moderately elevated, we believe that caution is warranted, and a higher cut-off value would facilitate interpretation during pregnancy.
Elevated SCC serum levels are found in between 57% and 70% of women with a primary squamous cell carcinoma of the cervix. Elevated levels are also found in between 24% and 53% of patients with squamous cell carcinomas of the head and neck, esophagus, and lung, and also in between 8% and 42% of patients with adenocarcinomas of the ovary and uterus . SCC is probably a marker of cellular differentiation for squamous cells, as the incidence of elevated serum levels is higher in women with grade 1 (78%) and grade 2 (67%) carcinomas than in those with grade 3 tumors (38% ). Sarandakou et al. sampled maternal serum, umbilical cord blood and amniotic fluid during delivery of 56 full-termed pregnancies ; they found a high incidence of SCC levels above the cut-off value of ≤2.5 µg/L (30% in maternal serum and 75% in umbilical cord blood). The levels found in amniotic fluid were extremely high (median 710 µg/L; range 30 to 7,692 µg/L), which led the authors to conclude that SCC is an oncofetal antigen . The analysis of in vitro culture of amnion cells and amniotic membranes revealed no accumulation of SCC in the supernatant, and no mRNA expression of SCC was found in the amnion, the cord or the placenta using a northern blot with a cDNA probe of SCC . Therefore, it is more likely that the fetus, and not the placenta, is the origin of SCC found in amniotic fluid, but this remains to be confirmed.
CA 125 is used for monitoring non-mucinous epithelial ovarian cancer [7, 41]. Of patients with ovarian carcinoma, 82% have CA 125 levels >35 U/mL, compared with 1% of apparently healthy non-pregnant individuals. During pregnancy, CA 125 is present in relatively high concentrations in decidual cells, amniotic fluid and amnion cells, and significantly lower levels are found in umbilical cord blood, suggesting that decidua and amnion cells (and not the fetus) produce and secrete CA 125 into the amniotic fluid [39, 41, 42]. Interestingly, the molecular weight of CA 125 identified in pregnancy was significantly higher than that observed in ovarian cancer, suggesting a different production and/or metabolism of CA 125 glycoprotein for different tissues . The large molecular weight of CA 125 in the fetoplacental unit prevents the passage of the antigen through the basal membranes. Therefore, a large difference exists between amniotic fluid and maternal serum concentrations of CA 125; disruption of the basal membranes can cause a higher permeability from the fetoplacental unit into the maternal circulation . Higher maternal serum CA 125 levels in the first trimester can be explained by the process of trophoblast invasion in the decidua during placentation. Higher levels in the third trimester, and more particularly in the puerperium, can be caused by detachment of the placenta from the uterus, during which time decidual CA 125 might reach the maternal circulation .
In persisting adnexal masses during pregnancy, expert ultrasonographic assessment plays a pivotal role in estimating the risk of malignancy, and planning conservative management for an adnexal mass that is probably benign versus surgical treatment during pregnancy for an adnexal mass that has malignant characteristics [43, 44]. Ovarian cancer during pregnancy is very rare and has an estimated incidence of 1 in 12,000 to 47,000 pregnancies . When uncertainty remains towards the type of adnexal mass, despite expert evaluation, tumor markers might be important to help formulate the differential diagnosis. From the data presented, it is clear that the usefulness of CA 125 in pregnant women must be carefully considered, as it is evident that maternal serum CA 125 concentrations are influenced by pregnancy, especially during the first trimester. Thus, an adjusted cut-off level should be established in order to interpret CA 125 levels in pregnant patients . Inhibin B and AMH are both serum markers for granulosa cell tumors. Granulosa cell tumors represent about 5% of all primary ovarian neoplasms, and the juvenile type has a higher incidence in children and young women. Currently, there is no evidence-based preference to use inhibin B or AMH as tumor marker in the non-pregnant patient . During pregnancy, an apparent increase in inhibin B immunoreactivity may reflect some cross-reaction with inhibin A. Consequently, it is to be expected that AMH measurements are more reliable during pregnancy than inhibin B.
Risk of bias
We aimed to minimize risk of bias of individual studies by excluding all studies reporting tumor markers measured in pregnancies with pathology (for example, miscarriage, intrauterine growth restriction, preeclampsia, aneuploidy) and/or without specification of gestational age. Publication bias and selective reporting within studies is not expected for this research area.
Limitations of the present review and aims for future research
There is no consensus on the clinical benefit of tumor markers and staging procedures. As a result, their practical use differs significantly among centers. Despite this, tumor markers are frequently used in clinical practice. When measured in the pregnant patient, the pregnancy-related physiologic alterations render the interpretation of tumor marker values more difficult. Therefore, we aimed to provide a better knowledge of tumor marker values during pregnancy. The available literature remains inconclusive for several reasons. The majority of studies were cross-sectional and used small cohorts, which may have led to underpowered conclusions. Comparability of study results is further complicated by the different definitions used for the three trimesters of pregnancy and, even more important, by the various types of assays with different intra-and inter-assay coefficients of variation and corresponding different degrees of precision, which were not always mentioned. Confidence intervals and standard deviations were not systematically stated, hence, outliers could not always be excluded. Normal values for pregnant women are still not well established. A longitudinal prospective study with sufficient participants to correct for interpatient heterogeneity would be more suitable to define the 2.5th and 97.5th percentiles for the different tumor markers during pregnancy .
Human epididymis secretory protein 4 (HE4, also known as WFDC2) is a new marker for epithelial ovarian carcinoma . HE4 was first proposed as a serum tumor marker for ovarian cancer in 2003 . So far, its value as an additional marker alongside CA 125 is still under debate [48, 49]. Interestingly, HE4 has an increased performance in the premenopausal group, mainly because, unlike CA 125, it is not overexpressed in cases of endometriosis . The expression of HE4 during normal pregnancy deserves further investigation.