Dietary vitamin A intake and the risk of ovarian cancer: a meta-analysis

Abstract BACKGROUND: Previous studies have demonstrated some associations between dietary vitamin A intake and ovarian cancer risk with an inconsistent relationship. We therefore performed the present study to further explore the association between them. METHODS: Databases of PubMed, Embase, and Web of Science were retrieved up to September 1, 2019. Summarized relative risk (RR) with corresponding 95% confidence intervals (CI) were calculated. Stata 14.0 software was used for data analysis. RESULTS: Fifteen articles involving 4882 cases and 443,179 participants were included in this meta-analysis. A positive association between dietary vitamin A intake and ovarian cancer risk was found (RR = 0.816, 95%CI = 0.723–0.920, I2 = 48.4%, P for heterogeneity = 0.019). Significant association was also found in case–control studies (RR = 0.769, 95%CI = 0.655–0.902), but not in cohort studies. When we performed the analysis between ovarian cancer risk and geographic locations, we found an inverse association in North American populations (RR = 0.825, 95%CI = 0.720–0.946), instead of other populations. CONCLUSIONS: In summary, findings from the present study suggested that higher dietary intake of vitamin A may contribute to the lower development of ovarian cancer, especially among North Americans.


Introduction
Ovarian cancer is the most deadly gynecological cancer. The American Cancer Society had estimated that there were 22,240 new cases developing in ovarian cancer and 14,070 ovarian cancer cases deaths in 2018 [1]. Efforts to identify lifestyle factors that may affect the risk of ovarian cancer had been ongoing and indicated that some reproductive factors, such as oral contraceptives, carrying children and tubal ligation, may affect disease risk [2,3]. However, these factors usually cannot be changed. Dietary antioxidants, including vitamin A, have been hypothesized to modify cancer risk [4,5]. A previous study had been published to explore the association about vitamin A consumption and ovarian cancer risk, resulted non-significant association [6]. Many articles about vitamin A intake and ovarian cancer risk had been published, with no consistent conclusion. For this reason, this paper increased the sample size and improved the vitamin A efficiency through a meta-analysis to obtain more authentic and reliable analysis results, which is helpful to clarify whether dietary vitamin A intake has some inverse effects on ovarian cancer development, and finally provides evidence of prevention on ovarian cancer.

Search strategy and inclusion criteria
Three electronic databases (PubMed, Embase and Web of Science) were searched for relevant studies that investigated the association between dietary vitamin A intake and risk of ovarian cancer from inception up to September 1, 2019. The following search terms were used: 'vitamin A' OR 'vitamin *' OR 'retinol' combined with 'ovarian cancer' OR 'ovarian tumor' . The bibliographies of the collected studies and relevant reviews were retrospectively assessed to identify additional articles. All the studies enrolled using this strategy was checked independently by two authors.
Studies were included based on the following criteria: (1) patients were diagnosed of ovarian cancer; (2) observational studies; (3) the interested association was about dietary vitamin A or retinol intake and ovarian cancer; (4) available relative risk (RR) and 95% confidence interval (CI) for ovarian cancer.
The following exclusion criteria were used: (1) reviews or meetings or abstracts or letter to the editors; (2) overlap articles or populations; (3) animal studies; (4) no available data of RR and 95%CI; (5) vitamin supplement.

Data extraction and quality assessment
Two researchers independently reviewed and extracted relevant information from all included studies. These pieces of information included: name of the first author, publishing date, country, ages, study types, vitamin types, sample sizes of the cases and controls, RR and 95%CI for ovarian cancer, adjustment for covariates. The disagreements with these two researchers were resolved by discussion and consensus. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included studies [7].

Statistical analysis
Data were summarized using a random-effects model for combined RR with its 95%CI [8]. A Q and I 2 test were performed to analysis the heterogeneity of the studies that included in this meta-analysis [9]. Moreover, meta-regression was performed to interpret the between-group heterogeneity [10]. Furthermore, sensitivity analyses were conducted to examine the stability of the results by removing each study one by one. Potential publication biases were examined using Begg's test and Begg's funnel plots [11]. Statistical analysis was performed using Stata version 14.0. A two-sided P value less than 0.05 was considered statistically significant.

Study selection and study characterization
After searching the pre-defined three databases, we got 3272 citations. Through removing the duplicated literatures among databases and those obviously did not meet the criteria by reading the title and abstract, 45 full texts of the papers were downloaded for the further screening. Thirty articles were further excluded due to some reasons (duplicate publication (n = 1); did not report RR (n = 8); reviews (n = 8); vitamin A supplement (n = 2); animal studies (n = 4); serum studies (n = 6); assessment of survival rate of ovarian cancer (n = 1)). Finally, 15 articles [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] were included this meta-analysis ( Figure 1). The quality evaluation score (Table 1) of each study ranged from 6 to 8 and the methodological quality was higher. The characteristics of the observational studies are shown in Table 1.

Dietary vitamin A intake and the risk of ovarian cancer
Pooled RR suggested that highest category of dietary vitamin A intake could significantly reduce the risk of ovarian cancer (RR = 0.816, 95%CI = 0.723-0.920, I 2 = 48.4%, P for heterogeneity = 0.019) (Figure 2), when compared with the lowest category. In the included studies, five studies were cohort design and the remaining 10 studies were case-control design. Significant association was also found in case-control studies (RR = 0.769, 95%CI = 0.655-0.902), but not in cohort studies (RR = 0.895, 95%CI = 0.736-1.088). When we performed the subgroup analysis between ovarian cancer risk and geographic locations, we found an inverse association in North American populations (RR = 0.825, 95%CI = 0.720-0.946), instead of European populations (RR = 0.890, 95%CI = 0.771-1.028). We did not assess the association between dietary vitamin A intake and the risk of ovarian cancer while only one study was from Asian population. Table 2 shows the results for both whole and subgroup analyses.

Publication bias and sensitivity analysis
Based on Begg's test (P = 0.318) and funnel plot (Figure 3), there existed no publication bias. Sensitivity analysis showed that no single study had a potential impact on the pooled RR ( Figure 4).

Discussion
Our findings based on 15 studies obtained that highest category of dietary vitamin A intake could significantly reduce the risk of ovarian cancer, when compared with the lowest category. We also found a significant association in case-control studies. An inverse association was found in North American populations, instead of other populations.
Our meta-analysis was different from the previous meta-analysis by Koushik et al. [6]. First, although the authors included 10 cohort studies, they said only 4 studies had previously published on vitamin consumption and ovarian  cancer risk, in which only 3 studies were about vitamin A and ovarian cancer risk. However, we included 15 articles to explore the association between vitamin A intake and the risk of ovarian cancer. Second, the authors only included cohort studies, which may omit many observational studies. However, we included both cohort studies and case-control studies in our meta-analysis. Third, they concluded that consumption of vitamin A during adulthood

Figure 3. Funnel plot for the analysis of publication bias between dietary vitamin A intake and ovarian cancer risk
does not play a major role in ovarian cancer risk. However, findings from our meta-analysis suggested that dietary vitamin A intake could reduce the risk of ovarian cancer. Interestingly, we obtained a consistent result in the cohort studies although we included 5 cohort studies, which is two more than Koushik et al. Previous meta-analyses had been published to assess the intake of vitamin A and cancer risk. Huang et al. and Zhang et al. had explored the association between vitamin A intake and pancreatic cancer [27,28], they obtained a consistent result, which might inversely correlate with pancreatic cancer while with vitamin A intake. Yu et al. concluded that higher category of dietary vitamin A intake could reduce the risk of lung cancer [29]. Lv et al. also concluded an inverse association between vitamin A intake and glioma risk [30]. Moreover, Kong et al. found that dietary vitamin A had a significant reduction in the risk of gastric cancer [31]. Our results are all consistent with the previous meta-analyses.
We found significant between-study heterogeneity in the whole pooled results of dietary vitamin A intake and ovarian cancer risk. Between-study heterogeneity in the meta-analysis is common, and it is an essential component to explore the heterogeneity existed in the between-study. Meta-regression was used to explore the causes of heterogeneity for covariates of publication year, vitamins type, study design, geographic locations and number of cases.

Figure 4. Sensitivity analyses between dietary vitamin A intake and ovarian cancer risk
Results from meta-regression suggested that geographic locations (P = 0.021) was significantly associated with this high heterogeneity. When we performed the subgroup analysis by geographic locations, the I 2 was reduced to 38.4% in North American populations and 0.0% in European populations. The result in subgroup of North American populations was consistent with the whole pooled result, while 12 of the 15 included studies were from North America.
However, several limitations should be attention. First, only English language articles were included, which may omit other languages studies. Furthermore, we only searched the articles which had been published in the journal, and did not be able including the meeting articles and some unpublished articles. However, we did not detect any publication bias, suggested our results were stable. Second, 10 of the 15 studies were case-control studies and only 5 were cohort studies. The selection bias, recall bias and some other confounding factors cannot be excluded; for example, some subjects may change their dietary vitamin A intake after the baseline assessment. However, case-control design was a very important epidemiological approach in the observational study. Therefore, it is requirement for evidence from prospective cohort studies. Third, 12 of the 15 studies were from North America, and the result was consistent with the whole pooled result. However, only 2 studies were from Europe and 1 study from Asia. We did not obtain an inverse association between dietary vitamin A intake and the risk of ovarian cancer in Europeans and Asians. Therefore, the result in the present study was more suitable for North America, but not for any populations else. Thus, more studies conducted in some other populations, instead of North Americans, are warranted to further explore the relationship between dietary vitamin A intake and the risk of ovarian cancer.

Conclusions
In summary, our results concluded that dietary intake of vitamin A may contribute to the lower development of ovarian cancer, especially among North Americans. As some limitations existed in our analysis, large scale studies with detailed amount of dietary vitamin A intake are needed to verify our results.