Preterm Birth and Breast Cancer Risk: A Systematic Review and Meta-Analysis CURRENT

Background: The characteristics of pregnancy, such as gestational age are related to the level of maternal hormones, which levels of these hormones can be associated with breast cancer (BC) risk. Therefore, the aim of this study was to determine the relationship between the preterm birth (PB) and BC risk in women in a systematic review and meta-analysis. Methods: In this systematic review and meta-analysis, published studies were located back to the earliest available publication date (1983), using the Medline/PubMed, Embase, Scopus and Web of Science (Clarivate analytics) bibliographic databases. Eligibility, methodological quality, and data extraction were done by two independent reviewers, and finally, to calculate the pooled estimates, Meta-analysis was performed. Results: Thirteen studies including a total of 2,845,553 women were included in this meta-analysis. Pooled results suggested that PB could increase the risk of BC (RR= 1.03, 95% CI: 1.00, 1.07; I2= 62.5%). Risk was significantly increased in women with a PB at >37 gestational weeks (RR = 1.03, 95% CI: 1.01, 1.06) and 26-31 gestational weeks (RR = 1.03, 95% CI: 1.01, 1.06) compared to those with 40-41 gestational weeks. A significant increment in the risk of BC in uniparous women with a PB (RR = 1.05, 95% CI = 1.01, 1.08) and women with >45 years (RR = 1.12, 95% CI = 1.01, 1.24) was observed. Conclusions: The results of this study supported the higher risk of BC in all woman with PB, primiparous women and women with >45 years. Therefore, more care and screening for early detection of the disease is recommended in these women.

3 lifestyle, obesity, reproductive factors and anthropometric factors, have an impact on BC and have contradictory results in this regard [1,5,[8][9][10][11][12][13][14][15]. The results of some studies have shown that the number of previous pregnancies, as well as the age at first pregnancy and delivery, is associated with the risk of BC in women. Changes observed in estrogen levels during pregnancy [16,17] as well as histologic changes in breast tissue can justify this relationship [18]. On the other hand, the characteristics of pregnancy, such as gestational age and birth weight are related to the level of maternal hormones, which levels of hormones can be associated with the risk of BC [19][20][21][22].
Swerdlow et al. [23] have shown in their study that gestational age is inversely associated with BC (especially before menopause), and the risk in women with gestational age of 26-31 weeks was 2.4 times compared to 40-41 weeks. However, M Kaijser et al. [24] suggested that PB and low birth weight are not associated with an increased risk of BC. Another study concluded that preterm labor cannot increase the risk of premenopausal BC, except for women with gestational age less than 32 weeks [25]. Therefore, there is no general consensus on this relationship.
In several other studies, conflicting results have been reported, which may be due to low sample size, methodological problems (in the design, analysis, and reporting of results) or the difference in risk factors in diverse populations. On the other hand, the primary studies in compared to meta-analysis study were hampered by low statistical power because of low sample size. Therefore, the aim of this study was to conduct a systematic review and meta-analysis of the relationship between the PB and BC risk in women.

Study design
This was a systematic review and meta-analysis. To design, run and report the findings, we followed the PRISMA Statement [26] (Preferred reporting items for systematic reviews and meta-analyses).
Data sources, search strategy, and selection criteria Published studies were located back to the earliest available publication date (1983), using the Medline, Embase, Scopus, Web of Science bibliographic databases, and by hand-searching of reference lists of identified studies and pertaining review papers. We also checked the citation lists of relevant publications to find additional pertinent studies. As recommended in the Meta-Analysis of 4 Observational Studies in Epidemiology (MOOSE) guideline [27], we searched unpublished studies using gray literature databases. The literature search was made with no language or publication date restrictions. Search details are available in Appendix s1. The search results of different sources were combined, and duplicates were removed. The search results were evaluated by two independent reviewers (M.S and A.A-H) by screening titles and abstracts, followed by a full-text review. Consensus was reached by discussion or third party opinion (S.V).

Eligibility criteria
In the present systematic review and meta-analysis, studies were included if they met the following inclusion criteria: (1) observational studies (cohort, case-control, nested case-control or case-cohort studies) that evaluated the associations of PB with the risk of developing BC, (2) and they reported any form of effect size estimate (odds ratio (OR), hazard ratio (HR), standardized incidence ratio (SIR) or rate ratio (RR)).We excluded studies if: (1) they had cross-sectional design, (2) we were not able to extract the exact details about research method or results; (3) and presented only as abstracts, conference paper, letters to the editor and editorials.
Data extraction and risk of bias assessment: All eligible studies were reviewed, and the following data was extracted by two investigators independently: (1) authors; (2) year of publication; (3) location; (4) study population; (5) duration of follow-up; (6) the number of cancer cases; (7) risk estimates with CIs; (8) confounders adjusted for in multivariate analysis. Methodological quality assessment for the included studies was done independently by two reviewers (M.S and J.H) using criteria as outlined in the Newcastle-Ottawa scaling for case-control and cohort studies. Explicit judgment regarding the following items was done: selection of the study groups, comparability of the groups and ascertainment of exposure and outcome. Any disagreement was resolved by discussion or third party opinion (S.V).

Statistical analyses
All effect size estimates (HRs, ORs and RRs) were treated as equivalent measures of risk. We calculated the pooled risk of BC associated with PB stratified by parity and menopausal status.
Extracted risk estimates from primary studies were pooled using inverse-variance weighted DerSimonian-Laird random-effect models which incorporates between-study variability into the calculations. To investigate whether the results of the meta-analysis were depend on a particular trial or group of trials, we recomputed the meta-analysis statistic after omitting one study at a time(sensitivity analysis). Additionally, we assessed the probability of publication bias with Egger's test, with P-value < 0.10 considered representative of statistically significant publication bias. All comparisons were two-tailed, and 95% confidence intervals (CI) were described where applicable. The Stata software (Version 13.0) (Stata Corp, College Station, Texas) was used for Meta-analysis.

Results
The Literature search Norway (1 study) and one in Iraq. In terms of study design, five of the thirteen studies were designed as a cohort, seven were case-control and one nested case-control study. Sample size ranged from 22,758 to 694,657 participants in cohort studies and 300 to 41,255 in case-control studies. The summary of methodological quality appraisal of the included studies is shown in additional file 2. All studies classified as good quality. All studies adopted appropriate approach to account for potential confounders. All cohort studies selected their exposed and nonexposed participants from the same community sample. Two of seven included case-control studies used hospital control and classified as moderate risk of selection bias. All studies provided adequate criteria for diagnosis of the outcomes of interest and provided a proper description of how the outcomes were measured.

BC diagnosis age
All studies were included in the meta-analysis of PB and BC risk by age status. The relationship between PB and BC risk showed a significant increment (RR = 1.12, 95% CI = 1.01, 1.24) in women with > 45 years category but in women with < 45 years category (RR = 0.95, 95% CI = 0.83, 1.07).

Discussion
To assess the relationship of gestational age and BC risk, we carried out a systematic review and meta-analysis in which, out of 3,426 potentially relevant articles, 13 relevant studies were included in the meta-analysis. The main result of this study revealed that there is mild evidence that support the relationship between PB and women BC risk, since the risk in women with PB were on average at a 3% greater risk of BC. And also, this meta-analysis provided some mild evidence of higher BC risk in women with a birth at 26-31 and 37-39 weeks compared to 40-41 weeks. The main findings of our study recognized that the PB increases the risk of BC in women with > 45 years. And also the results showed that PB in primiparous women could lead to an increased risk of BC, while in multiparous women, this relationship was not observed. However, it should be noted that in these analyzes, the effect of other effective variables on the relationship between PB and the risk of BC has not been adjusted, therefore, the interpretation and generalization of the findings must be done with caution.
The present systematic review and meta-analysis suggested an increase in the BC risk (RR = 1.03) in women with a PB 26-31 gestational weeks compared to 40-41 gestational weeks. Similar to our study, Swerdlow et al. [23] have shown in their study that the risk in women with gestational age of 26-31 weeks was 2.4 times compared to 40-41 weeks. Previous studies as well as the results of this study showed that early delivery may increase the risk of BC. Swerdlow et al. [23] have suggested that hormonal stimulation and breast proliferation at the beginning of pregnancy and the lack of enough opportunity for differentiation that occurs at the end of pregnancy are the cause of this relationship. Mammary cells in human and animals differentiate in the third trimester [28][29][30] and therefore a full term pregnancy is considered as a protective factor for BC [31]. Therefore, term or post-term pregnancy may be expected to increase the degree of differentiation, which will reduce the risk of BC.
Oestrogens are one of the effective factors in BC etiology [32], and increased concentrations of oestrogens during pregnancy may affect the risk of BC in daughters. Babies born before the 28th week of pregnancy have high levels of estrogen after birth and the previous studies have shown that birth before 32 weeks of pregnancy is a major risk factor for BC [24,33,34]. Therefore, the relationship between preterm delivery and the risk of BC can be explained by changes observed in levels of these hormones.
In our study, the risk of BC in women with preterm delivery at 26-31 weeks compared with compared with delivery at 41-41 weeks did not have a significant difference in risk of breast cancer. As same as our results, Innes KE and Byers TE in their study [35] concluded that very or extreme PB is related to higher risk of maternal BC risk. In another similar study by Melbye M et al. [25], the results showed a higher risk of BC in women with gestational age less than 32 weeks. Some studies have contradicted our findings. M Kaijser et al. [24] reported that PB are not associated with an increased risk of breast cancer.
Some studies have reported the relationship between the induced abortion and BC risk [36,37].
Probably a part of the relationship between abortion and BC risk can be attributed to the duration of pregnancy. On the other hand, "Collaborative Group on Hormonal Factors in Breast Cancer" in a meta-analysis of 53 studies suggested that abortion is not associated with increased risk of BC [38].
Therefore, this relationship is still ambiguous and further studies are needed.
The findings of this meta-analysis were in line with this, with the higher BC risk for PB, significantly for post-menopausal BC and primiparous women and also borderline significantly for BC overall. Some studies evaluated the association of PB and BC risk in parous and nulliparous women. Melbye M et al.
[25] reported a higher risk of BC in parous women with preterm delivery below 32 weeks compared with women with term delivery. Yongchun Deng et al. [36] in a meta-analysis study revealed that in parous women, induced abortion can increase the BC risk, but it was not significant in the nulliparous women.
Our study documented that the PB increases the risk of BC in women with > 45 years, but not in women with < 45 years. As accord to our results, Melbye M et al. [25] concluded that preterm labor cannot increase the risk of premenopausal breast cancer.
In terms of generalizability of our results, it seems the results are generalizable to various populations because it was a systematic review and meta-analysis and pooled the different results from different countries. It should also be mentioned that there was no significant heterogeneity between primary studies.
There are some limitations in this study. The most important limitation of this study was that the gestational age had different categories in primary studies, making it difficult to extract needed data and analysis, and led to different subgroups analyzes. Another limitation of this study was that there are some potential confounder variables in the relationship between PB and BC risk, which in this study was not possible to adjust their effect.

Conclusion
In summary, the results of this study showed that the risk of BC in women with very early PB is significantly higher. Also, PB in women with > 45 years, as well as primiparous women has a significant relationship with the increased risk of breast cancer.

Ethics approval and consent to participate
This work did not require any written patient consent.

Consent for publication
Not applicable.

Availability of data and material
The datasets of this article are included within the article.

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All authors declared no conflict of interest.