Article Title: Maternal Fetal Loss History and Increased Acute Leukemia Subtype Risk In

Article Title: Maternal fetal loss history and increased acute leukemia subtype risk in subsequent offspring: a systematic review and meta-analysis

Journal name: Cancer Causes and Control

Authors: M. A. Karalexi1, Nick Dessypris1, A. Skalkidou2, S.-I. Biniaris-Georgalis1, Ε. Ι. Kalogirou1, T. P. Thomopoulos1, E. Herlenius3, L. G. Spector4, D. Loutradis5, G. P. Chrousos6, E. Th. Petridou1

1Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, Greece

2Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

3Neonatal Research Unit, Department of Women's and Children׳s Health, Astrid Lindgren Children׳s Hospital both at Karolinska Institutet, S-171 76, Stockholm, Sweden

4Division of Pediatric Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, US

51st Department of Obstetrics and Gynecology of the University of Athens, Alexandra Hospital, Athens, Greece

6First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Athens, Greece

Correspondence:

Prof. Eleni Th. Petridou

Department of Hygiene, Epidemiology and Medical Statistics, Medical School,

National and Kapodistrian University of Athens

75 Mikras Asias Str, Athens, Greece 11527

Tel +30 210-7462187

Supplementary Material

Study protocol

This systematic review and meta-analysis was based on a pre-defined protocol following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)[1] guidelines. The authors’ checklist of the PRISMA is presented in Table S1.

Detailed search strategy

The Medline database was searched using the following combination of appropriate key words in a search algorithm:

(((fetal OR fetus OR foetus OR foetal) AND (loss OR losses OR lost OR death OR dead)) OR (reproductive AND history) OR abortion OR abortions OR abortive OR abortus OR miscarriage OR miscarriages OR stillbirth OR stillborn OR ((intrapartum OR uterus OR uterine) AND (death OR dead))) AND (leukemia OR leukaemia OR leukemias OR leukaemias OR lymphoma OR lymphomas) OR ((haematological OR hematological) AND (cancer OR cancers OR malignancy OR malignancies)) AND (child OR children OR childhood).

Results of search strategy

Out of the 3583 results retrieved through the literature search along with 55 additionnal articles derived from the ”snowball procedure”, 3553 were excluded by title or abstract, resulting in 85 potentially eligible articles. Following evaluation of their full-text, 36 were excluded due to specific reasons [2-34], as detailed in Table S2.In 18 articles, the respective authors were contacted as to provide additional analyses, out of which 9 did not respond [35-42,16].Among 9 authors who replied, the requested analyses were provided only by one study from the Children’s Oncology Group (COG)[43]. Reasons of refusal [44-51]included inappropriateness of the dataset for the requested analysis, no access to the data, long time elapsed since publication and lack of funding.

Finally, 32articles were considered eligible for inclusion in the meta-analysis in their published form or following contact of authors[52,51,46,53-55,43,56-74,48,75-79]. The successive steps of the study selection process are graphically presented in Figure 1.

Overlap between studies

All eligible studies were examined for potential overlap, based on the region where the study was conducted and the time period of recruitment; in case of multiple publications on the same cohort, the most recent or largest one was retained. Thereafter, 20 studies were excluded due to overlap with eligible articles. Particularly, in the US the study by Shu et al. (1996)[17] referred to the same population, yet for a shorter study period, as the more recent study by Ross et al. (1997)[80]. The articles by Spector et al. (2007)[18], Linabery et al. (2010)[19], and Ognjanovic et al. (2011)[20] studied the same population from the COG in the US, as was the study by Puumala et al (2010)[64] which availed thus a larger dataset. The studies by Brondum et al. (1999)[21] and Shu et al. (2002)[70] were excluded due to overlap with primary data contributed for the same time period by the main coordinator of COG, Prof. L. Spector. Seven studies conducted in the US, namely the studies by Ma et al. (2005)[25], Reynolds et al. (2002)[23], Ma et al. (2004)[24], Ma et al. (2005)[22], Jensen et al. (2004)[26], Chang et al. (2006)[27], and Ward et al. (2009)[28] were overlapping with the more recent and larger study by Oksuzyan et al. (2012)[62]. Similarly, the study by John et al. (1991)[29] was excluded due to overlap with the more recent one by Savitz et al. (1994)[67]. In France, the study by Menegaux et al. (2005)[30] although more recent than the study by Perillat et al. (2002)[63]was excluded, since history of fetal loss was solely explored as a potential confounder in the former study. Likewise, in UK, the more recent and larger study by Roman et al. (2005)[65] was included instead of the study by Fear et al. (2003)[31]. In addition, in Greece, the study by Karalexi et al. (2015)[61]was overlapping and thus substituted by primary unpublished data provided by NARECHEM covering the more recent study period (1996-2014). Lastly, in Germany, three studies by Schuz et al. (2003)[32], Kaatsch et al. (1998)[33], and Kaatsch et al. (1996)[34] were excluded due to overlapping population with the larger study by Schuz et al. (1999)[68]reporting data for a longer study period (1980-1997).

Quality of studies assessment

The nine-item Newcastle-Ottawa scale (NOS) was used for the evaluation of eligible studies, as presented in Supplementary Table 3. Following the completion of data abstraction, studies were classified by study design (case-control and cohort studies), and were separately evaluated for their quality.

Age was a priori considered the most important factor on comparability questions in both case-control and cohort studies, whereas controlling for any other factor via methodology or statistical analysis was awarded a second star. Regarding cohort studies, adequate duration of follow-up was a priori set at ≥4 years, whereas a follow-up completeness of at least 80% was required to be awarded a star.

Data synthesis

Individual effect estimates for each outcome were combined in meta-analyses. The random-effects model was applied to all analyses (DerSimonian-Laird), whereas heterogeinty was assessed via the I2 estimation and the Cochran Q statistic; level of statistical significance was set at p<0.10. Graphical presentation in forest plots was applied.

Specific analyses were implemented in some studies; namely the study by Ross et al. (1997) [80]on infant leukemia was used only in the subgroup analysis by age due to population overlap with the primary data contributed for the same time period by the main coordinator of COG, Prof. L. Spector. In the study by Yeazel et al.[48], separate effect estimates by age group are provided on history of miscarriage and risk of childhood ALL. We, thus, meta-analyzed the effect estimates of each age group (0-1, 2-3, 4-5, 6-7, 8-9, 10+ years of age) and included the pooled effect estimate in our meta-analysis on miscarriage history and ALL risk.

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