Research Article: Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study

Date Published: June 4, 2019

Publisher: Public Library of Science

Author(s): Yahia Al-Jebari, Ingrid Glimelius, Carina Berglund Nord, Gabriella Cohn-Cedermark, Olof Ståhl, Torgrim Tandstad, Allan Jensen, Hege Sagstuen Haugnes, Gedske Daugaard, Lars Rylander, Aleksander Giwercman, Wei Zheng

Abstract: BackgroundBecause of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk.Methods and findingsIn this nationwide register study, all singletons born in Sweden 1994–2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19–1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment–to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54–1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25–4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995–2000—both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited.ConclusionsNo additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

Partial Text: Children fathered by men treated for cancer might be at higher risk for congenital malformations (CMs) due to the mutagenic effects of irradiation and cytotoxic drugs. Adverse effects of oncological treatments on germ cells have been described in animal [1,2] and human studies [3–5]. Furthermore, a Danish–Swedish population-based study has shown that children conceived after a father’s cancer diagnosis have a slight increase in prevalence of severe CM [6]. A possible pathway for the increased malformations risk might be detrimental genetic alterations of germline DNA by oncological treatment, resulting in more frequent CMs in children conceived after paternal oncological treatment.

In this study, we found that children of fathers with TGCC had an approximately 30% increased malformation risk as compared to children of fathers without TGCC. This modest increase applied to more severe forms of malformations, as well. However, when comparing children conceived after radio- or chemotherapy to those conceived prior to these potentially mutagenic treatments, there was no increased risk associated with either treatment. While very few in numbers, the same was true even for children conceived after more extensive paternal chemotherapy regimens. Altogether, our results indicate that although children born to fathers with TGCC have a significantly increased risk of all and major CMs, it is unlikely to be due to the effects of radio- or chemotherapy.



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