1. Education Clinical Care Research Birth rates among female cancer survivors: a population-based study Presented by Jenny Liu 04 NOV 2011 Saw Swee Hock School of Public Health

2. Early diagnosis ↑ Effectiveness of cancer treatment ↑ women of fertile age → long term cancer survivors ↑ age at first birth Advances in fertility preservation techniques Introduction >75% women diagnosed with cancer < 45 years, survive at least 5 years One in every 1000 adults is a survivor of childhood cancer Hewitt M WS, Simone JV, eds: Childhood cancer survivorship: improving care and quality of life. 2003

3. Will I live to see my child grow up? Will I pass the cancer to my child? Will I be fit enough to have a baby? Will the treatment affect the health of my baby? Can I afford the expenses?

4. Methods Sweden Multi-Generation Register (Personal records, register of births) Sweden Cancer Register Cause of Death Register Migration Register Population censuses 1960, 1970, 1980 and 1990. (socioeconomic status)

5. Multi-Generation Register - Sweden Year1932 19602002 2003 2004 Birth year of Index persons Cause of Death register Cancer register Observation Period 1958

6. Statistical methods Relative birth rates were expressed as Standardized Birth Ratio (SBR) Multivariate Poisson regression modeling were applied using only data from cancer survivors and expressed as birth rate ratios (BRRs). Log (Event / risk) = α + β 1 X 1 + β 2 X 2 + β 3 X 3 +…+ β k X k Expected no. of births in cancer population No. of births in General Population Person years in General Population X Person Years in Cancer Population SBR Observed no. of births in cancer population Expected no. of births in cancer population = =

7. Table 1 Women diagnosed with cancer in Sweden 1960-2001 with information on subsequent birth(s) Number of women with previous cancer Number of women with births Total number of births Proportion of women who gave birth after cancer diagnosis Overall426914932808011.6% Parity status at diagnosis Nulliparous134373276598224.4% Parous29254165620985.7% Cancer site Breast121391242141.0% Reproductive (minus ovary)64933586485.5% Melanoma Skin463731520.7%

8. Table 2 Standardized Birth Ratios of women with a history of cancer. Overall0.74 (0.73-0.76) Parity status at diagnosis Nulliparous0.87 (0.85-0.89) Parous0.52 (0.50-0.55) Cancer site Reproductive (minus ovary)0.33 (0.30-0.36) Breast 0.55 (0.50-0.60) Ovary 0.57 (0.51-0.62) Brain & eye 0.67 (0.63-0.71) Hematopoietic0.68 (0.63-0.73) Bone 0.83 (0.77-0.89) Others 0.84 (0.74-0.93) Digestive tract0.91 (0.84-0.98) Thyroid 0.99 (0.94-1.04) Head & neck 1.00 (0.87-1.14) Thoracic 1.03 (0.77-1.33) Melanoma Skin 1.05 (1.00-1.11)

9. SBR same as background population Standardized Birth Ratios of women with a history of cancer by cancer site and parity status at diagnosis SBR for nulliparous women SBR for parous women

10. Table 4 Poisson Regression Model of relative likelihood of giving birth for women with a history of cancer Parity status at diagnosisAdjusted Birth Rate Ratio* (95% CI) Nulliparous1.00 Parous0.64 (0.61-0.68) Age at diagnosis 0-12 years old (Childhood)1.00 13-18 years old (Adolescence)1.26 (1.12-1.41) 19-45 years old (Adulthood)1.50 (1.31-1.72) Time since diagnosis 1-5 yrs1.00 6-10 yrs1.06 (0.99-1.12) 11-20 yrs1.16 (1.05-1.28) 21-35 yrs1.31 (1.09-1.58) *Adjusted for cancer site, period of diagnosis, calendar period, attained age and socio-economic status.

11. Findings Female cancer survivors were 26% less likely to give birth compared to the background population. Following a cancer diagnosis, women with the lowest fertility were those with previous child birth, cancer of the reproductive organs and breast, those diagnosed during childhood and recent diagnosis. Large differences in Standardized birth ratios by parity status at diagnosis are suggestive of differential willingness among cancer survivors to pursue a/another child. Identifying women at increased risk of infertility post-diagnosis will allow for possible family planning and still give women the choice of parenthood after a cancer diagnosis.

12. Acknowlegements Saw Swee Hock School of Public Health, National University of Singapore Prof Mikael Hartman Prof Chia Kee Seng Dr Agus Salim Miss Miao Hui Funding: NMRC/1180/2008 and NUS Start-up Fund DPRT Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden Prof Kamila Czene Swedish Initiative for research on Microdata in the Social and Medical Sciences (SIMSAM), grant number 80748301 Department of Radiology, University Medical Center Utrecht, The Netherlands Prof Helena M Verkooijen

13. Education Clinical Care Research Thank you for your attention!

14. Extra slides

15. Target Population Age 200219321961 Year of Birth Deceased/ emigrated 1932-1960 10 20 30 40 50 60 70 Target population = All index persons Born 1932 onwards Resident 1961 onwards Target population Female aged 16-45 Mothers of index persons

16. Table 1 Women diagnosed with cancer in Sweden 1960-2001 with information on subsequent birth(s) ICD7 codes Number of women with previous cancer Number of women with births Total number of births Proportion of women who gave birth after cancer diagnosis Overall-426914932808011.6% Parity status at diagnosis Nulliparous-134373276598224.4% Parous-29254165620985.7% Cancer site Breast170.0-170.9121391242141.0% Reproductive (minus ovary)171.0-174.9; 176.0-176.964933586485.5% Skin190.0-190.9463731520.7% Brain & eye192.0-193.937973424709.0% Thyroid194.0-195.936823074648.3% Hematopoietic201.0-208.9256626844810.4% Ovary175.0-175.92553958152137.5% Digestive tract150.0-158.92439639108426.2% Bone196.0-200.92109885143042.0% Others 180.0-181.9; 191.0-191.9; 209.0-209.9 122637667730.7% Head & neck140.0-148.9; 160.0-161.967446577669.0% Thoracic162.0-164.937617929647.6% Age at diagnosis 0-12 (Childhood)-152144086728.9% 13-18 (Adolescence)-1618638128239.4% 19-45 (Adult)-39552385459319.7% Year of diagnosis 1958-1968-2333841156036.0% 1969-1979-92191292224314.0% 1980-1990-154431664277710.8% 1991-2001-15696113515007.2% Socio-economic Status Blue Collar Workers-148001635268711.0% White Collar Workers-181982236372712.3% Self-employed-1134991748.7% Farmers-34431529.0% Unclassified-8215931144011.3%

17. Table 2 Standardized Birth Ratios of women with a history of cancer. SBR Overall0.74 (0.73-0.76) Parity status at diagnosis Nulliparous0.87 (0.85-0.89) Parous0.52 (0.50-0.55) Age at diagnosis 0-120.73 (0.68-0.78) 13-180.82 (0.78-0.87) 19-450.73 (0.71-0.75) Year of diagnosis 1958-19680.78 (0.74-0.82) 1969-19790.73 (0.70-0.76) 1980-19900.74 (0.72-0.77) 1991-20010.73 (0.69-0.77) Time since diagnosis 1-5 yrs0.71 (0.68-0.73) 6-10 yrs0.79 (0.75-0.82) 11-20 yrs0.80 (0.76-0.84) 21-35 yrs0.73 (0.67-0.81) Attained Age <22 0.77 (0.69-0.85) 22-27 0.78 (0.75-0.82) 28-33 0.77 (0.75-0.80) 34-39 0.68 (0.65-0.71) >39 0.58 (0.52-0.65) Socio-economic Status Blue Collar Workers0.68 (0.65-0.71) White Collar Workers0.82 (0.79-0.84) Self-employed0.74 (0.64-0.86) Farmers0.87 (0.65-1.12) Unclassified0.70 (0.66-0.74)

18. Table 2 Standardized Birth Ratios of women with a history of cancer by parity status at diagnosis and cancer site. Cancer siteOverallParousNulliparous Reproductive (minus ovary)0.33 (0.30-0.36)0.21 (0.18-0.24)0.53 (0.47-0.60) Breast0.55 (0.50-0.60)0.38 (0.33-0.43)0.94 (0.82-1.06) Ovary0.57 (0.51-0.62)0.48 (0.40-0.57)0.60 (0.54-0.67) Brain & eye0.67 (0.63-0.71)0.60 (0.52-0.68)0.69 (0.64-0.74) Hematopoietic0.68 (0.63-0.73)0.39 (0.32-0.46)0.77 (0.71-0.83) Bone0.83 (0.77-0.89)0.56 (0.46-0.66)0.92 (0.84-0.99) Others0.84 (0.74-0.93)0.76 (0.61-0.94)0.87 (0.76-0.99) Digestive tract0.91 (0.84-0.98)0.61 (0.50-0.72)1.02 (0.93-1.11) Thyroid0.99 (0.94-1.04)0.83 (0.76-0.91)1.08 (1.01-1.15) Head & neck1.00 (0.87-1.14)0.79 (0.60-1.00)1.12 (0.95-1.30) Thoracic1.03 (0.77-1.33)0.73 (0.43-1.12)1.28 (0.89-1.73) Skin1.05 (1.00-1.11)0.82 (0.74-0.89)1.19 (1.12-1.26)

19. Birth Rate RatiosUnadjusted BRR (95% CI)p-valueAdjusted BRR* (95% CI)p-value Parity status before diagnosis Nulliparous1.00 Parous0.40 (0.38-0.42)<.00010.64 (0.61-0.68)<.0001 Cancer site Melanoma Skin 1.00 Breast 0.24 (0.21-0.26)<.00010.52 (0.47-0.58)<.0001 Reproductive (minus ovary) 0.37 (0.33-0.41)<.00010.42 (0.38-0.47)0.2233 Brain & Eye 0.79 (0.73-0.85)<.00010.71 (0.65-0.77)<.0001 Ovary 0.83 (0.74-0.92)0.00040.70 (0.63-0.78)<.0001 Hematopoietic 0.87 (0.80-0.95)0.00220.74 (0.68-0.81)<.0001 Thyroid 0.98 (0.91-1.05)0.56710.96 (0.89-1.03)<.0001 Bone 1.14 (1.04-1.25)0.00370.97 (0.89-1.07)<.0001 Others 1.18 (1.04-1.34)0.00821.09 (0.96-1.24)0.2962 Digestive tract 1.23 (1.12-1.35)<.00011.06 (0.97-1.16)0.5877 Head & Neck 1.66 (1.44-1.91)<.00011.41 (1.22-1.64)<.0001 Thoracic 2.96 (2.25-3.91)<.00012.04 (1.54-2.70)0.1794 Age at diagnosis 0-121.00 13-181.31 (1.20-1.42)<.00011.26 (1.12-1.41)0.0001 19-450.88 (0.82-0.94)0.00031.50 (1.31-1.72)<.0001 Year of diagnosis 1958-19681.00 1969-19790.68 (0.64-0.72)<.00010.84 (0.77-0.92)0.0001 1980-19900.61 (0.57-0.65)<.00010.78 (0.68-0.88)<.0001 1991-20010.56 (0.52-0.60)<.00010.72 (0.62-0.85)<.0001 Time since diagnosis 1-5 yrs1.00 6-10 yrs1.35 (1.28-1.42)<.00011.06 (0.99-1.12)0.0789 11-20 yrs1.51 (1.42-1.60)<.00011.16 (1.05-1.28)0.0023 21-35 yrs1.86 (1.68-2.05)<.00011.31 (1.09-1.58)0.0041 Calendar period 1960-19691.00 1970-19790.67 (0.60-0.74)<.00010.86 (0.76-0.96)0.0093 1980-19890.50 (0.46-0.55)<.00010.90 (0.78-1.04)0.1524 1990-20020.61 (0.55-0.66)<.00011.09 (0.92-1.29)0.3289 Attained age 16-181.00 19-215.83 (4.19-8.10)<.00015.35 (3.85-7.45)<.0001 22-2410.98 (8.00-15.09)<.00019.26 (6.72-12.78)<.0001 25-2713.94 (10.18-19.10)<.000111.66 (8.44-16.10)<.0001 28-3013.86 (10.13-18.96)<.000112.12 (8.76-16.78)<.0001 31-3310.13 (7.40-13.86)<.00019.65 (6.95-13.41)<.0001 34-366.48 (4.73-8.88)<.00016.67 (4.78-9.31)<.0001 37-393.88 (2.82-5.33)<.00014.41 (3.14-6.19)<.0001 40-422.05 (1.47-2.86)<.00012.63 (1.85-3.75)<.0001 43-450.77 (0.51-1.17)0.22371.26 (0.81-1.96)0.3016 Socio-economic Status Blue Collar Workers1.00 White Collar Workers0.98 (0.93-1.03)0.44231.00 (0.95-1.05)0.9788 Self-employed2.60 (2.23-3.03)<.00012.05 (1.76-2.39)<.0001 Farmers3.67 (2.79-4.82)<.00012.16 (1.63-2.86)<.0001 Unclassified1.08 (1.01-1.15)0.01641.01 (0.94-1.08)0.7787

20. Standardized Birth Ratio in women with a history of cancer with increasing age by age at diagnosis

21. Standardized Birth Ratios of women with a history of cancer with increasing age by parity status at diagnosis