Influence of family size and birth order on risk of cancer: a population-based study

  • Melanie Bevier1Email author,

    Affiliated with

    • Marianne Weires1,

      Affiliated with

      • Hauke Thomsen1,

        Affiliated with

        • Jan Sundquist2, 3 and

          Affiliated with

          • Kari Hemminki1, 2

            Affiliated with

            BMC Cancer201111:163

            DOI: 10.1186/1471-2407-11-163

            Received: 15 March 2010

            Accepted: 9 May 2011

            Published: 9 May 2011

            Abstract

            Background

            Family size and birth order are known to influence the risk of some cancers. However, it is still unknown whether these effects change from early to later adulthood. We used the data of the Swedish Family-Cancer Database to further analyze these effects.

            Methods

            We selected over 5.7 million offspring with identified parents but no parental cancer. We estimated the effect of birth order and family size by Poisson regression adjusted for age, sex, period, region and socioeconomic status. We divided the age at diagnosis in two groups, below and over 50 years, to identify the effect of family size and birth order for different age periods.

            Results

            Negative associations for increasing birth order were found for endometrial, testicular, skin, thyroid and connective tissue cancers and melanoma. In contrast, we observed positive association between birth order and lung, male and female genital cancers. Family size was associated with decreasing risk for endometrial and testicular cancers, melanoma and squamous cell carcinoma; risk was increased for leukemia and nervous system cancer. The effect of birth order decreased for lung and endometrial cancer from age at diagnosis below to over 50 years. Combined effects for birth order and family size were marginally significant for thyroid gland tumors. Especially, the relative risk for follicular thyroid gland tumors was significantly decreased for increasing birth order.

            Conclusion

            Our findings suggest that the effect of birth order decreases from early to late adulthood for lung and endometrial cancer.

            Background

            Family size and birth order has been shown to have an effect on the risk of cancer through socioeconomic and biological factors. For example, local observations showed that lower birth weight as a consequence of higher birth order has been associated with a lower risk for breast cancer [13] and a lower risk for melanoma [2]. Negative association has also been detected in testicular cancer for children of higher birth order [46]. Higher birth order often implies higher parental age at conception, although the latter has not been reported to be a risk factor in some studies [7, 8] whereas in other studies there was an association found for cancer sites as breast and prostate cancer as well as childhood cancers [913]. Genetic diseases or cancer during childhood may shorten the reproduction phase of parents, which could cause higher risk for individuals in families with fewer children [14]. This might lead to an association of early-onset cancer or childhood cancers within last born children. Risks for many types of cancer and morbidities have been associated with the socioeconomic status of an individual [15, 16]. A decreasing risk for melanoma has been reported for increasing family size and was explained by limited affordability of sunny holidays and solarium visits of larger families [14, 17, 18]. Significant association between socioeconomic factors, family size and lung cancer has also been reported in a previous study based on the Swedish Family-Cancer Database [19, 20]. Socioeconomic factors have been shown to influence obesity which is an important risk factor for endometrial and other cancers such as liver cancer, non-Hodgkin lymphoma and multiple myeloma [2124]. The susceptibility to be overweight might be influenced by childhood environment and to be carried on to adulthood. Closer contact among family members of larger families has been shown to increase risk of infection with Helicobacter pylori and other Helicobacter pylori related cancers [2, 25, 26].

            The goal of the present study was to systematically analyze the effects of birth order and family size on different types of cancer. As we used the newest update of the Swedish Family Cancer-Database we had more than 75,000 additional registered cancer cases as previous studies with 178,365 cases [19]. This updated version included a total of 254,697 of cancer cases in offspring. Excluding the offspring with affected parents resulted in a study population of 134,896 individuals. The larger number of cancer cases leaded to more robust estimates of associations and allowed us to include also more rare cancers, such as esophageal, eye, small intestinal, laryngeal and salivary gland cancers. Additionally, we were able to divide the age at diagnosis in two categories to quantify the effect of family size and birth order. Differences in risk estimates for individuals diagnosed before and after 50 years of age are useful for identifying the effects of birth order and family size during life. Both influence the childhood environmental and lifestyle. Our aim was to see whether these factors still have an influence on cancer during early and later adulthood and whether they change over time. We focused on that aspect, as this has not been analyzed in previous studies.

            Methods

            The Swedish Family-Cancer Database includes data from the Second-Generation Register, the Swedish Cancer Registry, the National Census and the Death Notification Registry covering all cancers from 1961 to 2006 according to the seventh revision of the International Classification of Diseases (ICD-7) [27]. Cancer studies (Family-Cancer Database) in the MigMed Database was approved by the Lund regional ethical committee on 8/12/2008 (No. 409/2008) and with complementary approvals dated 9/1/2009 and 1/22/2010. A total of approximately 11 million individuals born after 1932 and their biological parents have been registered. The newest version assembled in 2009 contains also information on more than 1.2 million first and multiple primary cancers and in situ tumors [25]. For most of the individuals affected with cancer clinical information on tumors is also available. Additionally, residential and socioeconomic data are available from national censuses, which were carried out in 1960, 1970, 1980 and 1990.

            The study included all individuals from the database with identified parents. Individuals having parents affected with cancer were excluded, because parental cancer history should not be taken into account to avoid any confounding effect. The risk through parental cancer cases will be separated from the risk caused by birth order or family size. This lead to a study population of 5,657,455 individuals where 134,896 individuals were affected with cancer. The birth order of every individual was defined through the mother's parity (grouped 1, 2, 3-4, 5-17). The family size (grouped 1, 2, 3-4, 5-17) is defined as the number of children per mother. There were 669,137 singletons, more than 2.3 million offspring in families with two children, more than 2.2 million in families with three or four children and 437,907offspring in families with at least five children included in the study. To analyze the effects of birth order and family size for early and later adulthood the individuals were categorized for age at diagnosis less and over age 50.

            A four-digit diagnostic code according to ICD-7 was used to identify cancer sites. Some cancers were grouped according to the following codes: upper aerodigestive tract (140-141.9, 143.0-148.9), rectum excluding anus (154-154.0, 154.8), liver and gallbladder (155.0-156.9), lung (162.0-163), uterus (173-174), non-Hodgkin lymphoma (200-200.2, 202-202.2) and leukemia (204.0-209.9).

            Patients were followed up for a specific time interval depending on the information available for each person in the database. Follow up started at year of immigration, birth year, or start year of cancer registry (1961), whatever came latest, until year of diagnosis, death, emigration or end of the study (2006), whatever occurred first. Cancer cases and person-years were determined for every stratification class of the covariates included in the regression model. For the calculation of the relative risks and the corresponding 95% confidence intervals, age at stopfollow (5-year-bands), sex, calendar period (1961-1985, 1986-1990, 1991-1995, 1996-2000, 2001-2006), region (big cities, northern Sweden, southern Sweden, other), socioeconomic status (agricultural worker, white-collar worker, other worker, professional, private, other), family size, and birth order have been included as covariates. The Genmod procedure in SAS (SAS version 9.2; SAS Institute, Cary, NC, USA) was used to fit the Poisson regression model. The cancer status (affected or not affected) is specified as a response variable, whereas the included covariates are explanatory variables. Parameter estimates (β) are obtained by maximum likelihood estimation (MLE). These parameters are estimated numerically through an iterative fitting process. Cancer incidence for one group compared to the reference group was calculated to obtain relative risk estimates. P values for trend analysis were calculated using a Jonckheere-Terpstra test which is a nonparametric test for ordered differences among classes.

            Results

            The study included around 5.7 million individuals, of which 134,896 were affected with cancer. Table 1 gives an overview on the distribution of individuals and cancer cases by family size and birth order. In Table 2 the age at stop follow of the individuals included in the study is presented.
            Table 1

            Number of all individuals (and cancer cases) included in the study with respect to birth order and family size

            All families

              

            Family size

              

            Birth order

            1

            2

            3-4

            5-17

            All

            1

            669,137 (25,209)

            1,161,073 (26,279)

            681,658 (20,129)

            75,738 (4,226)

            2,587,606 (75,843)

            2

             

            1,169265 (18,325)

            686,860 (15,439)

            76,402 (3,543)

            1,932,527 (37,307)

            3-4

              

            851,555 (13,395)

            154,668 (5,315)

            1,006,223 (18,170)

            5-17

               

            131,099 (3,036)

            131,099 (3,036)

            All

            669,137 (25,209)

            2,330,338 (44,604)

            2,220,073 (48,963)

            437,907 (16,120)

            5,657,455 (134,896)

            Table 2

            Age at stopfollow of individuals (and cancer cases) included in the study

            Age at stopfollow

            All individuals

            Cancer cases (%)

            0-4

            551,205

            3,405 (0.62)

            5-9

            508,742

            2,277 (0.45)

            10-14

            566,083

            2,017 (0.36)

            15-19

            585,185

            2,753 (0.47)

            20-24

            493,490

            3,728 (0,76)

            25-29

            454,454

            5,161 (1.14)

            30-34

            446,358

            6,537 (1.46)

            35-39

            411,925

            8,014 (1.95)

            40-44

            376,844

            12,213 (2.71)

            45-49

            296,309

            13,364 (4.51)

            50-54

            273,077

            17,052 (6.24)

            55-59

            276,905

            20,842 (7.53)

            60-64

            264,047

            20,190 (7.65)

            65-69

            178,049

            14,516 (8.15)

            70-

            109,678

            4,827 (4.40)

            All

            5,657,455

            134,896 (2.33)

            Table 3 shows relative risk estimates for birth order of all cancer sites analyzed separately for age at diagnosis below 50 years or above 50 years and combining both. Significant results at 5% confidence level are written bold. A significantly increased relative risk for lung cancer (RR = 1.08, 99% CI: 1.00-1.15) was found independent of the age at diagnosis. Birth order was associated with a decreased risk for endometrial and testicular cancers, melanoma, squamous cell skin cancer, and cancers of the thyroid gland and connective tissue. The relative risk for cervical cancer (RR = 0.83) was significantly decreased for individuals diagnosed below age 50 years.
            Table 3

            Relative risks for birth order and age at diagnosis

              

            Age at diagnosis < 50 years

            Age at diagnosis ≥ 50 years

            All

               

            Birth order

            Ref

             

            Birth order

            Ref

             

            Birth order

            Ref

            Cancer site

            (ICD-7 code)

            N

            RR

            (95% CI)

            N

            N

            RR

            (95% CI)

            N

            N

            RR

            (95% CI)

            N

            Upper aero-digestive tract

            (140+)

            402

            0.95

            (0.82-1.09)

            396

            577

            1.09

            (0.98-1.21)

            807

            979

            1.04

            (0.95-1.14)

            1203

            Salivary glands

            (142)

            119

            0.79

            (0.63-0.99)

            141

            59

            0.93

            (0.65-1.33)

            96

            178

            0.85

            (0.70-1.04)

            237

            Esophagus

            (150)

            55

            0.89

            (0.59-1.37)

            52

            248

            0.89

            (0.75-1.05)

            435

            303

            0.89

            (0.76-1.05)

            487

            Stomach

            (151)

            261

            1.03

            (0.84-1.26)

            232

            505

            1.07

            (0.95-1.19)

            757

            766

            1.06

            (0.94-1.20)

            989

            Small intestine

            (152)

            84

            0.94

            (0.71-1.24)

            85

            147

            1.12

            (0.92-1.36)

            206

            231

            1.07

            (0.91-1.26)

            291

            Colon

            (153)

            938

            0.94

            (0.85-1.04)

            928

            1532

            0.97

            (0.91-1.04)

            2723

            2470

            0.97

            (0.91-1.02)

            3651

            Rectum

            (154/1541)

            376

            1.03

            (0.85-1.26)

            343

            1084

            1.03

            (0.96-1.11)

            1740

            1460

            1.03

            (0.95-1.12)

            2083

            Anus

            (1541)

            66

            1.08

            (0.77-1.50)

            56

            85

            0.95

            (0.74-1.24)

            133

            151

            1.02

            (0.83-1.24)

            189

            Liver and gallbladder

            (155, 156)

            217

            0.95

            (0.80-1.14)

            202

            467

            0.92

            (0.82-1.04)

            807

            684

            0.94

            (0.85-1.04)

            1009

            Pancreas

            (157)

            134

            0.88

            (0.69-1.12)

            128

            573

            0.93

            (0.81-1.07)

            972

            707

            0.93

            (0.84-1.03)

            1100

            Nose

            (160)

            49

            0.99

            (0.64-1.52)

            46

            47

            1.19

            (0.85-1.67)

            67

            96

            1.05

            (0.76-1.45)

            113

            Larynx

            (161)

            58

            0.82

            (0.61-1.10)

            71

            153

            1.05

            (0.83-1.32)

            227

            211

            1.00

            (0.83-1.19)

            298

            Lung

            (162, 163)

            589

            1.17

            (1.04-1.31)

            454

            2201

            1.03

            (0.97-1.09)

            3343

            2790

            1.08

            (1.02-1.13)

            3797

            Breast

            (170)

            5053

            1.03

            (0.82-1.28)

            4778

            5937

            0.98

            (0.95-1.01)

            8751

            10990

            1.00

            (0.91-1.11)

            13529

            Cervix

            (171)

            1609

            0.95

            (0.85-1.06)

            1597

            245

            0.83

            (0.71-0.97)

            401

            1854

            0.93

            (0.85-1.02)

            1998

            Endometrium

            (172)

            213

            0.72

            (0.64-0.81)

            1042

            321

            0.87

            (0.83-0.92)

            1924

            1255

            0.85

            (0.81-0.90)

            2245

            Uterus

            (173, 174)

            140

            0.91

            (0.79-1.04)

            151

            106

            0.99

            (0.82-1.19)

            166

            246

            0.95

            (0.85-1.06)

            317

            Ovary

            (175)

            902

            0.98

            (0.88-1.08)

            868

            806

            1.03

            (0.95-1.13)

            1177

            1708

            1.01

            (0.94-1.09)

            2045

            Other female genital

            (176)

            128

            1.34

            (1.09-1.64)

            90

            101

            1.03

            (0.85-1.26)

            138

            229

            1.20

            (1.04-1.38)

            228

            Prostate

            (177)

            92

            1.04

            (0.83-1.31)

            76

            4552

            1.03

            (1.00-1.06)

            7984

            4644

            1.03

            (1.00-1.06)

            8060

            Testis

            (178)

            1668

            0.90

            (0.84-0.97)

            1582

            65

            0.78

            (0.60-1.02)

            112

            1733

            0.89

            (0.83-0.95)

            1694

            Other male genital

            (179)

            71

            1.15

            (0.94-1.42)

            60

            81

            1.22

            (1.00-1.48)

            98

            152

            1.20

            (1.05-1.38)

            158

            Kidney

            (180)

            663

            1.00

            (0.90-1.10)

            608

            716

            0.99

            (0.89-1.10)

            1184

            1379

            0.99

            (0.92-1.06)

            1792

            Urinary bladder

            (181)

            489

            1.02

            (0.90-1.16)

            486

            1082

            0.94

            (0.88-1.02)

            1964

            1571

            0.97

            (0.91-1.04)

            2450

            Melanoma

            (190)

            2789

            0.88

            (0.83-0.95)

            2952

            1310

            0.87

            (0.81-0.93)

            2232

            4099

            0.88

            (0.84-0.92)

            5184

            Squamous cell skin

            (191)

            412

            0.97

            (0.84-1.12)

            405

            638

            0.87

            (0.79-0.95)

            1309

            1050

            0.90

            (0.83-0.98)

            1714

            Eye

            (192)

            297

            1.04

            (0.89-1.22)

            243

            88

            0.90

            (0.71-1.15)

            146

            385

            1.01

            (0.88-1.15)

            389

            Nervous system

            (193)

            3730

            1.00

            (0.95-1.06)

            3214

            1126

            0.99

            (0.92-1.07)

            1630

            4856

            1.01

            (0.96-1.06)

            4844

            Thyroid

            gland

            (194)

            821

            0.86

            (0.79-0.95)

            894

            156

            0.79

            (0.64-0.97)

            289

            977

            0.85

            (0.78-0.92)

            1183

            Endocrine glands

            (195)

            1013

            0.99

            (0.91-1.09)

            961

            568

            0.87

            (0.78-0.98)

            952

            1581

            0.95

            (0.89-1.02)

            1913

            Bone

            (196)

            500

            1.06

            (0.94-1.20)

            412

            37

            1.11

            (0.69-1.79)

            47

            537

            1.08

            (0.95-1.22)

            459

            Connective tissue

            (197)

            572

            0.88

            (0.78-0.98)

            576

            161

            1.00

            (0.82-1.21)

            254

            733

            0.90

            (0.82-0.99)

            830

            Non-Hodgkin lymphoma

            (200, 202)

            1330

            1.06

            (0.97-1.15)

            1115

            1029

            0.99

            (0.91-1.08)

            1611

            2359

            1.03

            (0.97-1.10)

            2726

            Hodgkin lymphoma

            (201)

            1001

            0.92

            (0.84-1.01)

            947

            76

            1.00

            (0.75-1.33)

            109

            1077

            0.93

            (0.85-1.01)

            1056

            Myeloma

            (203)

            119

            0.94

            (0.74-1.19)

            117

            332

            1.04

            (0.89-1.21)

            535

            451

            1.02

            (0.89-1.15)

            652

            Leukaemia

            (204 - 209)

            2208

            0.98

            (0.90-1.06)

            1910

            709

            1.02

            (0.93-1.12)

            1117

            2917

            1.00

            (0.94-1.07)

            3027

            Other and unspecified sites

            (other)

            406

            0.91

            (0.79-1.04)

            398

            838

            0.89

            (0.80-0.99)

            1505

            1244

            0.91

            (0.84-0.98)

            1903

            Any site

            (any)

            29574

            0.97

            (0.94-0.99)

            27895

            29479

            0.96

            (0.93-1.00)

            47948

            59053

            0.97

            (0.95-1.00)

            75843

            Reference group: first born child. Bold type, 95% CI does not include 1.00. Poisson regression adjusted for age, sex, period, region, socioeconomic status. Ref.: reference, N:number of cases

            The association between family size and cancer with singletons as reference is presented in Table 4. Family size was associated with a decreased relative risk for endometrial (RR = 0.76, 99% CI: 0.70-0.84) and testicular cancer, squamous cell skin cancer and melanoma, whereas the opposite was observed for cancer of the nervous system and leukemia (RR = 1.20). For lymphoid leukemia there was a relative risk of 1.30 (95% CI: 1.04-1.61) found for increasing family size (data not shown). In the stratified analysis for the age at diagnosis, the relative risk was increased for stomach cancer (RR = 1.17) and decreased for cervical cancer (RR = 0.82) for individuals above age 50 at diagnosis.
            Table 4

            Relative risks for family size and age at diagnosis

              

            Age at diagnosis < 50 years

            Age at diagnosis ≥ 50 years

            All

               

            Family size

            Ref

             

            Family size

            Ref

             

            Family size

            Ref

            Cancer site

            (ICD-7 code)

            N

            RR

            (95% CI)

            N

            N

            RR

            (95% CI)

            N

            N

            RR

            (95% CI)

            N

            Upper aero-digestive tract

            (140+)

            694

            1.00

            (0.81-1.23)

            104

            1068

            0.96

            (0.84-1.09)

            316

            1762

            0.97

            (0.87-1.09)

            420

            Salivary glands

            (142)

            222

            0.85

            (0.62-1.17)

            38

            117

            0.87

            (0.61-1.24)

            38

            339

            0.87

            (0.68-1.10)

            76

            Esophagus

            (150)

            85

            0.52

            (0.33-0.82)

            22

            528

            0.99

            (0.82-1.18)

            155

            613

            0.92

            (0.77-1.10)

            177

            Stomach

            (151)

            423

            0.91

            (0.68-1.21)

            70

            1009

            1.17

            (1.02-1.34)

            253

            1432

            1.11

            (0.96-1.29)

            323

            Small intestine

            (152)

            140

            0.76

            (0.53-1.09)

            29

            282

            1.14

            (0.91-1.44)

            71

            422

            1.03

            (0.84-1.27)

            100

            Colon

            (153)

            1633

            1.01

            (0.88-1.17)

            233

            3213

            0.95

            (0.89-1.02)

            1042

            4846

            0.97

            (0.91-1.03)

            1275

            Rectum

            (154/1541)

            632

            1.13

            (0.78-1.65)

            87

            2152

            0.96

            (0.88-1.04)

            672

            2784

            0.98

            (0.88-1.09)

            759

            Anus

            (1541)

            105

            0.93

            (0.59-1.48)

            17

            171

            1.03

            (0.75-1.41)

            47

            276

            1.01

            (0.79-1.30)

            64

            Liver and gallbladder

            (155, 156)

            376

            1.23

            (0.92-1.65)

            43

            972

            0.95

            (0.83-1.08)

            302

            1348

            0.99

            (0.88-1.11)

            345

            Pancreas

            (157)

            231

            1.00

            (0.72-1.40)

            31

            1176

            0.93

            (0.81-1.06)

            369

            1407

            0.94

            (0.84-1.05)

            400

            Nose

            (160)

            85

            1.24

            (0.58-2.67)

            10

            95

            1.53

            (0.96-2.44)

            19

            180

            1.39

            (0.89-2.17)

            29

            Larynx

            (161)

            111

            1.09

            (0.64-1.86)

            18

            304

            1.15

            (0.91-1.45)

            76

            415

            1.15

            (0.90-1.47)

            94

            Lung

            (162, 163)

            926

            1.20

            (0.97-1.48)

            117

            4254

            0.95

            (0.89-1.02)

            1290

            5180

            0.99

            (0.93-1.05)

            1407

            Breast

            (170)

            8325

            0.91

            (0.70-1.20)

            1506

            11473

            0.98

            (0.95-1.02)

            3215

            19798

            0.96

            (0.86-1.08)

            4721

            Cervix

            (171)

            2782

            0.97

            (0.82-1.14)

            424

            488

            0.82

            (0.69-0.98)

            158

            3270

            0.93

            (0.82-1.05)

            582

            Endometrium

            (172)

            412

            0.67

            (0.55-0.81)

            122

            2145

            0.78

            (0.72-0.84)

            821

            2557

            0.76

            (0.71-0.82)

            943

            Uterus

            (173, 174)

            258

            1.29

            (1.05-1.60)

            33

            208

            0.94

            (0.77-1.15)

            64

            466

            1.07

            (0.93-1.24)

            97

            Ovary

            (175)

            1532

            0.98

            (0.84-1.16)

            238

            1542

            0.99

            (0.89-1.11)

            441

            3074

            0.99

            (0.90-1.09)

            679

            Other female genital

            (176)

            195

            1.32

            (0.95-1.83)

            23

            189

            1.02

            (0.76-1.38)

            50

            384

            1.14

            (0.92-1.40)

            73

            Prostate

            (177)

            144

            0.85

            (0.60-1.21)

            24

            9489

            0.98

            (0.95-1.01)

            3047

            9633

            0.98

            (0.95-1.02)

            3071

            Testis

            (178)

            2857

            0.87

            (0.80-0.94)

            393

            139

            0.96

            (0.75-1.22)

            38

            2996

            0.87

            (0.81-0.94)

            431

            Other male genital

            (179)

            114

            1.08

            (0.80-1.46)

            17

            145

            1.16

            (0.91-1.49)

            34

            259

            1.14

            (0.95-1.36)

            51

            Kidney

            (180)

            1112

            1.01

            (0.86-1.19)

            159

            1460

            0.99

            (0.88-1.11)

            440

            2572

            0.99

            (0.91-1.08)

            599

            Urinary bladder

            (181)

            834

            1.04

            (0.88-1.22)

            141

            2295

            0.94

            (0.87-1.02)

            751

            3129

            0.96

            (0.89-1.03)

            892

            Melanoma

            (190)

            4919

            0.85

            (0.78-0.93)

            822

            2740

            0.96

            (0.88-1.04)

            802

            7659

            0.90

            (0.84-0.96)

            1624

            Squamous cell skin

            (191)

            708

            0.98

            (0.80-1.21)

            109

            1433

            0.89

            (0.81-0.97)

            514

            2141

            0.90

            (0.82-0.99)

            623

            Eye

            (192)

            480

            0.97

            (0.75-1.25)

            60

            181

            0.96

            (0.72-1.28)

            53

            661

            0.97

            (0.80-1.18)

            113

            Nervous system

            (193)

            6286

            1.16

            (1.05-1.29)

            658

            2192

            1.06

            (0.96-1.16)

            564

            8478

            1.13

            (1.05-1.21)

            1222

            Thyroid gland

            (194)

            1496

            1.00

            (0.87-1.14)

            219

            356

            1.12

            (0.89-1.41)

            89

            1852

            1.03

            (0.91-1.16)

            308

            Endocrine glands

            (195)

            1718

            1.00

            (0.88-1.14)

            256

            1189

            1.00

            (0.88-1.13)

            331

            2907

            1.01

            (0.92-1.10)

            587

            Bone

            (196)

            821

            1.04

            (0.84-1.29)

            91

            69

            1.12

            (0.71-2.17)

            15

            890

            1.08

            (0.89-1.31)

            106

            Connective tissue

            (197)

            1013

            0.96

            (0.81-1.14)

            135

            318

            0.94

            (0.76-1.17)

            97

            1331

            0.95

            (0.83-1.09)

            232

            Non-Hodgkin lymphoma

            (200, 202)

            2163

            1.00

            (0.85-1.18)

            282

            2038

            0.97

            (0.88-1.07)

            602

            4201

            0.98

            (0.90-1.07)

            884

            Hodgkin lymphoma

            (201)

            1736

            0.94

            (0.81-1.09)

            212

            141

            0.86

            (0.62-1.20)

            44

            1877

            0.93

            (0.81-1.07)

            256

            Myeloma

            (203)

            211

            1.32

            (0.89-1.94)

            25

            660

            0.96

            (0.82-1.11)

            207

            871

            1.00

            (0.87-1.15)

            232

            Leukaemia

            (204 - 209)

            3775

            1.30

            (1.07-1.59)

            343

            1429

            1.06

            (0.95-1.18)

            397

            5204

            1.20

            (1.08-1.33)

            740

            Other and unspecified sites

            (other)

            707

            1.00

            (0.81-1.24)

            97

            1766

            0.90

            (0.80-1.03)

            577

            2473

            0.93

            (0.84-1.02)

            674

            Any site

            (any)

            50261

            0.97

            (0.94-1.00)

            7208

            59426

            0.99

            (0.94-1.04)

            18001

            109687

            0.99

            (0.96-1.02)

            25209

            Reference group: one-child families. Bold type, 95% CI does not include 1.00. Poisson regression adjusted for age, sex, period, region, socioeconomic status. Ref: reference, N: number of cases

            The relative risk for cancer of the thyroid gland was marginally significantly decreased for birth order (P for trend = <.0001; data not shown). The relative risk for the second born (RR = 0.87) was slightly higher than for the third or fourth born (RR = 0.82) or higher birth orders (RR = 0.75).

            The relative risk for testicular cancer was inversely associated with family size (data not shown). It was decreasing with increasing family size. There was no significant combined effect with birth order even if the trend seemed to show an inverse association. Table 5 shows significantly decreased relative risks with increasing birth order for papillary (RR = 0.81, 95% CI: 0.72-0.92) and follicular thyroid gland tumors (RR = 0.70, 95% CI: 0.52-0.94).
            Table 5

            Relative risks for cancer of the thyroid gland

             

            All

            All

              

            Birth order *

            Ref

             

            Family size **

            Ref

            Cancer site

            N

            RR (95% CI)

            N

            N

            RR (95% CI)

            N

            Thyroid gland

                  

               papillary

            397

            0.81 (0.72-0.92)

            442

            736

            0.93 (0.77-1.12)

            103

               follicular

            58

            0.70 (0.52-0.94)

            82

            116

            0.76 (0.50-1.17)

            24

               medullary

            20

            0.81 (0.50-1.32)

            23

            37

            0.92 (0.49-1.74)

            6

               other

            31

            0.85 (0.59-1.24)

            45

            64

            1.17 (0.69-1.98)

            12

            Reference group: * = first born child, ** = one-child families. Bold type, 95% CI does not include 1.00. Poisson regression adjusted for age, sex, period, region, socioeconomic status.

            Ref: reference, N: number of cases

            In the separate analysis for the two groups of age at diagnosis (Figure 1), family size was positively associated with stomach cancer for age of diagnosis of at least 50 years. We found highly significant results independent of the birth order (one child families: RR = 0.67; two child families: RR = 0.73; three or four child families: RR = 0.75). Most of the stomach cancer cases occur with an age of diagnosis of at least 50 years and the separate analysis for the younger age group shows no significant associations.
            http://static-content.springer.com/image/art%3A10.1186%2F1471-2407-11-163/MediaObjects/12885_2010_2645_Fig1_HTML.jpg
            Figure 1

            Relative risks separated for age at diagnosis for lung and stomach cancer. Relative risks calculated with respect to birth order and family size. Bold type, 95% CI does not include 1.00. Poisson regression adjusted for age, sex, period, region, socioeconomic status

            Lung cancer was positively associated with birth order for lower age at diagnosis. The relative risk ranged from 1.02 for second born to 1.38 for third or fourth born offspring to 1.39 for the fifth born. In contrast the relative risk was not significant for different birth order when the age at diagnosis was at least 50 years even if a trend was still noticeable.

            Figure 2 shows a detailed analysis on endometrial cancer. There was an inverse association of risk and birth order for age at diagnosis below age 50. The relative risk ranges from 0.73 for second born to 0.74 for third or fourth born until 0.56 for at least fifth born with first born children are the reference. For age at diagnosis above 50 years the same trend was observed. Family size was negatively associated with relative risk for endometrial cancer for age at diagnosis below age 50 (one child families: RR = 0.65; two child families: RR = 0.64; three or four child families: 0.72). In contrast, the relative risk in the older age group was negatively associated with family size.
            http://static-content.springer.com/image/art%3A10.1186%2F1471-2407-11-163/MediaObjects/12885_2010_2645_Fig2_HTML.jpg
            Figure 2

            Relative risks separated for age at diagnosis for endometrial cancer. Relative risks calculated with respect to birth order and family size. Bold type, 95% CI does not include 1.00. Poisson regression adjusted for age, sex, period, region, socioeconomic status

            Discussion

            Our results show that there is an effect of family size and birth order on different cancer sites. A significantly decreased risk for testicular cancer by increasing birth order is in line with previously published results [5, 6]. Also family size was associated with testicular cancer which has been suggested to be the result of parental subfertility [28].

            Family size and birth order showed protective effects for melanoma, in agreement with previous results on socioeconomic status [15, 2931]. We observed a similar association for squamous cell carcinoma, which might be related to the same factors.

            Risk for cancer of the nervous system was positively associated with family size which is also supported by previous findings [32]. The number of siblings correlated with the risk for cancer suggesting an infectious etiology [33]. Some subtypes of leukemia as acute lymphoblastic leukemia have their origin in viral or bacterial infection [34, 35]. These can be shared easily in large families where all members have closer contact [36].

            Family size influenced the risk of stomach cancer. Offspring in families with five or more children had an increased risk which has also been shown in previous studies [19, 37]. Helicobacter pylori is an important cause of gastric cancer. The risk of infection is directly associated with sibship size [2, 3840]. As a consequence, members of larger families can easily share some infections.

            Risk for lung cancer was increased in large families, most likely because of an association with low socioeconomic status [41, 42]. An increasing risk with birth order and family size can clearly be seen for individuals diagnosed below age 50. This might be due to the fact that the effect of birth order and family size is stronger in younger ages, where children still live with their parents and siblings. The effect of birth order and family size decreased from early to later adulthood.

            Risk for endometrial cancer decreased with increasing birth order and family size. Family size showed a negative association for endometrial cancer in the group of people diagnosed before 50 years. This is in agreement with already published results reporting obesity as an important risk factor [21, 4345]. Obesity is associated with socioeconomic status [46, 47], which may explain the decreased risk of large families with lower socioeconomic status [7]. Low birth order has been shown to be associated with obesity, especially in young women [48]. This might be explained by dietary habits depending on paternal resource.

            Negative association between birth order and thyroid gland tumors is in line with already published results [14]. Nevertheless, more biological and epidemiological research is warranted to clarify the exact mechanisms through which higher birth order children have a decreased risk especially for subtypes as papillary and follicular thyroid gland tumors.

            There are some limitations to our study. The information of smoking was not registered in our data. We were not able to include the smoking habits in our analysis. This information might have explained the association of lung cancer and birth order in a better way. As well as active, passive smoking can also have an effect on the risk of lung cancer. Lower birth order could lead to more passive smoking if older siblings smoke during the individual's childhood. Active smoking has an effect on the risk of cancer which cannot be taken into account in our analysis. Additionally, the information of obesity was not present in our data which could have helped us to explain effects on the risk of endometrial cancer.

            Conclusion

            Our results agree with already published findings on the influence of birth order and family size in melanoma. As these can be explained by the socioeconomic status this could also be an explanation for squamous cell carcinoma which shows an association of risk with birth order and family size. Our findings show that the risk of endometrial cancer is associated with birth order and family size. This can be explained by dietary habits that differ in families with varying number of children. Family size and birth order are associated with different cancer sites not only because of the effect of socioeconomic status. Taken together, our results suggest that the effect of birth order and family size decreases from early to later adulthood for some cancer sites as lung cancer and endometrial cancer.

            Abbreviations

            CI: 

            Confidence interval

            RR: 

            relative risk

            ICD: 

            International Classification of Disease.

            Declarations

            Acknowledgements

            Supported by Deutsche Krebshilfe, the Swedish Cancer Society, The Swedish Council for Working Life and Social Research, LSHC-CT-2004-503465. The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.

            Authors’ Affiliations

            (1)
            Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ)
            (2)
            Center for Primary Health Care Research, Lund University
            (3)
            Stanford Prevention Research Center, Stanford University School of Medicine

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            Copyright

            © Bevier et al; licensee BioMed Central Ltd. 2011

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.