Prenatal and Perinatal Factors and Risk of Cancer in Middle and Older Adulthood among Men

There is growing evidence that the intrauterine environment plays a role in long-term health outcomes of the offspring. Although a number of epidemiologic studies have demonstrated associations between prenatal and perinatal factors and cancer development during early life, particularly childhood leukemia (1–4), the influence on cancer risk during adulthood is less understood given the need for decades long follow-up in prospective studies. Factors such as higher birth weight and older maternal age have been positively associated with breast cancer incidence (5, 6), and are thought to be driven in part by exposure to different levels of hormones and growth factors in utero, ultimately leading to more cells at risk of malignant transformation. Among men, there has been evidence that prenatal factors are associated with risk of testicular cancer, which is often diagnosed during early adulthood (7). However, there have been relatively few population-based studies of other cancers, and those that have included men have largely been case–control in design and have typically assessed measures of birth size only (8–10). Therefore, we used data from the Health Professionals Follow-up Study (HPFS) to prospectively investigate associations between several prenatal and perinatal factors, as reported by the mothers of participants, and cancer incidence in middle and older adulthood over long-term follow-up.

The HPFS is a prospective cohort of 51,529 male health professionals, aged 40 to 75 years at enrollment in 1986. Study participants completed a questionnaire at baseline and biennially thereafter on demographics, diet, lifestyle, medical history, and disease outcomes. Follow-up rates at each cycle have been more than 90%. The study protocol was approved by the institutional review board (IRB) of Harvard T.H. Chan School of Public Health, and those of participating registries as required. Each participant provided written informed consent.

In 1994, mothers of 6,065 HPFS participants completed a mailed questionnaire which covered information related to her pregnancy and birth of the participant, including maternal age at birth, pregnancy and infant anthropometrics, and smoking and alcohol drinking during pregnancy. Among participants whose mothers filled out the Mothers' Questionnaire, we excluded those who had a history of cancer (other than nonmelanoma skin cancer) prior to the 1994 questionnaire, leaving 5,845 men in this analysis.

Data on prenatal and perinatal factors were ascertained from the Mothers' Questionnaire. Maternal age was calculated by subtracting reported mother's date of birth from date of birth of the HPFS participant, and categorized as <25 years, 25 to 29.9 years, 30 to 34.9 years, and ≥35 years. Mothers reported birth order of the participant, which included live births only. Mothers were asked to consult any available records to provide the most accurate information for reporting participant's birth weight, which we categorized as <2.5 kg, 2.5–3.9 kg, and ≥4 kg, as well as their own height and usual prepregnancy weight, which were used to calculate prepregnancy body mass index (BMI) and categorized as <18.5 kg/m², 18.5 to 20.9 kg/m², 21 to 24.9 kg/m², and ≥25 kg/m². Mothers selected from prespecified categories of weight gain during pregnancy, which included <10 pounds, 10–14 pounds, 15–19 pounds, 20–29 pounds, and ≥30 pounds, and was converted to kg in analyses. Maternal age, birth order, birth weight, prepregnancy BMI, and maternal weight gain were modeled continuously as well as categorically. The Mothers' Questionnaire additionally asked whether the participant was born prematurely (<2 weeks early, 2–4 weeks early, >4 weeks early), which was used to calculate gestational age, whether the participant was breastfed, and whether the mother smoked or drank alcohol during pregnancy.

Covariate information on other prenatal factors (maternal and paternal education) were also obtained from the Mothers' Questionnaire. Data on the participant's adult characteristics were obtained from the HPFS biennial questionnaires.

Participants reported cancer diagnoses on biennial questionnaires. Researchers obtained permission from study participants to obtain medical records and pathology reports in order to confirm the cancer diagnosis and extract information on anatomical location, stage, histologic type, and other clinical factors. Cancers were defined according to the International Classification of Diseases, 9th revision (ICD-9). The outcomes of interest in this study included overall cancer, as well as common cancer sites and groups: prostate cancer, melanoma, gastrointestinal cancer (including cancers of the esophagus, stomach, small intestine, colon, rectum, anus, liver, gallbladder, bile ducts, pancreas, and other digestive organs), and hematologic cancer (including lymphomas, multiple myeloma, and leukemias). Deaths were identified through the National Death Index and next-of-kin, and confirmed by an endpoints committee of physicians.

For the current study, baseline was defined as date of return of the 1994 questionnaire. Person-years were calculated from baseline to date of any incident cancer, death, loss to follow-up, or end of follow-up (January 31, 2014). Cox proportional hazards models with age as the underlying time scale were used to calculate HRs and 95% confidence intervals (CI) for associations between prenatal and perinatal factors and cancer outcomes. Multivariable-adjusted models were adjusted for current age, questionnaire time period, race, family history of cancer, maternal education, and paternal education. In separate models, we also adjusted for adult participant characteristics (height, multivitamin use, aspirin use, alcohol intake, physical activity, prostate-specific antigen testing, colonoscopy or sigmoidoscopy, Alternate Healthy Eating Index-2010, total energy intake, BMI, and smoking status), and mutually adjusted for other prenatal and perinatal factors.

In secondary analyses, we stratified analyses of weight gain during pregnancy by maternal prepregnancy BMI and birth weight. In addition, we assessed whether associations between adult height and cancer risk differed by birth weight. All analyses were performed using SAS version 9.4 (SAS Institute Inc), and statistical tests were two-sided and considered statistically significant at P < 0.05.

In the overall study population, 82.7% of men had a birth weight between 2.5 and 3.9 kg and 58.6% were firstborn (Table 1). Mothers had a mean (SD) age at delivery of 26.5 (4.5) years. Men with higher birth weight were more likely to have mothers who did not smoke during pregnancy, have a higher gestational age, and tended to be taller as adults. Adult BMI was similar across birth weight categories.

During 20 years of follow-up, 1,228 incident cancers were diagnosed, including 638 prostate, 115 melanoma, 136 gastrointestinal, and 115 hematologic cancers. In multivariable-adjusted models, men who had a birth weight ≥4 kg had an increased risk of overall cancer (HR, 1.21; 95% CI, 1.02–1.43) compared with those with a birth weight of 2.5 to 3.9 kg (Table 2). There was no difference in risk for men of low birth weight compared with those with a birth weight of 2.5 to 3.9 kg. Higher maternal weight gain during pregnancy (≥13.6 kg vs. 6.8–8.6 kg) was also positively associated with overall cancer risk (HR, 1.22; 95% CI, 1.02–1.46). These associations were similar when additionally adjusting for adult cancer risk factors and when mutually adjusting for the other perinatal factors (Supplementary Table S1). There were no significant associations for the other prenatal and perinatal factors. Men with higher birth weight and whose mothers had higher weight gain during pregnancy tended to have greater risk of specific cancers, although none of the associations were statistically significant, possibly due in part to smaller numbers of cases (Supplementary Table S2).

When stratified by maternal prepregnancy BMI, maternal weight gain of more than 13.6 kg was associated with higher risk of overall cancer for men whose mothers had a prepregnancy BMI less than 21 kg/m² (HR, 1.30; 95% CI, 1.00–1.67) but not for ≥21 kg/m² (HR, 1.13; 95% CI, 0.85–1.51; Table 3), although the test for multiplicative interaction was not significant (P = 0.36). Associations for maternal weight gain were similar when stratified by birth weight. There was no significant difference in the association between adult height and overall cancer risk by birth weight (Supplementary Table S3).

In this prospective cohort study of men, we found that higher birth weight and maternal weight gain during pregnancy were associated with increased risk of overall cancer during middle and older adulthood. These results persisted even after adjusting for adult BMI and other major adult cancer risk factors.

Studies of prenatal factors and adult cancer risk have most commonly been in the context of breast cancer. In particular, measures of birth size have been consistently shown in meta-analyses to be positively associated with breast cancer risk (5, 11, 12). Prenatal factors have been examined to a lesser extent among men, although birth weight has been shown to be modestly associated with cancers of the prostate (8), testes (13), and colon (14, 15) in some, but not all studies. Many early studies were case–control in design, though some used record linkages which would reduce recall bias. Cohort studies of prenatal factors and total adult cancer incidence that have included men are sparse and have also focused on birth size and utilized data from population-based registers in Scandinavian countries. A Swedish cohort study found that men had an 8% increased risk of overall adult cancer incidence per SD increase in birth weight (16), and positive associations for birth weight and most site-specific cancers were reported in a large study of men and women in Denmark (17). As information on maternal weight gain during pregnancy has generally not been collected prospectively, it has not been well studied in relation to cancers later in life, although higher maternal weight gain weight has been associated with increased breast cancer risk in two case–control studies (18, 19). The potential influence of maternal weight gain is also supported by its association with birth weight (20).

While the mechanisms underlying the associations between birth size (and possibly maternal weight gain) and cancer risk are not completely understood, these factors are thought to be markers of increased exposure to growth factors and hormones in the fetal environment, which can in turn lead to greater stem-cell numbers and proliferation. This hypothesis is supported by both epidemiologic and experimental studies. Birth weight has been correlated with levels of estrogen (21, 22) and insulin-like growth factors (IGF1, IGF2; refs. 23–25) during pregnancy, and studies have previously reported associations between intrauterine IGF1, IGF binding protein-3, and estriol with hematopoietic stem cell and progenitor populations in umbilical cord blood (e.g., CD34⁺, CD34⁺CD38⁻, and granulocyte–macrophage colony-forming units; ref. 26). Additionally, in vivo and in vitro evidence has shown stem-cell self-renewal and differentiation in response to IGF1 and estrogen (27, 28). Other mechanisms may also be important. Although not statistically significant, men with higher birth order tended to have lower risk of hematologic cancers in our analysis, a finding which has been found in some studies of childhood leukemia, under the “delayed infection” hypothesis (29).

Our study had a number of strengths, including prospective design, a high follow-up rate within a well-established cohort, and assessment of multiple prenatal and perinatal factors. We were also able to incorporate detailed data on many cancer risk factors which allowed for rigorous adjustment for confounding. Several limitations should also be noted. First, the reported prenatal and perinatal factors are subject to misclassification. However, these measures were based on data collected from mothers of participants, which are likely to be more accurate than those from the participants themselves. Maternal recall of pregnancy-related factors have been previously shown to be highly valid even decades later, with a study showing prepregnancy weight (r = 0.86), birth weight (r = 0.91), and smoking (r = 0.86) to be highly correlated with data collected during pregnancy an average of 32 years in the past (30). Misclassification would also likely be nondifferential given the prospective study design, and thus would be expected to bias the results towards the null. Second, although we adjusted for several potential confounders, we cannot rule out residual or unmeasured confounding. Third, we had limited sample size for site-specific analyses. Additional prospective cohort studies with larger numbers for specific cancer types are needed. Fourth, we were unable to study cancers that occur in earlier adulthood. However, these constitute a small proportion of cancers that develop during adulthood, and our follow-up included ages where a majority of cancers are diagnosed. Future prospective studies assessing multiple prenatal factors and cancer risk during early adulthood will be important.

In conclusion, we found that men who had a high birth weight or mothers with higher weight gain during pregnancy had greater risk of overall cancer as adults. These findings support the hypothesis that prenatal and perinatal exposures influence cancer risk during middle and older adulthood in men.

B.C. Fu reports grants from NIH and Prostate Cancer Foundation during the conduct of the study. I.M. Chowdhury-Paulino reports grants from NRSA T32 CA 009001 during the conduct of the study. L.A. Mucci reports grants from NCI, Janssen, and Prostate Cancer Foundation during the conduct of the study, as well as grants, personal fees, and other support from Bayer and grants from AstraZeneca outside the submitted work. No disclosures were reported by the other authors.

B.C. Fu: Data curation, software, formal analysis, investigation, methodology, writing–original draft, writing–review and editing. I.M. Chowdhury-Paulino: Investigation, methodology, writing–review and editing. E.L. Giovannucci: Conceptualization, supervision, writing–review and editing. L.A. Mucci: Conceptualization, supervision, funding acquisition, writing–review and editing.

We would like to thank the participants and staff of the HPFS for their valuable contributions, as well as the following US state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data. The HPFS is supported by NIH grant U01 CA167552. B.C. Fu and I.M. Chowdhury-Paulino are supported by NIH grant T32 CA009001. L.A. Mucci is supported by the Prostate Cancer Foundation.

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