Abstract
Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33,086 participants of the Nurses’ Health Study II and the Nurses’ Mothers’ Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8,575 (25.9%) mothers and 18,874 (57.0%) fathers smoked during pregnancy. During follow-up, 7,825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥15 cigarettes/day during pregnancy were associated with increased risks of hypertension (RR 1.19, 95% CI 1.09 to 1.29, and RR 1.18, 95% CI 1.12 to 1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, while additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (RR 1.07, 95% CI 0.98 to 1.16, and RR 1.06, 95% CI 1.01 to 1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms.
Keywords: Pregnancy, parental smoking, hypertension, body mass index
Introduction
Fetal developmental adaptations to a suboptimal intrauterine environment may affect the structure, physiology and function of various organ systems. These adaptations lead to a better short-term survival through fetal growth retardation, but may increase the susceptibility of cardiovascular disease in adulthood.1 This hypothesis is supported by various studies reporting consistent associations between lower birth weight and the risk of hypertension in adulthood.2–4 Indeed, birth weight is a product of genetic and environmental factors affecting fetal growth and gestation length, but the specific intrauterine exposures and mechanisms linking low birth weight to an elevated risk of hypertension are not well understood.
Parental smoking during pregnancy is an established risk factor of a compromised intrauterine environment and might lead to developmental adaptations influencing postnatal blood pressure levels. Epidemiologic studies of parental smoking during pregnancy and blood pressure levels in offspring have demonstrated inconsistent results5–14, and the mechanisms through which prenatal smoke exposure might program blood pressure in later life are unclear. Prenatal smoke exposure is associated with reduced birth weight and increased risk of overweight in both childhood and adulthood. (Holly R. Harris, Walter C. Willett, Karin B. Michels, unpublished data, 2012)14–16 Birth weight is inversely associated with blood pressure in later life2–4, and overweight in adulthood is positively associated with the risk of hypertension, as demonstrated in Framingham Heart Study participants.17 Therefore, birth weight and body weight throughout life might mediate the association between maternal smoking and blood pressure development. Thus far, the majority of studies has been conducted in child populations, and has mainly focused on the effect of maternal smoking only on blood pressure development. The impact of parental smoking during pregnancy on the risk of adult hypertension is unclear.
Therefore, the aims of this study were to assess the associations of maternal and paternal smoking during pregnancy with hypertension in adulthood, and to examine whether birth weight or body weight throughout life explain these associations, in a large cohort of US women.
Methods
Study population
The Nurses’ Health Study II (NHS II) is an ongoing prospective cohort study of 116,430 female registered nurses that started in 1989.18 Participants are followed up via biennial self-administered questionnaires that inquire about health-related lifestyle, anthropometric variables and medical events. In 2001, the mothers of approximately 35,794 NHS II participants were enrolled in the Nurses’ Mothers’ Cohort.19 The participating mothers completed a questionnaire on the prenatal, perinatal and early-life exposures of the nurse daughters. The 113 Nurses who were adopted were excluded from the study, as were 1,013 nurses without information about maternal and paternal smoking during pregnancy with the nurse daughter. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard School of Public Health, Boston, USA, and the National cancer Institute, Bethesda, Maryland, USA.
Assessment of parental smoking
Information on smoke exposure in utero was collected on the 2001 Nurses’ Mothers’ Cohort questionnaire.20 Mothers were asked to report if they ever smoked cigarettes during pregnancy with the nurse daughter, the number of cigarettes they smoked daily during pregnancy, whether they stopped smoking during pregnancy, and if so, during which trimester. Maternal smoking was categorized as never smoked; stopped smoking in first trimester of pregnancy, continued smoking <15 cigarettes/day during pregnancy; and continued smoking ≥15 cigarettes/day during pregnancy. The questionnaire also inquired if the nurse’s father ever smoked during pregnancy and the number of cigarettes he smoked. Paternal smoking was categorized as never smoked; smoked <15 cigarettes/day during pregnancy; and smoked ≥15 cigarettes/day during pregnancy. To investigate the association of both parents smoking independent and combined with the risk of hypertension, maternal and paternal smoking during pregnancy data were categorized into no parental smoking during pregnancy; only paternal smoking during pregnancy; and maternal smoking only and both parents smoking during pregnancy.
Ascertainment of hypertension
The baseline and biennial follow-up questionnaires of the NHS II asked participants about physician-diagnosed hypertension and the year of diagnosis. Self-reported hypertension was previously validated in the NHS II.21 Review of the medical records of a randomly selected subset of participants, suggested a sensitivity of self-reported hypertension of 94% and a specificity of a nurse reporting no diagnosis of hypertension of 85%. For the current analysis, 1,582 women who reported physician-diagnosed hypertension at baseline (1989) were considered to have early onset, prevalent hypertension. Incident cases included participants who first reported hypertension on any of the subsequent questionnaires and whose date of diagnosis was after the return of the 1989 baseline NHS II questionnaire. For the analyses on incident cases, prevalent cases were excluded from the analysis, as the exact onset of their hypertension could not be dated.
Covariates
Information about covariates was obtained from the Nurses’ Mothers’ Cohort as well as the NHS II questionnaires. The 2001 Nurses’ Mothers’ Cohort questionnaire collected data on the nurse daughter’s gestational age, birth weight and breastfeeding status, maternal and paternal age at birth of the nurse daughter, educational level, occupation and home ownership at the time of the daughter’s birth, maternal prepregnancy weight, paternal weight and the occurrence of pregnancy complications (preeclampsia and eclampsia) during the pregnancy of the nurse daughter. The 1989 NHS II questionnaire assessed age, height, weight at age 18, self-classified race of the nurse, and family history of hypertension at baseline. To assess body fatness in childhood, a nine-level figure drawing originally developed by Stunkard22 was used to ascertain body shape at ages 5 and 10. Few participants reported their body fatness as greater than level 5 at ages 5 and 10, and therefore figures 5–9 were combined into a single category. Nurses’ weight, smoking status and oral contraceptive use were additionally ascertained from the 1989 NHS II questionnaire and were updated with data from each biennial questionnaire cycle. Body mass index (BMI) at age 18 and current BMI were calculated by dividing the participants’ reported weight in kilograms by height in meters squared as assessed in 1989. A Dietary Approaches to Stop Hypertension (DASH) score was calculated from the 1991 semi-quantitative food frequency questionnaire and updated every 4 years.23 The DASH score was constructed based on foods and nutrients emphasized or minimized in the DASH diet24, focusing on 8 components: high intake of fruits, vegetables, nuts and legumes, low-fat dairy products and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats. Information on alcohol intake was also retrieved from the 1991 semi-quantitative food frequency questionnaire and updated every 4 years. Physical activity was expressed in metabolic equivalent task scores, and was ascertained in 1989, 1993, 1997, 2001 and 2005.
Statistical methods
Cox proportional hazards regression models were used to estimate the rate ratios (RR’s) and 95% confidence intervals (CI’s) of the risk of incident hypertension by maternal and paternal smoking. Participants contributed follow-up time from the return of the 1989 questionnaire to the report of physician diagnosed hypertension, death, or end of follow-up on June 1, 2007. To investigate the association of parental smoking on early onset hypertension, logistic regression models were used to estimate the odds ratio’s (OR’s) and 95% CI’s of prevalent hypertension in 1989 by maternal and paternal smoking. We considered birth weight, childhood somatotype and BMI in adolescence and adulthood as potential explanatory variables for the associations of maternal and paternal smoking during pregnancy with the risk of hypertension.
Regression models were adjusted for age (Model 1), and in addition for perinatal variables (maternal and paternal age at delivery, maternal prepregnancy BMI, paternal BMI, maternal and paternal educational level, occupation, house ownership at the time of the daughter’s birth, and the occurrence of pregnancy complications (preeclampsia and eclampsia) during the mothers’ pregnancy, nurses’ ethnicity, gestational age, breastfeeding status and family history of hypertension) (Model 2), for birth weight (Model 3), and for adult life variables (nurses’ husbands’ educational level, pretax household income, smoking, oral contraceptive use, height, DASH score, alcohol intake and physical activity) (Model 4). To examine whether body weight throughout life explained the associations, we additionally adjusted Model IV for body shape of the nurses at age 5, body shape at age 10 and BMI at age 18 (Model 5) or current BMI (Model 6). The proportion of the associations potentially explained by current BMI was estimated using a SAS macro that calculates the point and interval estimates of the percent of exposure effect explained by the intermediate variable (Mediate SAS; Harvard School of Public Health; available at http://www.hsph.harvard.edu/faculty/donna-spiegelman/software/mediate/).25 To investigate the association of both parents smoking independent and combined with the risk of hypertension, we compared the effect estimates of smoking by father only (N = 12,165), and mother only and both parents combined (N = 8,575), with no parental smoking during pregnancy (N =12,346). Trend tests were performed across the level of the number of cigarettes smoked. Effect modification by current BMI was assessed with a likelihood ratio test comparing the model with the cross-product term between the exposure variable and the potential effect modifier, to the model with main effects only. Because time of observation was between the return of the NHS II questionnaire in 1989 and the NHS II questionnaire in 2007 and exposure was assessed in 2001, both prospective and retrospective analyses were combined in the analyses on incident hypertension. Therefore, sensitivity analyses were performed restricting follow-up to the prospective component, between the return of the NHSII Questionnaire 2001 (exposure assessment) and the NHSII Questionnaire 2007 (outcome assessment).
All statistical analyses were performed using the Statistical Analysis System (SAS) statistical software version 9.2 (SAS Institute Inc, Cary, North Carolina).
Results
1,582 Women reported physician-diagnosed hypertension at baseline (1989). During 533,902 person-years of follow up, 7,825 incident cases of physician-diagnosed hypertension were reported. Participant characteristics by maternal smoking during pregnancy are presented in Table 1. As compared to mothers who never smoked during pregnancy, mothers who continued smoking 15 cigarettes/day or more, were more likely to have attended college, and did less often own a house at the time of the nurses’ birth. Daughters of mothers who continued smoking ≥15 cigarettes/day during pregnancy, were born with lower birth weight, were less frequently breastfed, were more often smokers in adulthood, and had a higher alcohol intake than daughters of mothers who did not smoke during pregnancy. In total 12,346 (37.3%) mothers of the study participants reported that neither parent smoked during pregnancy, 1,866 (5.6%) reported maternal smoking only, 12,165 (36.8%) reported paternal smoking only, and 6,709 (20.3%) reported that both parents smoked during pregnancy.
Table 1.
Age-standardized characteristics of the study population of the mothers, fathers and nurse participants of the Nurses’ Health Study II Cohort by maternal smoking during pregnancy
| Subject characteristics | Maternal smoking during pregnancy | |||
|---|---|---|---|---|
| No maternal smoking during pregnancy (N = 24,511) | Quitted smoking in 1st trimester (N = 1,092) | Continued smoking during pregnancy <15 cig/day (N = 4,232) | Continued smoking during pregnancy >=15 cig/day (N = 2,626) | |
| Maternal | ||||
| Age at daughter’s birth (years) | 26.5 (5.1) | 25.4 (4.4) | 26.2 (4.7) | 25.8 (4.6) |
| BMI before pregnancy (kg/m2) | 21.4 (2.6) | 20.9 (2.3) | 20.9 (2.4) | 21.0 (2.6) |
| Attended college (%) | 36 | 42 | 41 | 38 |
| Professional occupation (%) | 3 | 4 | 3 | 3 |
| Paternal | ||||
| Age at daughter’s birth (years) | 29.2 (5.7) | 28.1 (5.3) | 29.1 (5.4) | 28.9 (5.3) |
| BMI (kg/m2) | 23.6 (2.8) | 23.5 (2.8) | 23.6 (2.7) | 23.5 (2.8) |
| Attended college (%) | 41 | 50 | 49 | 47 |
| Professional occupation (%) | 30 | 34 | 33 | 35 |
| Smoked during pregnancy (%) | 50 | 74 | 79 | 80 |
| Family owned house at daughter’s birth (%) | 49 | 38 | 44 | 43 |
| Pregnancy and childhood | ||||
| Preeclampsia or eclampsia during pregnancy (%) | 4 | 4 | 3 | 3 |
| Gestational age at birth (weeks) | 39.4 (2.3) | 39.5 (2.4) | 39.3 (2.4) | 39.2 (2.5) |
| Birth weight (g) | 3,336 (502) | 3,258 (510) | 3,162 (512) | 3,113 (512) |
| Ethnicity white (%) | 96 | 96 | 97 | 98 |
| Family history of hypertension (%) | 50 | 54 | 49 | 50 |
| Breastfed in infancy (%) | 56 | 46 | 43 | 44 |
| Body shape at age 5 <level 5 (%) | 94 | 93 | 93 | 93 |
| Body shape at age 10 <level 5 (%) | 89 | 89 | 87 | 88 |
| BMI at age 18 (kg/m2) | 20.9 (3.0) | 21.1 (3.0) | 21.3 (3.1) | 21.5 (3.4) |
| Adulthood (baseline, 1989) | ||||
| Age in 1989 (years)* | 34.3 (4.7) | 33.8 (4.5) | 34.0 (4.5) | 33.2 (4.4) |
| Smoking | ||||
| Never (%) | 71 | 62 | 61 | 62 |
| Past (%) | 20 | 25 | 25 | 23 |
| Current (%) | 9 | 13 | 14 | 15 |
| Oral contraceptive use | ||||
| Never (%) | 17 | 13 | 15 | 15 |
| Past (%) | 68 | 72 | 70 | 70 |
| Current (%) | 15 | 15 | 14 | 14 |
| Pretax household income >75,000 dollar (%) | 57 | 61 | 59 | 60 |
| Husband attended college (%) | 82 | 83 | 84 | 83 |
| Height (cm) | 165 (7.0) | 165 (7) | 165 (7) | 164 (7) |
| BMI (kg/m2) | 23.3 (4.4) | 23.5 (4.5) | 23.6 (4.5) | 24.0 (4.7) |
| Physical activity (METs/wk)† | 24.1 (34.1) | 24.4 (31.9) | 25.0 (34.6) | 26.1 (39.1) |
| Alcohol intake (g/day) | 2.9 (5.7) | 3.6 (5.4) | 3.8 (6.5) | 3.7 (6.9) |
| DASH score | 24.0 (5.1) | 24.2 (5.1) | 24.1 (5.1) | 23.8 (5.2) |
Abbreviations: BMI, body mass index
Values are means (SD) unless otherwise indicated
Value is not age adjusted
Metabolic equivalents from recreational and leisure-time activities
In the age-adjusted Cox proportional hazards model, maternal smoking of ≥15 cigarettes/day during pregnancy was associated with an increased incidence of hypertension in the offspring as compared to no maternal smoking during pregnancy (RR 1.19, 95% CI 1.09, 1.29) (Table 2). Adjustment for perinatal variables, birth weight and adult life variables did not appreciably change the observed associations. The RR’s were decreased by additional adjustment for body shape at age 5, body shape at age 10 and BMI at age 18 (RR 1.13, 95% CI 1.03, 1.23), and inclusion of current BMI completely eliminated the associations (RR 1.07, 95% CI 0.98, 1.16). In the age-adjusted models we did not observe an increased risk when mothers reported first trimester smoking only, or continued smoking of <15 cigarettes/day during pregnancy, although our results suggested a dose-response trend (P for trend <0.01). The trend test was no longer significant after additional adjustment for current BMI of the nurse. Body mass index was estimated to mediate 60% (95% CI 10%, 111%) of the association between maternal smoking of 15 cigarettes/day or more and the risks of adult onset hypertension accounting for possible confounding variables. Using similar models focused on the associations of the number of cigarettes smoked during pregnancy by the father with the risk of hypertension in the offspring, we observed in the age-adjusted models that as compared to no paternal smoking during pregnancy, paternal smoking of 15 cigarettes/day or more was associated with an increased risk of hypertension in the adult offspring (RR 1.18, 95% CI 1.12, 1.25) (Table 2). The RR’s only slightly changed after adjustment for perinatal variables, birth weight and adult life variables. Similarly, the effect of the quantity of paternal smoking attenuated after adjustment for body weight throughout life, although the associations of paternal smoking of 15 cigarettes/day or more remained significant. The estimated mediation proportion indicated that current BMI accounted for 49% (95% CI 22%, 76%) of the association between paternal smoking of 15 cigarettes/day or more and the risks of adult onset hypertension adjusting for possible confounders.
Table 2.
Maternal and paternal smoking during pregnancy and the risk of incident hypertension in the participants of the Nurses’ Health Study II Cohort
| Maternal smoking | Paternal smoking | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Level of adjustment | Non-smoker | Quitted smoking in 1st trimester | Continued smoking <15 cig/day | Continued smoking ≥15 cig/day | P for trend* | Non-smoker | <15 cig/day | ≥15 cig/day | P for trend * |
| Person years | 395,471 | 17,795 | 68,490 | 42,138 | 231,171 | 113,948 | 179,442 | ||
| No. of cases | 5,777 | 247 | 988 | 650 | 3,092 | 1,740 | 2,848 | ||
| RR (95% CI) | |||||||||
| Model 1 Adjusted for age | Reference | 1.02 (0.89, 1.16) | 1.01 (0.94, 1.08) | 1.19 (1.09, 1.29) | <0.01 | Reference | 1.07 (1.00, 1.13) | 1.18 (1.12, 1.25) | <0.01 |
| Model 2 Additionally adjusted for perinatal variables† | Reference | 1.04 (0.91, 1.19) | 1.02 (0.95, 1.10) | 1.20 (1.10, 1.31) | <0.01 | Reference | 1.05 (0.99, 1.12) | 1.15 (1.09, 1.21) | <0.01 |
| Model 3 Additionally adjusted for birth weight | Reference | 1.03 (0.90, 1.18) | 1.01 (0.94, 1.08) | 1.18 (1.08, 1.28) | <0.01 | Reference | 1.04 (0.98, 1.11) | 1.14 (1.08, 1.20) | <0.01 |
| Model 4 Additionally adjusted for adult life variables‡ | Reference | 1.05 (0.92, 1.19) | 1.00 (0.93, 1.08) | 1.18 (1.08, 1.28) | <0.01 | Reference | 1.04 (0.98, 1.11) | 1.13 (1.07, 1.19) | <0.01 |
| Model 5 Model 4 additionally adjusted for body shape and weight until age 18§ | Reference | 1.03 (0.90, 1.17) | 0.97 (0.90, 1.04) | 1.13 (1.03, 1.23) | 0.03 | Reference | 1.03 (0.97, 1.10) | 1.11 (1.05, 1.17) | <0.01 |
| Model 6 Model 4 additionally adjusted for current BMI | Reference | 0.99 (0.87, 1.13) | 0.95 (0.88, 1.01) | 1.07 (0.98, 1.16) | 0.31 | Reference | 1.01 (0.95, 1.08) | 1.06 (1.01, 1.12) | 0.02 |
Abbreviations: CI, confidence interval; BMI, body mass index; RR, Rate Ratio
P for trend across non-smokers, smoking 1–14 cigarettes/day and smoking ≥15 cigarettes/day
Maternal and paternal age at time of daughter’s birth, maternal prepregnancy BMI, paternal BMI, maternal and paternal educational level, maternal and paternal occupation, house ownership of parents at the time of the daughter’s birth, the occurrence of pregnancy complications during pregnancy, and nurse’s ethnicity, gestational age, breastfeeding status, and family history of hypertension
Nurse’s husbands’ educational level, pretax household income, nurse’s smoking behavior, oral contraceptive use, height, DASH score, and physical activity
Nurses’ body shape at age 5, body shape at age 10, and BMI at age 18
In the age-adjusted models, paternal smoking only, as well as maternal smoking only and both parents smoking during pregnancy combined, were associated with an increased risk of adulthood hypertension (Table 3); the strongest association was found for both parents smoking during pregnancy (RR 1.13, 95% CI 1.07, 1.20). However, the associations were reduced after adjusting for childhood body shape and BMI at age 18, and were eliminated when current BMI was added to the models (RR 1.01, 95% CI 0.95, 1.08).
Table 3.
Parental smoking during pregnancy and the risk of incident hypertension in the participants of the Nurses’ Health Study II Cohort
| Parental smoking during pregnancy | ||||
|---|---|---|---|---|
| Level of adjustment | No parental smoking | Paternal smoking only | Maternal or both parents smoking | P-Value* |
| Person-years | 200,551 | 194,920 | 138,431 | |
| No. of cases | 2,699 | 3,078 | 2,048 | |
| RR (95% CI) | ||||
| Model 1 Adjusted for age | Reference | 1.12 (1.06, 1.18) | 1.13 (1.07, 1.20) | <0.01 |
| Model 2 Additionally adjusted for perinatal variables† | Reference | 1.09 (1.03, 1.15) | 1.13 (1.06, 1.20) | <0.01 |
| Model 3 Additionally adjusted for birth weight | Reference | 1.08 (1.03, 1.14) | 1.11 (1.04, 1.18) | <0.01 |
| Model 4 Additionally adjusted for adult life variables‡ | Reference | 1.08 (1.02, 1.14) | 1.11 (1.04, 1.18) | <0.01 |
| Model 5 Model 4 additionally adjusted for body shape and weight until age 18§ | Reference | 1.07 (1.01, 1.13) | 1.06 (1.00, 1.13) | 0.04 |
| Model 6 Model 4 additionally adjusted for current BMI | Reference | 1.04 (0.99, 1.10) | 1.01 (0.95, 1.08) | 0.59 |
Abbreviations: CI, confidence interval; BMI, body mass index; RR, Rate Ratio
P for trend across no parental smoking, paternal smoking only and maternal or both parents smoking
Maternal and paternal age at time of daughter’s birth, maternal prepregnancy BMI, paternal BMI, maternal and paternal educational level, maternal and paternal occupation, house ownership of parents at the time of the daughter’s birth, the occurrence of pregnancy complications during pregnancy, and nurse’s ethnicity, gestational age, breastfeeding status, and family history of hypertension
Nurse’s husbands’ educational level, pretax household income, nurse’s smoking behavior, oral contraceptive use, height, DASH score, and physical activity
Nurses’ body shape at age 5, body shape at age 10, and BMI at age 18
No significant interactions were observed for the risk of hypertension, by current BMI. When restricting follow-up to incident events counted after exposure assessed in 2001, the RR’s of the fully adjusted models were slightly higher for both maternal smoking in first trimester only and continued smoking of <15 cigarettes/day, and marginally lower for maternal smoking ≥15 cigarettes/day. The RR’s of the fully adjusted models of paternal smoking remained stable, with larger confidence intervals.
Comparably, in the logistic regression models on prevalent hypertension cases in 1989, the associations of the quantity of both maternal and paternal smoking during pregnancy decreased after adding body weight throughout life to the models, and were completely eliminated after adjustment for current BMI (OR 0.99, 95% CI 0.81, 1.21, and OR 1.05, 95% CI 0.92, 1.18, respectively) (please see http//:hyper.ahajournals.org). Adding body weight throughout life to the logistic regression models similarly decreased the association of both parents smoking independent and combined, compared to no parental smoking during pregnancy with the risk of early onset hypertension (please see http//:hyper.ahajournals.org).
Discussion
In this prospective cohort study of 33,086 nurses, we observed weak positive associations between both maternal and paternal smoking during pregnancy with the risk of hypertension in their adult daughters. However, observed associations were largely eliminated after adjustment for body weight throughout life, with BMI closest to the diagnosis of hypertension having the greatest impact. Most of the effect of parental smoking during pregnancy on the daughter’s hypertension risk was mediated through current BMI, but some independent effect remained.
Blood pressure shows moderate tracking between childhood and adulthood26, and factors that influence blood pressure in early life might have consequences for the risk of hypertension in later life. Studies of parental smoking during pregnancy in relation to the development of blood pressure in the offspring have mainly focused on childhood blood pressure and had inconsistent results. Several studies suggested a positive association of fetal smoke exposure with blood pressure during childhood5–8, while other studies found no evidence of an effect of maternal smoking on blood pressure.9–10 A systematic review of nine observational studies suggested that maternal smoking during pregnancy was associated with a slightly elevated blood pressure in children.12 The inconsistent results between studies might be explained by a diminishing influence of parental smoking behavior during pregnancy on offspring blood pressure with increasing age, when influences from behavior and environmental factors such as BMI become increasingly important. In adult participants of the 1958 British Birth Cohort, adult offspring of mothers who smoked during pregnancy had a higher blood pressure on average than offspring of non-smokers, but the associations were attenuated after adjustment for postnatal influences across life.14 Second, previous studies varied in the level of adjustment for possible confounders, most notably postnatal weight or BMI.
In the present analysis, adjustment for body weight throughout life attenuated considerably the association of parental smoking during pregnancy and adult hypertension. Previous studies suggested that intrauterine smoke exposure leads to adaptations in weight and predispose to an increased risk of overweight and obesity in the offspring in childhood, adolescence and adulthood.(Holly R. Harris, Walter C. Willett, Karin B. Michels, unpublished data, 2012)14–16 Obesity and weight gain are major risk factors for developing hypertension.17, 27 Thus the association of parental smoking during pregnancy with the risk of hypertension in adulthood might be mediated through the programming of body weight throughout life. These findings are supported by a study in children, which suggested that childhood BMI and weight trajectory largely mediated the associations of maternal smoking during pregnancy with the offspring’s systolic blood pressure at the age of seven.11 However, parental smoking in pregnancy may also be a proxy of behavioral lifestyle factors clustering in smoking families that not only affect the risk of adult onset hypertension, but also fosters the development of overweight and obesity throughout life.
Because of the inverse relation between birth weight and blood pressure in later life, and the widely acknowledged association of maternal smoking during pregnancy with birth weight, we also investigated the influence of birth weight on the association of parental smoking during pregnancy and adult hypertension. The influence of birth weight in the pathway appeared to be limited. In line with our findings, in a recent meta-analysis, the associations of fetal smoke exposure with child overweight were independent of birth weight.15
In the present study cohort, we observed similar effect estimates for the associations of paternal smoking during pregnancy with the risk of hypertension in the offspring, compared to maternal smoking. Although passive smoke exposure is known to cause cardiovascular disease in adults28, and maternal exposure to second hand smoke in pregnancy is associated with a reduction in birth weight29, the effect of maternal active smoking is expected to be larger than the effect of maternal second hand smoke exposure in pregnancy. If the associations between maternal smoking during pregnancy with blood pressure in the offspring would be due to direct intrauterine mechanisms, we would expect stronger effects for maternal than paternal smoking on health outcomes in the offspring. Moreover, the associations of numbers of cigarettes smoked by the parents and the specific period during pregnancy of fetal smoke exposure with risk of hypertension also attenuated after adjustment for life course body weight. Brion and colleagues reported in children aged seven years similar associations for maternal and paternal smoking during pregnancy with offspring systolic blood pressure.13 The authors subsequently concluded that differences in child blood pressure found in minimally adjusted models are not because of a biological influence of maternal smoking on the intrauterine environment, but rather are a marker for other environmental factors. In addition, the effects of postnatal passive smoke exposure might be more important than the effects of intrauterine smoke exposure, especially in childhood when children live in close proximity to their parents. In healthy preschool children, parental smoking during childhood was an independent risk factor for higher blood pressure in the offspring.30
A limitation of the study was that data on parental smoking and associated covariates were collected retrospectively after several decades. We expect that any resulting misclassification is likely to be non-differential with respect to adult disease status and would therefore bias the associations towards the null. However, in a subgroup of our study population a high agreement of the daughters’ reports of maternal smoking during pregnancy as compared to the mothers’ reports was reported (sensitivity ranged from 74% to 85% and specificity ranged from 90% to 95%, kappa = 0.72–0.81).20 Second, both prospective and retrospective analyses were combined. However, actual exposure took place a considerable time before the outcome of interest, and it is assumed that reporting of exposure is independent of the outcome of interest. In addition, in the sensitivity analysis performed with time of observation between 2001 and 2007, the results were not appreciably changed. Third, the diagnosis of hypertension was obtained through self-reports. Although hypertension reporting has been validated previously in the NHS II21, and self reported hypertension appeared strongly predictive of coronary heart disease in the Nurses’ Health Study I31, it cannot be excluded that misclassification has occurred. Finally, although comprehensive information about covariates was available, the possibility of residual confounding due to insufficient measured or unmeasured factors should be considered. The major strengths of the study are the large sample size and the availability of information on paternal smoking during pregnancy. The study relied primarily on maternal reports of parental smoking during pregnancy, which are likely to be superior to the reports of the daughters.
Perspectives
Parental smoking is a modifiable risk factor of compromised intrauterine environment and there is broad evidence of its deleterious effects on fetal health. Understanding the influence of adverse fetal environment on cardiovascular disease and its risk factors may have important implications on the knowledge of the etiology and prevention of cardiovascular disease. This study provides limited evidence of a direct intrauterine effect of prenatal smoke exposure on vascular function. The weak associations of maternal and paternal smoking during pregnancy with the risk of hypertension in adulthood were largely attenuated after adjustment for body weight throughout life. Our observations may be explained by a mediating role of BMI of the effect of parental smoking on hypertension through the programming of body weight throughout life, or a marker of unhealthy lifestyle behaviors clustering in smoking families, that influence the development of BMI. The exact mechanisms linking parental smoking, body weight and the risks of incident hypertension in adulthood remain subject for further investigation.
Novelty and Significance.
1. What is new?
Both paternal and maternal smoking during pregnancy are associated with adult onset hypertension.
These associations are largely explained by body weight throughout life, with body mass index closest to the diagnosis of hypertension having the greatest impact.
2. What is relevant?
Parental smoking is a modifiable risk factor of compromised intrauterine environment, and understanding the influence of this adverse fetal environment on cardiovascular disease and its risk factors may have implications on the knowledge of the etiology and prevention of cardiovascular disease.
3. Summary
The associations of maternal and paternal smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life.
Acknowledgments
Sources of funding
The Nurses’ Mothers’ Cohort Study was funded by the Intramural Research Program of the National Cancer Institute, Research Contract N02-RC-17027 from the National Cancer Institute, and by P.O. 263 MQ 411027 from the National Cancer Institute. NHS II is supported by Public Health Service grant CA50385 from the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Layla L. de Jonge was partially supported by Dutch Heart Foundation (nr. 2008B114), Erasmus Trust Fund and Foundation “De Drie Lichten” in The Netherlands.
Footnotes
Conflict of interest
The authors declare that they have no conflicts of interest.
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