Abstract
Background: Fetal exposure to parental smoking may have long-term impact on the development of disease in adulthood. We examined the association of parental smoking during pregnancy with risk of gestational diabetes mellitus (GDM) in the daughter.
Methods: We included 15 665 singleton pregnancies from 10 152 women in the Nurses' Health Study II cohort whose mothers participated in the Nurses’ Mothers’ Cohort Study. Data on maternal and paternal smoking during pregnancy and associated covariates were recalled by the mothers. GDM diagnosis was self-reported by the daughters and was validated by medical record review in a previous study. We used log-binomial models with generalized estimating equations to estimate relative risks (RRs) and 95% confidence intervals (CIs).
Results: We observed a positive association between maternal heavy smoking during pregnancy and risk of GDM in the daughter. The multivariable-adjusted RRs (95% CIs) of GDM among women whose mothers did not smoke during pregnancy, continued smoking 1–14, 15–24, and ≥25 cigarettes/day were 1.00 (reference), 1.05 (0.81–1.35), 1.27 (0.95–1.70) and 1.98 (1.18–3.30), respectively ( P for trend = 0.01). Further adjustment for the women’s perinatal variables, adult-life characteristics and body mass index during various periods of life modestly attenuated the association. No association was observed between paternal smoking during the pregnancy period and risk of GDM in the daughter.
Conclusions: Maternal heavy smoking (≥25 cigarettes/day) during pregnancy was associated with higher risk of gestational diabetes in the daughter. Further studies are warranted to confirm our findings and to elucidate the underlying mechanisms.
Keywords: Gestational diabetes mellitus, maternal smoking during pregnancy
Key Messages
This study examined the association of parental smoking during pregnancy with risk of gestational diabetes in the daughter among 15 665 singleton pregnancies from 10 152 women in the Nurses' Health Study II cohort whose mothers participated in the Nurses’ Mothers’ Cohort Study.
We demonstrated that maternal heavy smoking (≥25 cigarettes/day) during pregnancy was associated with higher risk of gestational diabetes in the daughter. We did not observe an association between paternal smoking during pregnancy and risk of gestational diabetes in the daughter.
Introduction
The developmental origins of health and disease hypothesis, or ‘Barker hypothesis’, 1 continues to fuel research interest in examining the health consequences of in utero exposures. Maternal smoking during pregnancy represents a common deleterious fetal exposure in many populations. 2–4 The short-term effects of maternal smoking during pregnancy on multiple adverse pregnancy and perinatal outcomes, including fetal growth restriction and low birthweight, have long been recognized and established. 5 Maternal smoking during pregnancy has also been associated with an increased risk of obesity during childhood and adulthood in some, although not all, studies. 6–10 There is limited evidence regarding the long-term impact of fetal exposure to maternal smoking on the risk of chronic disease in adulthood, which emerges as a new focus of research interests. 11
Gestational diabetes mellitus (GDM) is a common pregnancy complication characterized by glucose intolerance, with onset or first recognition during pregnancy. 12 GDM is not only associated with short-term adverse perinatal outcomes, 13 but also related to long-term metabolic risk in both mothers and their children. 12,14,15 Thus, it is crucial to identify modifiable risk factors that may contribute to the prevention of GDM in current and subsequent generations. Animal studies have suggested that fetal exposure to maternal smoking may lead to impaired glucose metabolism by altering pancreatic islet development and inducing beta cell apoptosis. 16,17 In addition, epidemiological studies, although still limited, suggest that maternal smoking during pregnancy may increase the risk of diabetes in adulthood. 18,19 However the association, in particular the dose-response relation, between fetal exposure to maternal smoking and risk of GDM is not well established. Moreover, no previous study has examined the association between fetal exposure to paternal smoking, a major source of maternal passive smoking, and subsequent risk of GDM. In this study, we aimed to examine the dose-response relation of maternal and/or paternal smoking during pregnancy with risk of GDM in the daughter.
Methods
Study population
The Nurses’ Health Study II (NHSII) is an ongoing prospective cohort study of 116 430 female nurses aged 24–44 years at study inception in 1989. The participants receive a biennial questionnaire regarding lifestyle behaviours, anthropometric variables and disease outcomes. In 2001, mothers of the NHSII participants were invited to complete a questionnaire regarding their nurse daughter. Details about the Nurses’ Mothers’ Cohort Study have been described elsewhere. 20 We included NHSII participants in the current analyses if they reported at least one singleton pregnancy lasting greater than 6 months between 1989 and 2001 and their mothers participated in the Nurses’ Mothers’ Cohort Study and reported data on pregnancy and perinatal variables associated with the nurse daughter. The NHSII participants were excluded if they had been adopted, were missing information on maternal smoking or had type 2 diabetes reported in 1989 or before GDM. Figure 1 depicts the flowchart of study participants. This study has been approved by the Partners Human Research Committee (Boston, MA), with participants’ consent implied by the return of the completed questionnaires.
Figure 1.
The flowchart of study participants. Exclusion criteria are not mutually exclusive and individual reasons may not total the number of excluded participants. GDM denotes gestational diabetes mellitus; NHSII, Nurses’ Health Study II; NMS, Nurses’ Mothers’ Cohort Study; T2DM, type 2 diabetes mellitus.
Assessment of parental smoking
We used information on parental smoking during pregnancy from the 2001 Nurses’ Mothers’ Cohort Study questionnaire. 21 The mothers reported whether they ever smoked cigarettes during pregnancy with the nurse daughter, the number of cigarettes (i.e. 1–14, 15–24, 25–34 or≥ 35) they smoked daily during pregnancy, whether they quit smoking during pregnancy, and if so, in which trimester. In a separate validation study, the validity of recalled maternal smoking during pregnancy was found to be high in the National Collaborative Perinatal Project (sensitivity = 0.86, specificity = 0.94). 22 We categorized maternal smoking as: never smoked; quit smoking in first trimester of pregnancy; continued smoking 1–14 cigarettes/day during pregnancy; continued smoking 15–24 cigarettes/day during pregnancy; and continued smoking 25 or more cigarettes/day during pregnancy. We also asked the mothers whether the nurse’s father ever smoked during pregnancy and the number of cigarettes he smoked. We categorized paternal smoking as: never smoked; smoked 1–14 cigarettes/day during pregnancy; smoked 15–24 cigarettes/day during pregnancy; and smoked 25 or more cigarettes/day during pregnancy. Previous studies based on the same cohort as the current analysis have found maternal smoking during pregnancy be associated with an increased risk of overweight and obesity in the daughter across adolescence and adult life. 7
Ascertainment of gestational diabetes
The NHSII participants (i.e. the daughters) reported prevalent GDM in 1989 and incident GDM on each biennial questionnaire through 2001. GDM was not ascertained after the 2001 questionnaire in the NHSII cohort, because the majority of NHSII participants had passed reproductive age by then. In a previous validation study among a subgroup of the NHSII cohort, 94% of GDM self-reports were confirmed by medical records. 23 In a random sample of parous women without GDM, 83% reported a glucose screening test during pregnancy and 100% reported frequent prenatal urine screenings, suggesting a high level of GDM surveillance in this cohort. 23
Covariates assessment
Covariates for maternal, paternal and perinatal characteristics were obtained from the Nurses’ Mothers’ Cohort Study. The 2001 Nurses’ Mothers’ Cohort Study questionnaire requested data on the daughter’s gestational age at birth, birthweight and breastfeeding status, maternal and paternal age at birth of the daughter, educational level, occupation and home ownership at the time of the daughter’s birth, maternal height, maternal pre-pregnancy weight, weight gain during pregnancy (< 10, 10–14, 15–19, 20–29, 30–40, > 40 pounds; to convert pounds into kilograms, multiply pounds by the conversion factor 0.453592.), paternal weight, paternal height, maternal consumption of alcoholic beverages during pregnancy, and the occurrence of maternal pregnancy complications (gestational diabetes and preeclampsia) during the pregnancy of the daughter.
Covariates related to the daughters’ characteristics were obtained from the NHSII questionnaires. The 1989 NHSII questionnaire assessed the daughters’ age, height, race/ethnicity and family history of diabetes at baseline. The daughters’ weight at 18 years old and current weight, parity, and smoking status (including the number of cigarettes per day) were self-reported from the 1989 NHSII questionnaire and were updated with data from each biennial questionnaire cycle. Self-reported weight was highly correlated with measured weight (r = 0.97) in a previous validation study. 24 Body mass index (BMI) was computed as weight in kilograms divided by height in metres squared. Dietary intake was collected every 4 years since 1991 using a previously validated semi-quantitative food frequency questionnaire. 25–27 To assess the overall diet quality of the participants, we derived a diet score, the Alternate Healthy Eating Index 2010 (AHEI-2010) for each participant, as previously described. 28 The overall AHEI-2010 ranged from 0 to 110 points, with a higher score indicating a better diet quality. Physical activity was ascertained in 1989, 1991, 1997 and 2001 by frequency of engaging in common recreational activities, from which metabolic equivalent (MET)-hours per week were derived. The questionnaire-based estimates of total physical activity correlated well with detailed activity diaries in a previous validation study (r = 0.56). 29 Cumulative average of physical activity, total energy intake and AHEI-2010 score were calculated for each individual at each time period throughout the follow up, to reduce within-subject variation and represent long-term habitual diet and physical activity. 30
Statistical analysis
We used log-binomial models with generalized estimating equations to estimate the relative risks (RRs) and 95% confidence intervals (CIs) of GDM for maternal and paternal smoking, separately and jointly. Generalized estimating equations allowed us to account for correlations among repeated observations (pregnancies) contributed by a single participant (i.e. the nurse daughter). In the multivariable regression models, we adjusted for: age and race/ethnicity of the daughters (Model 1); and additionally for maternal and paternal variables including maternal and paternal age at time of daughter’s birth, maternal pre-pregnancy BMI, paternal BMI, maternal weight gain during pregnancy, maternal pregnancy complications (gestational diabetes, preeclampsia) and maternal alcohol consumption during pregnancy (Model 2); for the daughters’ perinatal variables including gestational age at birth, birthweight, and breastfeeding status (Model 3); for the daughters’ adult life variables including parity, family history of diabetes, cigarette smoking, total energy intake, overall diet quality (i.e. Alternate Healthy Eating Index) and physical activity (Model 4); for the daughters’ BMI at 18 years old (Model 5); and for the daughters’ pre-pregnancy BMI (Model 6). We mutually adjusted for maternal and paternal smoking during pregnancy in all these models. Wald tests were used to assess the differences between maternal and paternal associations. The daughters’ BMI and other adult life covariates were updated during the follow-up. When categorizing each categorical covariate, we created a category for missing data. We considered Model 3–Model 6 as sensitivity analyses, because the daughter’s perinatal variables, adult-life variables and adulthood BMI in these models are potential intermediates or explanatory variables for the associations of maternal and paternal smoking during pregnancy with the risk of GDM. Tests for linear trend were performed across the categories of the number of cigarettes smoked for mothers who continued to smoke throughout pregnancy, with non-smoking during pregnancy as the reference group (for maternal smoking, the test for trend excluded the category of mothers who quit smoking during pregnancy). Statistical analyses were performed using the SAS statistical software version 9.2 (SAS Institute Inc., Cary, NC) and the Stata statistical software version 14.0 (StataCorp LP, College Station, TX).
Results
We included 15 665 singleton pregnancies from 10 152 women in the Nurses' Health Study II cohort whose mothers participated in the Nurses’ Mothers’ Cohort Study. Of them, 736 GDM pregnancies were documented. Characteristics of mothers, fathers and daughters are shown in Table 1 according to maternal smoking status during pregnancy. Mothers who smoked more frequently during pregnancy were more likely to consume alcoholic beverages during the pregnancy. The biological fathers of the daughters whose mothers smoked during pregnancy were also more likely to smoke during the pregnancy. Women who were exposed to frequent maternal smoking during pregnancy had a lower birthweight, were less likely to be breastfed and were heavier and more likely to smoke in adulthood.
Table 1.
Age-standardized maternal, paternal, and the daughter’s characteristics by maternal smoking status during pregnancy a
|
Maternal cigarette smoking during pregnancy
|
|||||
|---|---|---|---|---|---|
| Non-smoker | Quit smoking in the first trimester | Continued smoking 1–14 cigarettes/day | Continued smoking 15–24 cigarettes/day | Continued smoking ≥ 25 cigarettes/day | |
| Number of participants | 7478 | 373 | 1369 | 793 | 139 |
| Maternal characteristics | |||||
| Age at daughter’s birth (years) | 26.68 (4.83) | 25.33 (4.34) | 26.39 (4.75) | 26.23 (4.66) | 26.90 (4.65) |
| Prepregnancy BMI (kg/m 2 ) | 21.41 (2.60) | 21.00 (2.26) | 20.88 (2.46) | 21.09 (2.70) | 21.24 (2.61) |
| Attended college (%) | 40.21 | 47.11 | 43.04 | 40.89 | 46.57 |
| Ever consumed alcoholic beverages during pregnancy (%) | 25.03 | 44.82 | 60.43 | 63.59 | 63.68 |
| Pregnancy complications b (%) | 4.03 | 4.26 | 3.90 | 3.84 | 3.44 |
| Paternal characteristics | |||||
| Age at daughter’s birth (years) | 28.70 (4.78) | 27.85 (4.68) | 28.59 (4.67) | 28.57 (4.64) | 29.63 (4.52) |
| BMI at daughter’s birth (kg/m 2 ) | 23.80 (2.81) | 23.86 (3.08) | 23.78 (2.80) | 23.72 (2.83) | 23.40 (2.75) |
| Attended college (%) | 45.90 | 54.68 | 51.51 | 48.45 | 57.90 |
| Ever smoked during pregnancy (%) | 44.61 | 71.72 | 73.86 | 78.26 | 74.26 |
| Characteristics of the daughter in early life | |||||
| Gestational age at birth (weeks) | 39.42 (2.26) | 39.55 (2.32) | 39.32 (2.40) | 39.12 (2.54) | 39.25 (2.54) |
| Birthweight (g) | 3358.28 (493.41) | 3291.89 (491.44) | 3176.63 (498.50) | 3070.21 (514.39) | 3056.42 (523.58) |
| Caucasian (%) | 95.05 | 95.42 | 96.03 | 95.84 | 95.86 |
| Breastfed during infancy (%) | 43.46 | 47.81 | 32.07 | 34.65 | 23.07 |
| Characteristics of the daughter during adulthood c | |||||
| Age in 1989 (years) | 30.62 (3.42) | 30.57 (3.27) | 30.85 (3.42) | 30.33 (3.31) | 30.40 (3.29) |
| BMI (kg/m 2 ) | 22.81 (3.93) | 23.01 (4.01) | 22.87 (3.64) | 23.32 (4.13) | 23.64 (4.66) |
| Nulliparous (%) | 7.68 | 7.50 | 6.02 | 8.21 | 5.81 |
| Family history of diabetes (%) | 10.08 | 8.51 | 8.60 | 7.55 | 7.88 |
| Current smoking (%) | 6.54 | 11.06 | 10.86 | 11.36 | 10.95 |
| Alcohol intake (g/day) | 2.55 (4.67) | 3.15 (4.79) | 3.42 (5.74) | 3.30 (5.66) | 3.33 (6.12) |
| Physical activity (MET-h/week) | 25.88 (36.49) | 26.26 (38.56) | 27.59 (37.17) | 28.19 (44.22) | 28.31 (34.78) |
| Total energy intake (kcal/day) | 1882.42 (545.50) | 1837.95 (522.48) | 1871.40 (549.03) | 1850.16 (540.46) | 1873.85 (559.33) |
| AHEI-2010 d | 47.42 (10.67) | 48.72 (10.70) | 48.38 (11.09) | 48.08 (10.56) | 47.85 (10.75) |
AHEI-2010 indicates Alternate Healthy Eating Index 2010; BMI, body mass index; MET, metabolic equivalent.
a Values are means (standard deviations) for continuous variables and percentages for categorical variables and are standardized to age distribution of the NHSII participants (i.e. the daughters).
b Maternal pregnancy complications included gestational diabetes and preeclampsia.
c Adulthood characteristics are provided for 1989, except diet information (i.e. total energy intake, alcohol intake and the derived alternate healthy eating index) which was first collected in the Nurses’ Health Study II cohort in 1991.
d AHEI-2010 was derived for each participant, as previously describe, 28 to assess the overall diet quality of the participants.
We observed a dose-response relation between in utero exposure to maternal smoking and risk of GDM ( Table 2 ). After adjustment for the daughter’s age, race/ethnicity and maternal and paternal variables, the RRs (95% CIs) of GDM among women whose mothers did not smoke during pregnancy or continued smoking 1–14, 15–24 or ≥ 25 cigarettes/day were 1.00 (reference), 1.05 (0.81–1.35), 1.27 (0.95–1.70) and 1.98 (1.18–3.30), respectively ( P for trend = 0.02). Further adjustment for the daughter’s perinatal variables and adult life variables, including pre-pregnancy BMI, only slightly changed the association. No association was observed between paternal smoking during pregnancy and the risk of GDM ( Table 3 ). Wald tests showed suggestive statistical evidence that the maternal smoking associations may differ from the paternal smoking associations with GDM risk ( P = 0.10). We further examined the joint effect of both maternal and paternal smoking during pregnancy on the risk of GDM. Women whose mother or both parents smoked during pregnancy ≥ 15 cigarettes/day had a higher risk of GDM (RR 1.43, 95% CI 1.11–1.85), compared with women whose parents did not smoke during pregnancy or smoked < 15 cigarettes/day ( Supplementary Figure 1 , available as Supplementary data at IJE online).
Table 2.
Maternal cigarette smoking during pregnancy and the risk of gestational diabetes in the daughter
|
Maternal cigarette smoking during pregnancy
|
P for trend d | |||||
|---|---|---|---|---|---|---|
| Non-smoker | Quit smoking in the first trimester | Continued smoking 1 – 14 cigarettes/day | Continued smoking 15 – 24 cigarettes/day | Continued smoking ≥ 25 cigarettes/day | ||
| GDM cases/pregnancies | 522/11525 | 33/559 | 95/2122 | 68/1238 | 18/221 | |
| Model 1: Adjusted for the daughter’s age and race/ethnicity | 1.00 | 1.26 (0.84–1.87) | 1.00 (0.79–1.28) | 1.22 (0.92–1.62) | 1.86 (1.12–3.09) | 0.02 |
| Model 2: Model 1 + additionally adjusted for maternal and paternal variables a | 1.00 | 1.27 (0.85–1.89) | 1.05 (0.81–1.35) | 1.27 (0.95–1.70) | 1.98 (1.18–3.30) | 0.01 |
| Model 3: Model 2 + additionally adjusted for the daughter’s perinatal variables b | 1.00 | 1.25 (0.84–1.86) | 1.01 (0.78–1.30) | 1.21 (0.90–1.63) | 1.89 (1.13–3.15) | 0.04 |
| Model 4: Model 3 + additionally adjusted for the daughter’s adult-life characteristics c | 1.00 | 1.28 (0.87–1.90) | 1.01 (0.78–1.30) | 1.23 (0.91–1.65) | 1.97 (1.20–3.24) | 0.02 |
| Model 5: Model 4 + additionally adjusted for the daughter’s BMI at age 18 years | 1.00 | 1.27 (0.86–1.87) | 1.00 (0.77–1.28) | 1.22 (0.91–1.64) | 1.88 (1.15–3.07) | 0.03 |
| Model 6: Model 5 + additionally adjusted for the daughter’s most recent pre-pregnancy BMI | 1.00 | 1.24 (0.85–1.81) | 1.00 (0.78–1.29) | 1.17 (0.88–1.56) | 1.85 (1.12–3.04) | 0.05 |
Paternal smoking during pregnancy was adjusted in all the models.
a The maternal and paternal variables included maternal and paternal age at time of the daughter’s birth, maternal pre-pregnancy body mass index, paternal body mass index, maternal weight gain during pregnancy, maternal pregnancy complications (gestational diabetes, preeclampsia), and maternal consumption of alcoholic beverages during pregnancy. The information was reported in the Nurses’ Mothers Study questionnaire.
b The perinatal variables included the daughter’s gestational age at birth, birthweight and breastfeeding status. The information was reported in the Nurses’ Mothers Study questionnaire.
c The daughters’ adult-life variables included parity, family history of diabetes, cigarette smoking, physical activity, total energy intake, and overall diet quality (i.e. Alternate Healthy Eating Index). The information was reported in the Nurses’ Health Study II questionnaire.
d P for trend across non-smokers, smoking 1–14 cigarettes/day, smoking 15–24 cigarettes/day and smoking ≥ 15 cigarettes/day.
Table 3.
Paternal cigarette smoking during pregnancy and the risk of gestational diabetes in the daughter
|
Paternal cigarette smoking during pregnancy
|
P for trend | ||||
|---|---|---|---|---|---|
| Non-smoker | 1–14 cigarettes/day | 15–24 cigarettes/day | ≥ 25 cigarettes/day | ||
| GDM cases/total participants | 350/7527 | 128/3071 | 166/3433 | 92/1634 | |
| Model 1: Adjusted for the daughter’s age and race/ethnicity | 1.00 | 0.91 (0.73–1.13) | 1.02 (0.83–1.26) | 1.19 (0.92–1.54) | 0.26 |
| Model 2: Model 1 + additionally adjusted for maternal and paternal variables a | 1.00 | 0.92 (0.74–1.15) | 1.02 (0.82–1.25) | 1.16 (0.90–1.51) | 0.32 |
| Model 3: Model 2 + additionally adjusted for the daughter’s perinatal variables b | 1.00 | 0.91 (0.73–1.13) | 1.01 (0.82–1.24) | 1.14 (0.88–1.48) | 0.38 |
| Model 4: Model 3 + additionally adjusted for the daughter’s adult-life characteristics c | 1.00 | 0.91 (0.73–1.14) | 1.00 (0.81–1.22) | 1.09 (0.84–1.41) | 0.59 |
| Model 5: Model 4 + Additionally adjusted for the daughter’s BMI at age 18 years | 1.00 | 0.91 (0.73–1.13) | 0.98 (0.80–1.21) | 1.07 (0.82–1.39) | 0.69 |
| Model 6: Model 5 + additionally adjusted for the daughter’s most recent pre-pregnancy BMI | 1.00 | 0.92 (0.74–1.15) | 0.99 (0.80–1.21) | 1.03 (0.80–1.33) | 0.86 |
BMI denotes body mass index.
Maternal smoking during pregnancy was adjusted in all the models.
a The maternal and paternal perinatal variables included maternal and paternal age at time of the daughter’s birth, maternal pre-pregnancy body mass index, paternal body mass index, maternal weight gain during pregnancy, maternal pregnancy complications (gestational diabetes, preeclampsia), and maternal consumption of alcoholic beverages during pregnancy. The information was reported in the Nurses’ Mothers Study questionnaire.
b The perinatal variables included the daughter’s gestational age at birth, birthweight and breastfeeding status. The information was reported in the Nurses’ Mothers Study questionnaire.
c The daughters’ adult-life variables included parity, family history of diabetes, cigarette smoking, physical activity, total energy intake and overall diet quality (i.e. Alternate Healthy Eating Index). The information was reported in the Nurses’ Health Study II questionnaire.
In an analysis on the joint effect of maternal smoking during pregnancy and the participants’ smoking during adulthood, we found that the women who smoked < 15 cigarettes/day and whose mothers smoked ≥ 15 cigarettes/day during pregnancy had an RR (95% CI) of 1.28 (1.00–1.64) for GDM, compared with neither the mothers nor the participants smoking ≥ 15 cigarettes/day ( Figure 2 ). We also performed a stratified analysis according to the daughters’ own smoking status. Among the daughters who never smoked, the adjusted RRs (95% CIs) of GDM were 1.30 (0.79–2.13), 0.94 (0.67–1.32), 1.13 (0.77–1.65) and 2.15 (1.19–3.88) for the daughters whose mothers smoked but quit smoking in the first trimester, continued smoking 1–14, 15–24 or ≥ 25 cigarettes/day, respectively, compared with those whose mothers did not smoke during pregnancy.
Figure 2.
Joint effect of maternal smoking during pregnancy and the daughter’s smoking during adulthood on the risk of GDM in the daughter. The symbol ‘+’ indicates smoking ≥ 15 cigarettes/day, ‘-’ indicates no smoking or smoking < 15 cigarettes/day. The symbol before and after the ‘/’ denotes smoking status of the mothers and the daughters, respectively. Covariates included the daughters’ age, maternal and paternal age at time of the daughter’s birth, maternal pre-pregnancy body mass index, paternal body mass index, maternal weight gain during pregnancy, maternal pregnancy complications (gestational diabetes, preeclampsia), maternal consumption of alcoholic beverages during pregnancy, paternal smoking during pregnancy, daughter’s race/ethnicity, gestational age at birth, breastfeeding status, birth eight, parity, family history of diabetes, physical activity, total energy intake, overall diet quality (i.e. Alternate Healthy Eating Index), BMI at 18 years old and updated adulthood BMI.
Discussion
We observed a positive association between maternal smoking during pregnancy and risk of GDM in the daughter. Specifically, maternal smoking of ≥ 25 cigarettes/day during pregnancy was associated with 98% higher risk of GDM in the daughter. The association was independent of other major risk factors during and after pregnancy and it was only slightly changed after adjustment for the daughter’s birthweight and adult life variables including pre-pregnancy BMI. We did not find an association between paternal smoking and GDM in the daughter.
With detailed information on smoking exposure as well as covariates during and after the pregnancy, our study expands previous findings on maternal smoking during pregnancy and GDM risk. The MoBa Cohort in Norway recently reported that in utero exposure to maternal tobacco smoke was associated with increased risk of GDM. 8 However, the dose-response relation between maternal smoking during pregnancy and GDM risk in the daughter was not assessed in that study (i.e. maternal smoking was assessed by yes versus no, without information on the dose). Furthermore, other maternal variables were not available in that study, which may have limited its ability to evaluate the impact of potential confounders on the observed association. A subsequent study using data from the Swedish Medical Birth Register yielded similar findings in a younger population (age range 13–28 years, with 70% ≤ 24 years). 9 However, the generalizability of results among this younger population may be limited, given that the incidence of GDM is higher in women aged 30 years or older. 31 In addition, the registry had relatively limited information on maternal covariates. In the present study, detailed information on maternal and paternal characteristics was collected in the Nurses’ Mothers’ Cohort Study. Thus, the combination of parental data with the daughter’s data collected in the NHSII provides a unique opportunity to examine the long-term intergenerational impact of parental smoking on adulthood diseases in the daughter. Our results were also in line with previous studies regarding the association between maternal smoking during pregnancy and risk of type 2 diabetes in adulthood. 18,19
The observed association between maternal heavy smoking during pregnancy and higher GDM risk is biologically plausible. Maternal smoking, as a deleterious in utero environmental insult, may lead to structural, physiological and metabolic changes to the fetus and result in impaired glucose metabolism and metabolic diseases in adulthood. 18,32 Animal studies suggest that fetal exposure to smoking might lead to altered pancreatic islet and adipose tissue development, beta cell apoptosis at birth and postnatal endocrine and metabolic changes. 16,17 The observed divergent associations of maternal and paternal smoking during pregnancy with GDM risk in the daughter may indicate a specific intrauterine effect of maternal smoking, rather than shared familial confounding factors, 33 on GDM risk. This is in line with findings from a recent meta-analysis showing greater effect estimates of maternal smoking in pregnancy than paternal smoking in association with childhood obesity in the offspring. 34
There has been little evidence regarding in which trimester of pregnancy fetal exposure to smoking most influences pancreatic islet and other metabolic effects that may increase the risk of GDM or type 2 diabetes. In the current study, we observed a dose-response relation between continued maternal smoking during pregnancy and GDM risk in the daughter. We also observed suggestive evidence that the daughters of women who smoked only in the first trimester had a higher risk of GDM. Coincidentally, a previous study found that fetal exposure to maternal smoking during the first trimester only was associated with type 2 diabetes in adulthood. 19 These results indicated that the first trimester of pregnancy might be a sensitive window for the development of diabetes induced by maternal smoking, which warrants confirmation in future studies.
Our study had several strengths, including the large sample size, the availability of detailed information on both maternal and paternal smoking during pregnancy that allows analyses on dose-response relation, and the comprehensive information on potential confounders collected in the Nurses’ Mothers’ Cohort Study. Moreover, the study relied primarily on maternal reports of parental smoking during pregnancy, which is likely to be less misclassified than reports by the daughters.
We acknowledge that there were several limitations. First, the ascertainment of GDM was based on self-reports in the NHSII cohort. A previous validation study in a subset of this cohort found a high validity (94%) of GDM self-reports compared with medical record reviews, 23 reducing the concern of outcome misclassification. Second, data on parental smoking and associated covariates during pregnancy were collected retrospectively in the Nurses’ Mothers’ Cohort Study. Although the validity of recalled maternal smoking during pregnancy was found to be high (sensitivity = 0.86, specificity = 0.94) in a similar study, 22 it is possible that mothers who smoked during pregnancy were more likely to be misclassified as not smoking than non-smoking mothers were to be misclassified as smokers. Such differential misclassification would lead to an underestimation of the true association of maternal smoking on daughter’s GDM risk in this study. In addition, the mothers, in particular those who had other children besides the nurse daughter, might misremember the circumstances (including parental smoking status) surrounding the pregnancy of the nurse daughter a long time after their pregnancies. It would be even more challenging for the mothers to recall paternal smoking status during the specific pregnancy with the nurse daughter. However, since the data about parental smoking during pregnancy were collected without reference to the daughter’s GDM status in the present study, any misclassification due to misremembering the parental smoking status during pregnancy would be non-differential with respect to GDM outcome in the daughter, which may also lead to an underestimation of the true association. Therefore, the true detrimental effects of maternal smoking on daughter’s GDM risk would be even stronger if misclassification bias could be minimized. Third, we did not have information about maternal smoking before pregnancy. Mothers who quit smoking before pregnancy were combined with never smokers in the reference group, which may underestimate the true effect of maternal smoking during pregnancy on the daughter’s risk of GDM. Fourth, the Nurses’ Mothers' Cohort was limited to mothers who were alive and able to complete the questionnaire in 2001. At that time, half of the mother participants were over 70 years old. Since smoking is associated with higher risk of mortality and various morbidities, mothers who had smoking habits were less likely to survive or be able to participate in this cohort. As a result, the survival effect may underestimate the true association in this study. Fifth, our study population consisted mostly of Caucasian American women. Future research among other race/ethnic groups is needed. However, the relative homogeneity of the study population reduces potential confounding due to unmeasured socio-economic variability. Finally, although we have considered many potential confounders in this analysis, we cannot completely exclude the possibilities of residual confounding from unmeasured factors. For instance, genetic factors may also confound the association in addition to other factors. It has been demonstrated that a genetic variant related to smoking behaviour is associated with adiposity, which will in turn be associated with GDM, even among people who have never smoked. 35
In conclusion, maternal heavy smoking (≥ 25 cigarettes/day) during pregnancy was associated with higher risk of GDM in the daughter. This study expanded our knowledge on the adverse health effects of maternal smoking during pregnancy, not only leading to short-term adverse pregnancy and perinatal outcomes but also increasing the long-term intergenerational risk of GDM in the daughter. It adds evidence to support the recommendation that maternal smoking during pregnancy should be strongly discouraged. Further studies are warranted to confirm our findings and to elucidate the underlying mechanisms.
Funding
This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract No. HHSN275201000020C). The Nurses’ Health Study II was funded by research grants DK58845, CA50385, P30 DK46200 and UM1 CA176726 from the National Institutes of Health. 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. D.T. was supported by a mentored fellowship from the American Diabetes Association (No. 7‐12-MN-34) and a K01 grant from National Institute of Diabetes and Digestive and Kidney Diseases (DK58845). A.G. was supported by a training grant from National Institute of Diabetes and Digestive and Kidney Diseases (T32-DK007703‐16).
Contributors
W.B. and C.Z. conceived the idea and designed the study. W.B. wrote the manuscript. K.B.M., D.K.T., S.L., J.E.C, A.J.G., A.A.V., F.B.H. and C.Z. interpreted the results and reviewed and edited the manuscript. S.L. conducted technique review for this manuscript. W.B. and C.Z. had primary responsibility for final content. All authors provided intellectual input into the paper, and all authors read and approved the final manuscript.
Conflict of interest : All the authors declare no conflicts of interest.
Supplementary Material
References
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