Comments
Abstract
Rationale: Children with lower birth weight are at increased risk of asthma symptoms.
Objectives: To examine associations of fetal and infant growth with childhood lung function and asthma.
Methods: This study was embedded in a population-based prospective cohort study of 5,635 children. Growth was estimated by repeated ultrasounds in the second and third trimesters, and measured at birth and at 3, 6, and 12 months. At age 10 years, spirometry was performed and asthma was assessed by parental questionnaire. Restricted and accelerated growth were defined as the growth percentile change between time periods less than −0.67 and more than 0.67 SD scores (SDSs), respectively. We applied multiple regression analyses, including conditional regression analyses, to account for correlations between repeated growth measures.
Measurements and Main Results: Overall greater weight in the second and third trimesters, at birth, and at 12 months was associated with higher FEV1 and FVC (range of z-score difference, 0.04–0.08, per SDS increase in weight). Greater weight at 3 months was associated with lower FEV1/FVC and forced expiratory flow at 75% of the pulmonary volume (FEF75%) (z-score differences [95% confidence interval]: −0.09 [−0.14 to −0.05] and −0.09 [−0.13 to −0.05] per SDS increase in weight, respectively). Restricted fetal weight growth was associated with lower childhood lung-function measures, partly depending on infant weight growth patterns (range of z-score difference, −0.25 to −0.13). Accelerated fetal weight growth was associated with higher FVC and lower FEV1/FVC only if followed by accelerated infant weight growth. Fetal and infant weight growth was not associated with childhood asthma.
Conclusions: Both restricted fetal weight growth, partly depending on infant weight growth, and accelerated fetal and infant weight growth predispose children to lower lung function and a potential risk for respiratory diseases later in life.
Previous studies suggested that low birth weight is associated with lower lung function and risk of asthma in later life. Not much is known about the longitudinal fetal and infant growth patterns that predispose to chronic obstructive respiratory diseases.
This study suggests that fetal and infant length patterns are not associated with childhood lung function and asthma. Children with fetal restricted weight growth partly depending on infant weight growth (“catch up”) and those with persistently large fetal and infant weight growth (“fat happy wheezer”) are most likely at risk for lower lung function. These two distinct growth patterns might increase the risk of chronic obstructive respiratory diseases in later life.
Early growth characteristics have been associated with an increased risk of respiratory morbidity in later life (1, 2). Altered fetal and infant growth may result in developmental adaptations with smaller airway dimensions, leading to lower lung function and increased risk of asthma (3). Previous studies that examined individual growth characteristics showed that higher fetal crown–rump length (CRL) in the first trimester, a greater abdominal circumference, and a higher femur length in second pregnancy were associated with a lower risk of wheezing, atopic wheezing, asthma, or higher FEV1, FVC, and forced expiratory flow, midexpiratory phase (FEF25–75%) at age 5–10 years (4–6). Also, we previously showed that fetal growth restriction is associated with higher respiratory resistance in children 6 years of age (7), and that weight gain acceleration in early infancy is associated with an increased risk of asthma symptoms in preschool children (8). Studies focused on combined fetal and infant growth patterns with respiratory morbidity in late childhood are scarce (6–8), and specific critical periods of growth have not yet been fully identified. Additionally, a child’s current body mass index (BMI) and atopy might affect associations of early growth with childhood lung function and asthma (9).
Therefore, we aimed to identify specific periods in fetal life and early infancy that showed the effects of adverse growth on respiratory morbidity in a population-based, prospective cohort study. We examined the associations of fetal and infant individual growth measures, and combined growth patterns throughout fetal life and early infancy, with lung function and asthma among 5,635 children 10 years of age. Additionally, we examined whether these associations were modified by the children’s current BMI or inhalant allergic sensitization.
This study was embedded in the Generation R Study, a population-based, prospective cohort study of fetal life onward in Rotterdam, the Netherlands (10). The study protocol was approved by the Medical Ethics Committee of the Erasmus Medical Centre, Rotterdam (MEC 40020.078.12/2012/165). Written informed consent was obtained from parents or legal representatives (n = 7,393). Twins and children with missing data for all fetal and infant growth measures (n = 213), lung function, or current asthma (n = 1,545) were excluded, resulting in a total of 5,635 children for the current analyses (Figure E1 in the online supplement).
Gestational age was established by ultrasound in the first trimester (8). We used the CRL to assess fetal growth only in mothers with a known and reliable first day of the last menstrual period and a regular cycle of 28 (range, 24–32) days (11). In the second and third trimesters, head circumference, abdominal circumference, and femur length were measured using standardized ultrasound procedures. Femur length was used as proxy for fetal length. Estimated fetal weight was calculated using the Hadlock equation (12). Fetal growth characteristics were converted into SD scores (SDSs) according to reference growth charts (13). Length and weight at birth were obtained from midwives, general practitioners, and hospital registries. Gestational age–adjusted SDSs for length and weight at birth were constructed using reference growth charts (14). Infant growth characteristics were measured at community health centers according to standard procedures at the ages of 3 months (range, 3.0–4.0 mo), 6 months (range, 5.0–9.9 mo), and 12 months (range, 10.0–13.0 mo). SDSs for postnatal length and weight were obtained using reference growth charts (Growth Analyzer 3.0, Dutch Growth Research Foundation) (15). We used both fetal and infant length and weight measures to explore the role of growth in childhood lung function and asthma.
Spirometry was performed at a median age of 9.7 years (range, 8.5–12.0 yr) according to the American Thoracic Society and European Respiratory Society (ATS/ERS) recommendations. Additionally, we included 122 children with individual spirometry curves with a >5% deviation, but with at least one blow (according to ATS/ERS criteria) with adequate reach and duration of plateau. We observed no difference in lung-function values between the children with and without stringent criteria, and no difference in the size or direction of the effect estimates in our analyses when we included or excluded these children. FEV1 and FEV1/FVC are the most important measures of spirometry for detecting obstructive lung function. However, FEF25–75% and FEF at 75% of the pulmonary volume (FEF75%) have been hypothesized to be better predictors of small airways disease than FEV1 and FEV1/FVC (16, 17), although the importance of the small airways disease phenotype is the subject of much debate (18, 19). We therefore included FEF25–75% and FEF75% in our analyses. All lung-function variables were converted into sex-, age-, height-, and ethnicity-adjusted z-scores according to Global Lung Initiative reference data (20). Statistical analyses were used to identify differences in the mean z-scores of lung-function measures in relation to early growth characteristics. Ever-physician-diagnosed asthma, wheezing, and use of inhalant medication (bronchodilators or corticosteroids) in the previous 12 months at age 10 years were reported on a parental questionnaire. The response rate was 75%. Current asthma (no/yes) was defined as ever-physician-diagnosed asthma with either wheezing or the use of inhalant medication in the previous 12 months. Last, we assessed the associations of remittent wheezing symptoms. Remittent wheezing symptoms was defined as ever wheezing between ages 1 and 3 years, and between ages 4 and 6 years, with wheezing or current asthma at age 9 years.
Information about maternal age, prepregnancy BMI, highest level of education (primary or secondary, or higher), history of asthma and atopy (no/yes), psychological distress during pregnancy (no/yes), and parity (nulli- or multiparous) was obtained from a maternal questionnaire completed at enrollment. The Global Severity Index was used to measure psychological distress during pregnancy (21). Maternal smoking during pregnancy (never, until pregnancy was known, or continued throughout pregnancy) was assessed by questionnaires throughout pregnancy. Child’s sex and gestational age were obtained from midwives and hospital registries at birth. Child’s ethnicity was based on the parental countries of birth and classified according to the Global Lung Initiative definitions (20). Breastfeeding information (never/ever) was collected using questionnaires administered at 2, 6, and 12 months after birth. Inhalant allergic sensitization (no/yes) for Dermatophagoides pteronyssinus, 5-grass mixture (Dactylis glomerata, Festuca pratensis, Lolium perenne, Phleum pratense, and Poa pratensis), birch (Betula verrucosa), cat (Felis catus), and dog (Canis familiaris) (ALK-Abelló B.V.) was measured by skin-prick tests using the scanned-area method (22). Inhalant allergic sensitization and child’s length and weight were measured at the time of spirometry.
First, we compared the characteristics of children included and not included in the study using ANOVA, Mann-Whitney tests, and chi-square tests. Second, we applied conditional regression analyses to identify independent critical early-life growth periods associated with respiratory outcomes (23). For these analyses, we constructed length and weight variables using standardized residuals resulting from the linear regression model of length and weight regressed on the prior corresponding growth measurements. We first calculated the standardized residuals of the linear regression models of, for example, weight measured at time point 2, resulting from the linear regression model of weight measured at time point 2 on weight measured at time point 1. Therefore, the standardized residuals for weight measured at time point 2 (residuals [weight2]) are derived from the model weight2 = β0 + βweight1. Accordingly, the conditional change in weight between time points 2 and 3 (residuals [weight3]) was calculated as the standardized residuals obtained from regressing weight measured at time point 3 on weight measured at both time points 2 and 1 simultaneously: weight3 = β0 + βweight1 + βweight2. This calculation was performed for each subsequent time point, resulting in measures of conditional growth that are mutually uncorrelated. These variables are statistically independent of each other, allowing simultaneous inclusion in multiple regression models. A similar construction was accomplished for length (23). Third, we explored growth patterns throughout early life. Restricted weight growth and accelerated weight growth were defined as the weight growth percentile change between the time periods of less than −0.67 SDS or more than 0.67 SDS, respectively. A change of 0.67 SDS represents the width of each percentile band on standard growth charts, which helps to indicate growth acceleration and deceleration in clinical practice (8, 24). We assessed the associations of restricted and accelerated weight growth between the second trimester and birth, between birth and 3 months, and between 3 and 12 months using linear and logistic regression models. To assess the assumed relative importance of fetal growth compared with growth in early infancy, we also created specific combinations of fetal and early infancy growth. We combined restricted and accelerated weight growth patterns in fetal life (second trimester to birth) and infancy (birth to 3 mo) to enable comparison with previous studies (25, 26) and our current observations, using normal fetal and infant weight growth patterns as a reference category. Selection of covariates was based on literature if the effect estimate of the unadjusted analyses changed ≥10% after adjustment for a covariate, or if covariates were strongly related to the determinant and outcome, and not in the causal pathway. The percentage of missing data for covariates was <20%, except for maternal psychological distress during pregnancy (24.5%). Missing data in covariates were imputed to reduce bias and improve efficiency using the Markov chain Monte Carlo method to select the most likely value for a missing response (27). We constructed 10 new datasets from which we calculated pooled estimates (28). No differences in results were observed between analyses with and without imputed data. We only present results based on imputed data. We tested the modifying effects of a child’s current BMI and inhalant allergic sensitization by adding them as product terms with the growth characteristics in the models. Analyses were performed using SPSS version 21.0 for Windows (IBM).
Maternal and child characteristics are presented in Tables 1 and 2. Children were born after a median pregnancy duration of 40.1 (2.5–97.5% range: 35.8–42.3) weeks with a mean birth weight of 3,437 (SD 555) g. Current asthma was reported in 5.7% (n = 269). Mothers lost to follow-up were younger, less educated, had more psychological distress, and smoked more during pregnancy, and their children were more often of nonwhite ethnicity (Table E1).
| Study Population (N = 5,635) | |
|---|---|
| Maternal characteristics | |
| Age, yr | 31.0 (4.9) |
| Prepregnancy body mass index, kg/m2* | 23.7 (18.8–35.6) |
| Education, % (n) | |
| None, primary, or secondary | 51.6 (2,909) |
| Higher | 48.4 (2,726) |
| History of asthma or atopy, yes, % (n) | 39.6 (2,234) |
| Psychological distress, yes, % (n) | 8.9 (503) |
| Nulliparity, % (n) | 57.3 (3,229) |
| Smoking during pregnancy, % (n) | |
| Never | 75.6 (4,262) |
| Until pregnancy known | 9.0 (508) |
| Yes, continued | 15.4 (865) |
| Child characteristics | |
| Female sex, % (n) | 50.3 (2,829) |
| Gestational age at birth, wk* | 40.1 (35.8-42.3) |
| Birth weight, g | 3,437 (555) |
| Ethnicity, % (n) | |
| White | 81.4 (4,588) |
| Black | 14.6 (822) |
| Asian | 2.6 (144) |
| Other/mixed | 1.4 (81) |
| Breastfeeding, ever, % (n) | 92.5 (5,212) |
| Inhalant allergic sensitization, yes, % (n) | 33.1 (1,397) |
| Body mass index, kg/m2* | 17.0 (14.0–24.8) |
| FEV1, L | 2.01 (0.30) |
| FVC, L | 2.32 (0.37) |
| FEV1/FVC | 0.87 (0.06) |
| FEF25–75%, L/s | 2.69 (0.65) |
| FEF75%, L/s | 1.14 (0.35) |
| Current asthma, yes, % (n) | 5.7 (269) |
| Growth Characteristics | Number of Individuals | Mean (SD) |
|---|---|---|
| First trimester | ||
| Crown–rump length, mm | 1,096 | 60.9 (11.7) |
| Second trimester | ||
| Abdominal circumference, mm | 4,870 | 157.1 (14.8) |
| Femur length, mm | 4,872 | 33.5 (3.5) |
| Estimated fetal weight, g | 4,846 | 363.9 (59) |
| Third trimester | ||
| Abdominal circumference, mm | 4,976 | 264.5 (16.7) |
| Femur length, mm | 4,987 | 57.5 (3.0) |
| Estimated fetal weight, g | 4,968 | 1,626 (263) |
| Birth | ||
| Weight, g | 5,635 | 3,436 (556) |
| Length, cm | 3,532 | 50.3 (2.4) |
| 3 mo | ||
| Weight, g | 3,410 | 6,281 (758) |
| Length, cm | 2,905 | 61.4 (2.5) |
| 6 mo | ||
| Weight, g | 4,261 | 7,858 (909) |
| Length, cm | 3,813 | 67.6 (2.7) |
| 12 mo | ||
| Weight, g | 3,951 | 9,625 (1,060) |
| Length, cm | 3,947 | 74.3 (2.6) |
Conditional analyses showed that fetal and infant lengths at different ages were not independent of other time periods associated with lung-function measures or current asthma (Table E2). Conditional analyses showed associations of weight growth with childhood lung function (Table 3). Greater weight in the second and third trimesters was associated with higher FEV1 and FVC (range of z-score difference, 0.04–0.08 per SDS increase in weight) independently of other time periods. Greater weight at 3 months was associated with higher FVC, FEV1/FVC, and FEF75%, and at 12 months with higher FEV1 and FVC. Only a greater weight at birth was associated with an increased risk of childhood asthma (odds ratio [OR] [95% confidence interval (CI)], 1.34 [1.09–1.66] per SDS increase in weight). A greater weight at 3 months was associated with a higher FVC (z-score [95% CI], 0.06 [0.02 to 0.10]) and a lower FEV1/FVC and FEF75% (−0.09 [−0.14 to −0.05] and −0.09 [−0.13 to −0.05], respectively).
| FEV1 z-Score (95% CI) | FVC z-Score (95% CI) | FEV1/FVC z-Score (95% CI) | FEF25–75% z-Score (95% CI) | FEF75% z-Score (95% CI) | Current Asthma Odds Ratio (95% CI) | |
|---|---|---|---|---|---|---|
| Weight (SDS) | ||||||
| Second trimester | 0.05 (0.01 to 0.10)* | 0.05 (0.01 to 0.09)* | 0.01 (−0.03 to 0.05) | −0.01 (−0.05 to 0.04) | 0.03 (−0.01 to 0.07) | 1.18 (0.95 to 1.46) |
| Third trimester | 0.08 (0.04 to 0.13)† | 0.07 (0.03 to 0.11)† | 0.01 (−0.03 to 0.05) | 0.04 (−0.01 to 0.08) | 0.02 (−0.02 to 0.06) | 1.05 (0.85 to 1.30) |
| Birth | 0.07 (0.03 to 0.11)† | 0.07 (0.03 to 0.11)† | −0.01 (−0.05 to 0.04) | 0.01 (−0.04 to 0.05) | −0.00 (−0.04 to 0.04) | 1.34 (1.09 to 1.66)† |
| 3 mo | 0.00 (−0.04 to 0.05) | 0.06 (0.02 to 0.10)† | −0.09 (−0.14 to −0.05)† | 0.03 (−0.02 to 0.07) | −0.09 (−0.13 to −0.05)† | 1.09 (0.89 to 1.35) |
| 6 mo | 0.02 (−0.02 to 0.06) | 0.04 (−0.00 to 0.07) | −0.04 (−0.08 to 0.01) | 0.02 (−0.03 to 0.06) | −0.03 (−0.07 to 0.01) | 0.96 (0.78 to 1.18) |
| 12 mo | 0.04 (0.00 to 0.08)* | 0.05 (0.01 to 0.09)* | −0.02 (−0.06 to 0.02) | −0.03 (−0.07 to 0.02) | −0.00 (−0.04 to 0.04) | 1.02 (0.83 to 1.25) |
When we assessed the associations per critical period, we observed that restricted weight growth between the second trimester and birth was not associated with lung-function measures or asthma, whereas accelerated growth was associated with higher FVC (0.10 [0.03 to 0.16]) and lower FEV1/FVC (−0.08 [−0.15 to −0.01]) compared with normal weight growth in that period (Figure 1; Table E3). Between birth and age 3 months, restricted weight growth was associated with an increased risk of childhood asthma (OR [95% CI], 1.57 [1.01 to 2.45]), and accelerated weight growth with a lower FEV1, FEV1/FVC, and FEF75% (−0.10 [−0.18 to −0.02], −0.08 [−0.16 to −0.00], and −0.07 [−0.14 to −0.00], respectively) compared with normal weight growth. Weight growth patterns between the ages of 3 and 12 months were not associated with lung-function measures or asthma.
Figure 1. Associations of weight growth patterns with lung function and current asthma. Values are z-scores (95% CI) for FEV1, FVC, FEV1/FVC, FEF25–75%, and FEF75%, and odds ratio of current asthma per 1 SDS increase in growth characteristics from linear and logistic regression models. Restricted fetal growth was defined as a <−0.67 SDS increase between the second trimester and birth, and restricted infant growth was defined as a <−0.67 SDS increase between birth and 3 months, and between 3 and 12 months. Accelerated fetal growth was defined as a >0.67 SDS increase between the second trimester and birth, and accelerated infant growth was defined as a >0.67 SDS increase between birth and 3 months, and between 3 and 12 months. Children with normal fetal and infant weight growth were used as reference. *P < 0.05, **P < 0.01. Models were adjusted for maternal age, prepregnancy body mass index, educational level, history of asthma or atopy, psychological distress during pregnancy, parity, smoking during pregnancy, and child’s sex, gestational age, ethnicity, and breastfeeding. CI = confidence interval; FEF25–75% = forced expiratory flow, midexpiratory phase; FEF75% = forced expiratory flow at 75% of the pulmonary volume; SDS = SD score.
[More] [Minimize]When we combined restricted and accelerated weight growth patterns in fetal life and infancy, we observed that restricted fetal weight growth was associated with a lower FEV1 independently of the infant weight growth pattern, compared with normal weight growth in fetal life and infancy (n = 293) (z-score differences [95% CI]: restricted infant weight growth [n = 87], −0.25 [−0.51 to −0.00]; normal infant weight growth [n = 228], −0.17 [−0.31 to −0.02]; and accelerated infant weight growth [n = 306], −0.13 [−0.26 to −0.01]) (Figure 2; Table E4). Restricted fetal weight growth was associated with a lower FVC and FEF25–75% (−0.30 [−0.53 to −0.06] and −0.29 [−0.56 to −0.01], respectively) if followed by restricted infant weight growth, with lower FEV1/FVC (−0.18 [−0.32 to −0.04] and −0.13 [−0.25 to −0.00], respectively) if followed by normal or accelerated infant weight growth, and with lower FEF75% (−0.17 [−0.31 to −0.03]) if followed by normal infant growth. Normal fetal weight growth followed by accelerated infant weight growth (n = 644) was associated with a higher FEF25–75% (0.14 [0.01 to 0.27]). Accelerated fetal weight growth followed by accelerated infant weight growth (n = 301) was not associated with FEV1, but was associated with a higher FVC (0.23 [0.07 to 0.38]) and lower FEV1/FVC (−0.23 [−0.39 to −0.07]).
Figure 2. Associations of weight growth patterns combined from fetal life and infancy with lung function and current asthma. Values are z-scores (95% CI) for FEV1, FVC, FEV1/FVC, FEF25–75%, and FEF75%, and odds ratio of current asthma per 1 SDS increase in growth characteristics from linear and logistic regression models. Restricted fetal and infant growth was defined as a <−0.67 SDS increase between the second trimester and birth, and between birth and 3 months, respectively. Accelerated fetal and infant growth was defined as a >0.67 SDS increase between the second trimester and birth, and between birth and 3 months, respectively. Children with normal fetal and infant weight growth were used as reference and are represented by the white dot. *P < 0.05, **P < 0.01. Models were adjusted for maternal age, prepregnancy body mass index, educational level, history of asthma or atopy, psychological distress during pregnancy, parity, smoking during pregnancy, and child’s sex, gestational age, ethnicity, and breastfeeding. For definition of abbreviations, see Figure 1.
[More] [Minimize]Fetal and infant growth patterns were not associated with current asthma (Figure 2; Table E2) and remittent wheezing symptoms (Table E4). Associations between fetal and infant weight growth and lung function and asthma were not modified by a child’s current BMI or inhalant allergic sensitization (P values for interaction > 0.05).
We observed that overall greater weight in the second and third trimesters, at birth, and at 12 months was associated with higher FEV1 and FVC, whereas greater weight at 3 months was associated with a lower FEV1/FVC and FEF75%, but not asthma, independently of weight in other periods. When weight growth patterns were combined, restricted fetal weight growth was associated with a lower childhood FEV1, FVC, FEV1/FVC, FEF25–75%, and FEF75%, partly depending on weight growth patterns in infancy. Accelerated fetal weight growth was associated with higher FVC and lower FEV1/FVC, but only if followed by accelerated infant weight growth. Length throughout fetal life and infancy was not associated with lung function and asthma in childhood. The results were not modified by a child’s current BMI or inhalant allergic sensitization.
A limited number of studies have examined the associations of fetal growth with lung function and asthma (4–6, 8). A prospective birth cohort study among 927 children showed that a higher CRL in the first trimester was associated with a higher FEV1, FVC, and FEF25–75%, and a lower risk of wheezing and asthma until age 10 years (4, 5). Also, a higher femur length in the second trimester was associated with a lower risk of asthma (4). Compared with persistent greater growth in the first and second trimesters (defined as a greater CRL in the first trimester and a greater biparietal diameter in the second trimester), persistent smaller growth was associated with a lower FEV1 and increased risk of asthma (5). In a population-based birth cohort of 1,548 children, a greater abdominal circumference between 19 and 34 weeks of gestation was associated with a lower risk of atopic wheezing at age 3 years (6). Smaller fetal head circumference growth between 11 and 19 weeks of gestation was associated with an increased risk of nonatopic wheeze (6). We did not observe any associations of CRL in the first trimester with respiratory outcomes at age 10 years (data not shown), which is in line with our observations at age 4 years (8) but in contrast to findings from another birth cohort (6). This difference could be explained by the different ages of the participants and our use of lung function as a more objective measure of respiratory health. We did observe similar associations between femur length and childhood lung function. However, in conditional analyses, we observed that femur length (as a proxy for fetal length) and infant length were not independently associated with lung function or current asthma in childhood.
Studies on the associations of infant length with childhood lung function and asthma have provided conflicting results (6–8, 25). Two studies reported that length growth between birth and 12 months was not associated with wheezing at ages 3 and 4 years (6, 8). More rapid height gain in early childhood and mid-childhood was associated with lower FEV1 and FVC at age 15 years, but not with other lung-function measures or with lung function at age 8 years (25). In our cohort, lower infant length growth was previously associated with higher airway resistance (as measured using the interrupter technique) (7). We observed that infant length growth was not associated with childhood lung function or the risk of asthma, which suggests that length measures in early infancy are not independently associated with childhood lung function and asthma. Differences between our results and the previous findings could be explained by the transient character of wheezing in early childhood and our use of conditional modeling.
Previous studies reported inconsistent associations of estimated fetal weight growth with childhood wheezing or asthma (4, 7, 8). Restricted fetal weight growth has been associated with increased respiratory resistance (7) and lower FEV1 in childhood (4). In our previous study, restricted weight growth between birth and 3 months (defined as a negative change of more than 0.67 SD) was not associated with asthma symptoms until the age of 4 years (8). In the current study, we observed an association between current asthma at age 10 years and restricted weight growth between birth and 3 months. This difference might be due to the age of the subjects, as it is difficult to diagnose asthma in young children, and such a diagnosis is partly biased by transient wheezing phenotypes. Furthermore, our current analyses may have been limited by the relatively low number of asthma cases. Thus, larger birth cohort studies and collaborations are necessary to identify specific periods of growth in early life that are associated with respiratory health across the life course. We did not observe associations of restricted fetal weight growth with lung function or asthma, when infant weight growth was not taken into account. In contrast, we observed that accelerated fetal weight growth between the second trimester and birth was associated with a higher FVC and lower FEV1/FVC. However, when infant weight growth patterns were taken into account, the associations of restricted and accelerated fetal weight growth structurally changed, suggesting a strong influence of weight growth in early infancy.
A previous study reported that term-born children with greater infant weight growth had lower FEV0.4 values in the first 3 months of life (29), and that increased weight growth between 1 and 12 months of age was associated with lower maximal flow at functional residual capacity during the same period (30). Another population-based cohort study of 4,492 term-born children with follow-up until age 18 months showed that infant weight and infant weight gain velocity were associated with an increased risk of wheezing (OR, 1.28 and 1.30, respectively) (31). In a cohort study comprising 9,723 children, greater weight gain between birth and 3 months was associated with lower FEV1/FVC and FEF25–75% at age 8 years (25). We observed that accelerated weight growth between birth and 3 months, but not between 3 and 12 months, was associated with lower FEV1, FEV1/FVC, and FEF75%, when we did not take fetal growth into account. This is in line with a meta-analysis of BMI gain in early childhood and mid-childhood, which showed that a greater BMI gain in the first 2 years of life, but not thereafter, was associated with an increased incidence of asthma at age 6 years (32). Similarly, in a meta-analysis of 25,000 European children, greater weight gain in the first year of infancy was associated with higher FEV1 but lower FEV1/FVC and FEF75%, and an increased risk of childhood asthma (1). Additionally, our current study indicates that associations of infant weight growth with lung function and asthma in childhood are partly dependent on fetal weight growth.
In summary, our results suggest that fetal and infant lengths are not independently associated with childhood lung function and asthma. The associations of fetal weight growth are partly dependent on infant weight growth and vice versa, which suggests that the combined weight growth in fetal life and the first 3 months of infancy is most strongly associated with childhood respiratory health.
We observed that both restricted and accelerated fetal weight growth were associated with lower childhood lung function and asthma. Different pathways might be responsible for this similar direction in association. The highest rates of airway and alveoli development occur in fetal life, although both the airways and alveoli continue to develop until the age of 21 years (33). According to animal studies, fetal growth restriction might affect airway compliance (34). Restricted fetal growth might lead to impaired growth of bronchial walls, alterations in mucus-producing tissues, a decrease in the number of alveoli, thicker interalveolar septa, and a greater volume density of lung tissue (35). This is in line with our observations that restricted fetal weight growth was associated with lower FEV1 independently of weight growth in infancy, and that restricted fetal weight growth followed by restricted, normal, or accelerated infant weight growth was associated with lower FVC and FEF25–75%, lower FEV1/FVC and FEF75%, and lower FEV1/FVC, respectively.
Furthermore, the association of greater fetal weight growth with an increased risk of respiratory morbidity may be confounded by catch-up growth in infancy. Recent studies suggested that catch-up growth is associated with lower pulmonary function and an increased risk of childhood asthma (1, 2). This is in line with our observations, although we observed that among children with restricted fetal weight growth, accelerated infant weight growth was associated with a lower FEV1 and FEV1/FVC, but not with asthma or remittent wheezing symptoms. Also, accelerated fetal weight growth followed by accelerated weight growth between birth and 3 months was associated with a higher FVC, but not with FEV1, resulting in a lower FEV1/FVC. This could suggest dysanapsis, a determinant of expiratory flow limitation, in which disproportionate growth of the airways relative to the lung volume occurs (36).
We did not observe any modification of effect by a child’s current BMI. The major limitation of the BMI is that it does not distinguish fat mass from free-fat mass. Further research using more detailed measures of body composition should provide new insight into the effect of current body composition on the association of early growth with childhood respiratory health (37). Several potential mechanisms may underlie the link between early growth and respiratory diseases in children. Increased weight could lead to increased intrathoracic and abdominal fat deposition, which would reduce the pulmonary vital capacity and increase obstruction-related respiratory resistance and the risk of asthma symptoms (38). Also, adiposity-related inflammation and an effect of energy-regulating hormones such as leptin and adiponectin might cause tissue-specific immunological and inflammatory effects with lung and airway remodeling (9). Future mechanistic studies are needed to explore possible mechanisms underlying the effects of fetal and infant growth patterns on lung development and obstructive respiratory diseases.
Our results may be useful in clinical models to predict the probability of developing lower lung function and asthma in childhood. An early risk prediction for the development of lower lung function and asthma in childhood would support the development of prevention strategies in early life to reduce respiratory health problems in later life. Also, further studies are needed to explore how to optimize fetal and infant growth to improve respiratory health across the life course.
This study was embedded in a population-based, prospective cohort study with a large number of subjects who were being studied from early fetal life onward. Detailed and frequent measurements of head circumference, length, and weight in fetal and infant life were performed prospectively. Some limitations do apply. As in any prospective cohort study, our population was subject to loss to follow-up. We did observe differences with individuals who were not included for analyses, which may have led to selection bias and limits the generalizability of our results. Although the Hadlock formula is a validated tool to estimate fetal weight, and intra- and interobserver reproducibility for measurements of fetal growth in early pregnancy was high (39), we cannot exclude the possibility of random measurement errors, which might have led to under- or overestimation of the true effect estimates. It is difficult to diagnose asthma in children. We used validated questionnaires and parent-reported symptoms and medication use to define asthma cases. Still, as compared with objective lung-function measures, our definition of current asthma might be limited by the broad phenotype. We adjusted for a large number of confounders based on literature and univariate analyses. However, as in any observational study, we are not able to rule out the possibility of residual confounding. Finally, our models using linear and logistic regression models might have resulted in false-positive results due to multiple testing. This does not apply to our conditional regression models, as all determinants were added into one statistical model and therefore only one statistical test was performed.
In conclusion, our results suggest that fetal and infant lengths are not independently associated with childhood lung function and asthma. Restricted fetal weight growth between the second trimester and birth, partly depending on infant weight growth, and accelerated fetal weight growth between the second trimester and birth combined with accelerated infant growth between birth and 3 months predispose children to lower lung function and potentially an increased risk of respiratory diseases in later life. Further research into the biological mechanisms involved and possible interventions is warranted.
| 1. | den Dekker HT, Sonnenschein-van der Voort AMM, de Jongste JC, Anessi-Maesano I, Arshad SH, Barros H, et al. Early growth characteristics and the risk of reduced lung function and asthma: a meta-analysis of 25,000 children. J Allergy Clin Immunol 2016;137:1026–1035. |
| 2. | Sonnenschein-van der Voort AM, Arends LR, de Jongste JC, Annesi-Maesano I, Arshad SH, Barros H, et al. Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children. J Allergy Clin Immunol 2014;133:1317–1329. |
| 3. | Duijts L, Reiss IK, Brusselle G, de Jongste JC. Early origins of chronic obstructive lung diseases across the life course. Eur J Epidemiol 2014;29:871–885. |
| 4. | Turner SW, Campbell D, Smith N, Craig LC, McNeill G, Forbes SH, et al. Associations between fetal size, maternal alpha-tocopherol and childhood asthma. Thorax 2010;65:391–397. |
| 5. | Turner S, Prabhu N, Danielan P, McNeill G, Craig L, Allan K, et al. First- and second-trimester fetal size and asthma outcomes at age 10 years. Am J Respir Crit Care Med 2011;184:407–413. |
| 6. | Pike KC, Crozier SR, Lucas JS, Inskip HM, Robinson S, Roberts G, et al.; Southampton Women’s Survey Study Group. Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years. Thorax 2010;65:1099–1106. |
| 7. | Sonnenschein-van der Voort AM, Gaillard R, de Jongste JC, Hofman A, Jaddoe VW, Duijts L. Foetal and infant growth patterns, airway resistance and school-age asthma. Respirology 2016;21:674–682. |
| 8. | Sonnenschein-van der Voort AM, Jaddoe VW, Raat H, Moll HA, Hofman A, de Jongste JC, et al. Fetal and infant growth and asthma symptoms in preschool children: the Generation R Study. Am J Respir Crit Care Med 2012;185:731–737. |
| 9. | den Dekker HT, Ros KPI, de Jongste JC, Reiss IK, Jaddoe VW, Duijts L. Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide, and asthma at school-age. J Allergy Clin Immunol 2017;139:810–818.e6. |
| 10. | Kooijman MN, Kruithof CJ, van Duijn CM, Duijts L, Franco OH, van IJzendoorn MH, et al. The Generation R Study: design and cohort update 2017. Eur J Epidemiol 2016;31:1243–1264. |
| 11. | Mook-Kanamori DO, Steegers EA, Eilers PH, Raat H, Hofman A, Jaddoe VW. Risk factors and outcomes associated with first-trimester fetal growth restriction. JAMA 2010;303:527–534. |
| 12. | Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body, and femur measurements: a prospective study. Am J Obstet Gynecol 1985;151:333–337. |
| 13. | Verburg BO, Steegers EA, De Ridder M, Snijders RJ, Smith E, Hofman A, et al. New charts for ultrasound dating of pregnancy and assessment of fetal growth: longitudinal data from a population-based cohort study. Ultrasound Obstet Gynecol 2008;31:388–396. |
| 14. | Niklasson A, Ericson A, Fryer JG, Karlberg J, Lawrence C, Karlberg P. An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977-1981). Acta Paediatr Scand 1991;80:756–762. |
| 15. | Fredriks AM, van Buuren S, Burgmeijer RJ, Meulmeester JF, Beuker RJ, Brugman E, et al. Continuing positive secular growth change in The Netherlands 1955-1997. Pediatr Res 2000;47:316–323. |
| 16. | Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med 2014;2:497–506. |
| 17. | Luigi DB, Emanuel DT, Federica DB, Fabrizio DT. FEF75 in asthma management. Eur Ann Allergy Clin Immunol 2007;39:333–336. |
| 18. | Quanjer PH, Weiner DJ, Pretto JJ, Brazzale DJ, Boros PW. Measurement of FEF25-75% and FEF75% does not contribute to clinical decision making. Eur Respir J 2014;43:1051–1058. |
| 19. | Boutin B, Koskas M, Guillo H, Maingot L, La Rocca MC, Boulé M, et al. Forced expiratory flows’ contribution to lung function interpretation in schoolchildren. Eur Respir J 2015;45:107–115. |
| 20. | Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al.; ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40:1324–1343. |
| 21. | Derogatis LR. Brief symptom inventory (BSI): administration, scoring and procedures. Minneapolis, MN: National Computer Systems; 1993. |
| 22. | van der Valk JP, Gerth van Wijk R, Hoorn E, Groenendijk L, Groenendijk IM, de Jong NW. Measurement and interpretation of skin prick test results. Clin Transl Allergy 2016;6:8. |
| 23. | Keijzer-Veen MG, Euser AM, van Montfoort N, Dekker FW, Vandenbroucke JP, Van Houwelingen HC. A regression model with unexplained residuals was preferred in the analysis of the fetal origins of adult diseases hypothesis. J Clin Epidemiol 2005;58:1320–1324. |
| 24. | Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 2000;320:967–971. |
| 25. | Sonnenschein-van der Voort AM, Howe LD, Granell R, Duijts L, Sterne JA, Tilling K, et al. Influence of childhood growth on asthma and lung function in adolescence. J Allergy Clin Immunol 2015;135:1435–43.e7. |
| 26. | van der Gugten AC, Koopman M, Evelein AM, Verheij TJ, Uiterwaal CS, van der Ent CK. Rapid early weight gain is associated with wheeze and reduced lung function in childhood. Eur Respir J 2012;39:403–410. |
| 27. | Yuan YC. Multiple imputation for missing data: concepts and new development. Presented at the 25th Annual SAS Users Group International Conference, 2000, Cary, NC. Paper No. 267. |
| 28. | Spratt M, Carpenter J, Sterne JA, Carlin JB, Heron J, Henderson J, et al. Strategies for multiple imputation in longitudinal studies. Am J Epidemiol 2010;172:478–487. |
| 29. | Lucas JS, Inskip HM, Godfrey KM, Foreman CT, Warner JO, Gregson RK, et al. Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function. Am J Respir Crit Care Med 2004;170:534–540. |
| 30. | Turner S, Zhang G, Young S, Cox M, Goldblatt J, Landau L, et al. Associations between postnatal weight gain, change in postnatal pulmonary function, formula feeding and early asthma. Thorax 2008;63:234–239. |
| 31. | Popovic M, Pizzi C, Rusconi F, Galassi C, Gagliardi L, De Marco L, et al. Infant weight trajectories and early childhood wheezing: the NINFEA birth cohort study. Thorax 2016;71:1091–1096. |
| 32. | Rzehak P, Wijga AH, Keil T, Eller E, Bindslev-Jensen C, Smit HA, et al.; GA2LEN-WP 1.5 Birth Cohorts. Body mass index trajectory classes and incident asthma in childhood: results from 8 European birth cohorts: a Global Allergy and Asthma European Network initiative. J Allergy Clin Immunol 2013;131:1528–1536. |
| 33. | Narayanan M, Owers-Bradley J, Beardsmore CS, Mada M, Ball I, Garipov R, et al. Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance. Am J Respir Crit Care Med 2012;185:186–191. |
| 34. | Cock M, Hanna M, Sozo F, Wallace M, Yawno T, Suzuki K, et al. Pulmonary function and structure following mild preterm birth in lambs. Pediatr Pulmonol 2005;40:336–348. |
| 35. | Harding R, Snibson K, O’Reilly M, Maritz GS. Early life origins of human health and disease. Basel: Karger; 2009. |
| 36. | Green M, Mead J, Turner JM. Variability of maximum expiratory flow-volume curves. J Appl Physiol 1974;37:67–74. |
| 37. | den Dekker HT, Ros KPI, de Jongste JC, Reiss IK, Jaddoe VW, Duijts L. Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide, and asthma at school-age. J Allergy Clin Immunol 2017;139:810–818 e6. |
| 38. | Permaul P, Kanchongkittiphon W, Phipatanakul W. Childhood asthma and obesity: what is the true link? Ann Allergy Asthma Immunol 2014;113:244–246. |
| 39. | Verburg BO, Mulder PG, Hofman A, Jaddoe VW, Witteman JC, Steegers EA. Intra- and interobserver reproducibility study of early fetal growth parameters. Prenat Diagn 2008;28:323–331. |
The Generation R Study is supported by the Erasmus Medical Centre, Rotterdam, Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development. V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (ZonMw-VIDI) and a European Research Council Consolidator Grant (ERC-2014-CoG-648916). L.D. received an additional grant from the Lung Foundation Netherlands (no. 3.2.12.089; 2012). This work was also supported by the European Union’s Horizon 2020 Research and Innovation Programme (LIFECYCLE project, grant agreement 733206; 2016) and ERA-Net on Biomarkers for Nutrition and Health (ERA-HDHL; ALPHABET project, Horizon 2020, grant agreement 696295; 2017), ZonMW The Netherlands (529051014; 2017), Science Foundation Ireland (SFI/16/ERA-HDHL/3360), and the European Union.
Author Contributions: H.T.d.D. and L.D. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, and contributed to the study concept and design, data analysis and interpretation, drafting, and revision of the manuscript. I.K.R., J.C.d.J., and V.W.V.J. contributed to the study concept, data interpretation, and writing of the manuscript.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.201703-0631OC on September 20, 2017
Author disclosures are available with the text of this article at www.atsjournals.org.
