Association of Maternal Weight Gain in Pregnancy With Offspring Obesity and Metabolic and Vascular Traits in Childhood
Background— We sought to examine the association of gestational weight gain (GWG) and prepregnancy weight with offspring adiposity and cardiovascular risk factors.
Methods and Results— Data from 5154 (for adiposity and blood pressure) and 3457 (for blood assays) mother-offspring pairs from a UK prospective pregnancy cohort were used. Random-effects multilevel models were used to assess incremental GWG (median and range of repeat weight measures per woman: 10 [1, 17]). Women who exceeded the 2009 Institute of Medicine–recommended GWG were more likely to have offspring with greater body mass index, waist, fat mass, leptin, systolic blood pressure, C-reactive protein, and interleukin-6 levels and lower high-density lipoprotein cholesterol and apolipoprotein A1 levels. Children of women who gained less than the recommended amounts had lower levels of adiposity, but other cardiovascular risk factors tended to be similar in this group to those of offspring of women gaining recommended amounts. When examined in more detail, greater prepregnancy weight was associated with greater offspring adiposity and more adverse cardiovascular risk factors at age 9 years. GWG in early pregnancy (0 to 14 weeks) was positively associated with offspring adiposity across the entire distribution but strengthened in women gaining >500 g/wk. By contrast, between 14 and 36 weeks, GWG was only associated with offspring adiposity in women gaining >500 g/wk. GWG between 14 and 36 weeks was positively and linearly associated with adverse lipid and inflammatory profiles, with these associations largely mediated by the associations with offspring adiposity.
Conclusions— Greater maternal prepregnancy weight and GWG up to 36 weeks of gestation are associated with greater offspring adiposity and adverse cardiovascular risk factors. Before any GWG recommendations are implemented, the balance of risks and benefits of attempts to control GWG for short- and long-term outcomes in mother and child should be ascertained.
Received August 31, 2009; accepted April 13, 2010.
A recent systematic review found evidence of associations of maternal prepregnancy weight and greater gestational weight gain (GWG) with a wide range of adverse perinatal health outcomes.1 Fewer studies have examined the long-term effects of these on offspring health, and this systematic review and the recently revised 2009 US Institute of Medicine (IOM) guidance on GWG identified a need for further high-quality research with long-term offspring outcomes.1,2
Clinical Perspective on p 2564
Several studies have examined associations of GWG with offspring adiposity and have consistently (all but 1 study3) reported positive associations with offspring body mass index (BMI) in childhood,4–6 adolescence,7 and adulthood.8 Other studies have examined the association with offspring blood pressure (BP), with conflicting results.4,8–12 The 2 most recent and largest studies suggest positive associations of GWG with offspring BP in childhood4 and adulthood8 that may be mediated by the association of GWG with offspring adiposity.8
No studies have examined associations of maternal prepregnancy weight or GWG with offspring cardiovascular risk factors other than BMI and BP. Most previous studies have been unable to examine patterns of GWG with offspring outcomes. No studies have examined associations of the newly defined IOM GWG categories with offspring outcomes.2 Our aim was to examine associations of GWG and prepregnancy weight with a range of offspring cardiovascular risk factors (BMI, fat mass, waist circumference, BP, lipids, apolipoproteins, adiponectin, leptin, interleukin-6 [IL-6], and C-reactive protein [CRP]) with the use of detailed repeat measures of gestational weight.
The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective, population-based birth cohort study that recruited 14 541 pregnant women resident in Avon, UK, with expected dates of delivery April 1, 1991, to December 31, 1992 (http://www.alspac.bris.ac.uk.).13 There were 13 678 mother-offspring pairs from singleton live births who survived to at least 1 year of age; only singleton pregnancies are considered in this article. We further restricted analyses in this article to women with term deliveries (between 37 and 44 weeks of gestation; n=12 447). Of these women, 11 702 (94%) gave consent for abstraction of data from their obstetric records, and 6668 offspring (57%) of these 11 702 women attended the 9-year follow-up clinic. Of the 6668 mother-offspring eligible pairs, complete data on GWG, offspring anthropometry, BP, and potential confounders were available for 5154 (77% of attendees; 41% of 12 47 total). In addition, 3457 (52% of attendees; 28% of total) had complete data on offspring blood assays.
Six trained research midwives abstracted data from obstetric medical records. There was no between-midwife variation in mean values of abstracted data, and repeat data entry checks demonstrated error rates consistently <1%. Obstetric data abstractions included every measurement of weight entered into the medical records and the corresponding gestational age and date. To allocate women to IOM categories (Table 1), we used weight measurements from the obstetric notes and subtracted the first from the last weight measurement in pregnancy to derive absolute weight gain. Prepregnancy BMI was based on the predicted prepregnancy weight with the use of multilevel models (see below) and maternal report of height.
Maternal age, parity, mode of delivery (cesarean section/vaginal delivery), and the child’s sex were obtained from the obstetric records. On the basis of questionnaire responses, the highest parental occupation was used to allocate the children to family social class groups (classes I [professional/managerial] to V [unskilled manual workers]). Information on maternal smoking in pregnancy, categorized as (1) never smoked, (2) smoked before pregnancy or in the first trimester and then stopped, and (3) smoked throughout pregnancy, was obtained from questionnaire responses.
Offspring weight and height were measured in light clothing, without shoes. Weight was measured to the nearest 0.1 kg with the use of Tanita scales. Height was measured to the nearest 0.1 cm with the use of a Harpenden stadiometer. Waist circumference was measured to the nearest 1 mm at the midpoint between the lower ribs and the pelvic bone with a flexible tape and with the child breathing normally. Fat mass was assessed with the use of dual-energy x-ray densitometry. We examined BMI, waist circumference, and fat mass as continuously measured variables. We also examined binary outcomes of overweight/obese (BMI) and abdominally obese (waist circumference) subjects using age- and sex-specific thresholds for both child BMI (International Obesity Task Force)14 and waist circumference (≥90th percentile15 based on waist circumference percentile curves derived for British children16).
BP was measured with the use of a Dinamap 9301 Vital Signs Monitor with the child rested and seated and with the arm supported at chest level on a table. Two readings of systolic and diastolic BP (SBP and DBP, respectively) were recorded, and the mean of each was used. Nonfasting blood samples were taken with the use of standard procedures with samples immediately spun and frozen at −80°C. The measurements were assayed in plasma in 2008 after a median of 7.5 years in storage with no previous freeze-thaw cycles during this period. Analysis of lipids (total cholesterol, triglycerides, and high-density lipoprotein cholesterol [HDL-C]) was performed by modification of the standard Lipid Research Clinics protocol with the use of enzymatic reagents for lipid determinations. Apolipoprotein A1 (apoA1) and apolipoprotein B (apoB) were measured by immunoturbidimetric assays (Hitachi/Roche). Leptin was measured by an in-house enzyme-linked immunosorbent assay validated against commercial methods. Adiponectin and high-sensitivity IL-6 were measured by enzyme-linked immunosorbent assay (R&D Systems), and CRP was measured by automated particle-enhanced immunoturbidimetric assay (Roche UK, Welwyn Garden City, UK). All assay coefficients of variation were <5%. Non–HDL-C was calculated as total cholesterol minus HDL-C.
All pregnancy weight measurements (median number of repeat measurements per woman, 10; range, 1, 17) were used to develop a linear spline multilevel model (with 2 levels: woman and measurement occasion) relating weight (outcome) to gestational age (exposure). Full details of this statistical modeling are provided in the online-only Data Supplement. High levels of agreement were found between estimated and observed weights (Table I and Figure II in the online-only Data Supplement). We scaled maternal prepregnancy weight and gestational weight change to be clinically meaningful, examining the variation in offspring outcomes per additional 1 kg of maternal weight at conception and per 400-g gain per week of gestation for GWG.2 Sensitivity analyses were conducted in which we repeated analyses including only those women who had at least 9 measurements of gestational weight.
Associations of offspring outcomes with the IOM categories and with the estimates of maternal prepregnancy weight and early-, mid-, and late-pregnancy GWG were undertaken with the use of linear regression. We explored the linearity of the relationships between all outcomes and the exposures using fractional polynomials. When there was evidence of nonlinearity, we used spline models to approximate the relationship. In the basic model, we adjusted for offspring gender and age at the time of outcome measurement and for all models with fat mass for height and height squared. We considered the following potential confounders: prepregnancy weight and GWG in the previous period (for the multilevel model exposures only), gestational age (for IOM categories only because this is taken into account in the multilevel models), maternal age, parity, smoking during pregnancy, social class, and mode of delivery. To examine whether effects were mediated by birth weight, we adjusted for it, and for nonadiposity outcomes, we also examined potential mediation by adiposity. Triglycerides, leptin, CRP, and IL-6 were log transformed to normalize their distributions. The resultant regression coefficients were exponentiated to give a ratio of geometric means per change in exposure. Results are presented jointly for mothers of female and male offspring because associations were very similar in both genders.
Ethical approval for all aspects of data collection was obtained from the ALSPAC Law and Ethics Committee (IRB 00003312) and the local Research Ethics Committee.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Table II in the online-only Data Supplement shows the characteristics of mothers and offspring. Table 2 shows the association of IOM categories with adiposity and cardiovascular risk factors. Offspring of women who gained more than IOM-recommended GWG were more likely to have greater BMI, waist circumference, fat mass, leptin, SBP, CRP, and IL-6 levels. They were also more likely to have lower HDL-C and apoA1 levels. Children of women who gained less than recommended amounts had lower levels of adiposity, but other cardiovascular risk factors tended to be similar in this group to those of offspring of women gaining recommended amounts. IOM categories were not associated with DBP, non–HDL-C, apoB, or triglyceride levels. Associations remained with adjustment for confounders. IOM categories were associated with binary outcomes of offspring overweight/obesity. In confounder-adjusted models, offspring of women who gained less than recommended levels compared with those gaining recommended levels had odds ratios of overweight/obesity (based on BMI) of 0.80 (0.67, 0.96) and of central obesity (based on waist) of 0.79 (0.69, 0.90), and offspring of mothers who gained more than recommended levels compared with those gaining recommended levels had odd ratios of overweight/obesity and central obesity of 1.73 (1.45, 2.05) and 1.36 (1.19, 1.57), respectively.
When we used multilevel models including repeat measures of gestational weight to estimate GWG in more detail, 3 distinct periods of GWG were identified: early pregnancy, 0 to 14 weeks; mid pregnancy, >14 to 36 weeks; and late pregnancy, >36 weeks (Figure). In early pregnancy, 20.0% of women either lost weight or remained stable. The majority of women in both mid (99.9%) and late pregnancy (95.7%) gained weight. Table III in the online-only Data Supplement shows the correlations between estimated prepregnancy weight, estimated GWG in early, mid, and late pregnancy, total absolute GWG over the whole pregnancy, and birth weight. Most correlations were modest or weak. There was a strong inverse association of estimated GWG in early and late pregnancy and a strong positive association of estimated GWG in mid and late pregnancy.
Table 3 shows the associations of estimated prepregnancy weight (per 1-kg change) and estimated GWG (per 400 kg/wk) with offspring adiposity (BMI, waist circumference, fat mass, leptin) and BP. Estimated prepregnancy weight was positively linearly associated with all 4 measurements of offspring adiposity and SBP and DBP, with these associations remaining after adjustment for confounders.
For associations of estimated GWG with adiposity and BP, there was evidence of nonlinearity with knots (changes in the direction and/or magnitude of association) at 0 and 500 g/wk for GWG in early pregnancy and at 250 and 500 g/wk in both mid and late pregnancy. Estimated GWG in all 3 periods generally had U-shaped associations with offspring adiposity, with null or inverse associations in women gaining low levels of weight, then null associations in the middle range of estimated GWG, and then positive associations (model 1, Table 3). However, with adjustment for confounding factors (model 2), the inverse associations at low levels of estimated GWG attenuated. In the confounder-adjusted model, women who lost weight or did not gain weight in early pregnancy (ie, low estimated GWG women) had no association between their average gestational weight change per week and offspring adiposity. However, for those women (ie, medium or high estimated GWG women) gaining weight during this period, there was a positive association of estimated GWG with measures of offspring adiposity, which strengthened in women gaining on average >500 g/wk.
For mid pregnancy, estimated GWG up to 500 g/wk (ie, low or medium estimated GWG) was not associated with offspring adiposity, but offspring adiposity increased linearly with estimated GWG in mid pregnancy after this level (ie, in women with high GWG). There was no clear association of estimated GWG in late pregnancy (beyond 36 weeks) with offspring adiposity or of estimated GWG in any periods with SBP or DBP. Associations of prepregnancy weight and estimated GWG with binary outcomes of adiposity (Table IV in the online-only Data Supplement) were consistent with those seen for the continuously measured variables shown in Table 3.
Table 4 shows the associations of estimated prepregnancy weight and estimated GWG with lipids, apolipoproteins, and inflammatory markers. For these outcomes, there was no strong evidence of nonlinear associations. Estimated prepregnancy weight and GWG in mid pregnancy were positively associated with triglyceride levels and IL-6 and inversely associated with HDL-C and apoA1, although for triglycerides and apoA1, confidence intervals were wide and included the null value. Estimated prepregnancy weight was also positively associated with non–HDL-C, apoB, and CRP but not with adiponectin. GWG in early and late pregnancy was not associated with lipids, apolipoproteins, or inflammatory markers, with point estimates all close to the null value.
Further adjustment for birth weight did not substantively alter any of the confounder-adjusted models (Table Va to Vc in the online-only Data Supplement). All associations of maternal exposures that were present in confounder-adjusted models were attenuated to the null with further adjustment for offspring fat mass (Table VIa and VIb in the online-only Data Supplement). When these additional analyses were repeated with offspring BMI, waist circumference or leptin results instead of fat mass results were very similar to those presented.
We found no evidence that associations of estimated GWG with any of our outcomes were modified by prepregnancy BMI or weight, irrespective of whether this was estimated or observed (all P for interaction >0.2). When the analyses with estimated GWG were repeated with only those women who had at least 2, 4, and 3 measures in each time period, respectively (ie, total of at least 9 per woman across pregnancy), there was no substantial change in the results. Associations with estimated GWG in late pregnancy did not differ substantively from those presented when we used absolute weight gain. Associations did not differ substantively with the removal of women whose first antenatal measurement was after 15 weeks or whose last measurement was before 35 weeks.
To our knowledge, this is the most detailed study of the association of GWG and prepregnancy weight with offspring adiposity and associated cardiovascular risk factors. Women who gained more weight than recommended by the 2009 IOM criteria had offspring who were more adipose and had higher levels of SBP, CRP, and IL-6 and lower levels of HDL-C and apoA1. When we examined these associations in more detail, we found that any weight gain in the first 14 weeks of gestation was incrementally associated with increased offspring adiposity, but for between 14 and 36 weeks of gestation, only GWG >500 g/wk was associated with increased offspring adiposity. By contrast, the cardiovascular risk factors that were associated with GWG (triglycerides, HDL-C, apoA1, and IL-6) were associated with GWG linearly across all levels of GWG in mid pregnancy (>14 to 36 weeks). Prepregnancy weight was positively associated with offspring adiposity and adverse cardiovascular risk factors, but we found no interaction between prepregnancy weight/BMI and GWG in their associations with offspring outcomes. The associations of greater than recommended IOM weight gain, prepregnancy weight, and GWG in mid pregnancy with adverse lipid profiles and inflammatory markers appeared to be largely mediated by offspring adiposity.
A number of mechanisms may explain our findings. First, our results could reflect tracking in size across the life course. However, consistent with previous studies,4,5,8 we found only weak associations of prepregnancy weight and GWG with birth weight, and adjustment for birth weight did not substantively alter associations. Furthermore, GWG in early pregnancy (up to 14 weeks) was associated across the entire distribution with offspring adiposity (compared with GWG >14 to 36 weeks, which was only associated if women gained >500 g/wk), but at this stage most GWG will be related to maternal fat deposition and not to fetal growth. Second, offspring could inherit their mother’s genetic potential to gain weight. We are unable to assess this possibility in our study. Third, mothers with greater GWG may engage in lifestyles (high-energy diet and low levels of physical activity) during and after their pregnancy that promote weight gain, and they may pass them on to their offspring. Fourth, greater maternal prepregnancy adiposity and GWG might program greater adiposity and cardiovascular risk in offspring resulting from the persistent and adverse influences on the fetus that arise from the greater delivery of glucose, amino acids, and free fatty acids to the developing fetus in utero.17 The continuous association, across the whole distribution, of GWG up to 14 weeks with offspring adiposity provides some support for this because most weight gain in this period will be an increase in maternal fat stores, with concomitant increases in circulating glucose, amino acids, and free fatty acids. The fact that GWG in this period was not statistically strongly associated with cardiovascular risk factors might be a consequence of limited statistical power, and, ideally, replication of our findings in larger cohorts with detailed repeat measurements of weight in pregnancy would be useful, although we are unaware of other larger cohorts with such detailed measurements. Finally, our results may be due to chance. We examined a large number of maternal exposure–offspring outcomes in this study. However, we believe that this is a strength of our study. Our work builds importantly on previous publications examining only offspring adiposity and BP and using very limited information on GWG. We acknowledge that replication of these associations in larger studies, but with similarly detailed exposure and outcome measurements, would be beneficial.
The levels of attrition in ALSPAC are similar to those found in previous studies. Offspring of women from higher socioeconomic positions, of more educated women, and of older women are more likely to attend follow-up clinics in ALSPAC.13 However, we found no evidence of differences in distributions of GWG between women whose offspring had outcome measurements and those whose offspring did not (all P>0.4). The consistency of associations between adiposity measurements and circulating leptin levels suggests that exclusion of those participants who did not complete a blood test did not bias these associations. Offspring blood tests were completed on nonfasting blood samples, but the majority of measures are not appreciably altered by this approach.18–20 We used maternal self-report of height to calculate prepregnancy BMI, which may be inaccurate. With respect to associations examined (outcomes assessed in offspring 9 years later), any measurement error would be nondifferential, and therefore the expectation would be that it might bias results toward the null.
The fact that GWG in mid pregnancy was only associated with offspring adiposity in women gaining >500 g/wk suggests that from 14 to 36 weeks, women could “safely” (with respect to offspring adiposity) gain 11 kg, which is close to the range of recommended levels of weight gain across the whole of pregnancy for normal and overweight women according to IOM categories, but we found no evidence that this (or other) associations differed by maternal prepregnancy BMI categories. It should be acknowledged that in this cohort, just 7% of women were obese before pregnancy, and obesity prevalence is greater for contemporary women. The lack of association with GWG beyond 36 weeks may reflect the fact that the length of this period varies for different maternal-offspring pairs. Very large sample sizes would be required to determine whether different patterns in this late stage were important.
Maternal prepregnancy weight was more consistently associated with offspring adiposity and a wider range of cardiovascular risk factors in offspring than were any measurements of GWG, and this finding supports initiatives aimed at maintaining healthy weight in women of reproductive age. Long-term follow-up of ongoing randomized controlled trials aimed at controlling GWG21 and mendelian randomization studies (using genetic variants that are robustly associated with maternal adiposity and fat gain in pregnancy as instrumental variables)22 are necessary to establish whether the associations we have found are causal. The extent to which antenatal care guidelines should be modified to monitor GWG and promote adherence to IOM levels requires additional research that establishes clear benefits and lack of important risk in the short and long term for both mother and child.
We are grateful to all of the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.
Sources of Funding
This work was funded by a grant from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK077659). The UK Medical Research Council, Wellcome Trust, and University of Bristol provide core funding support for ALSPAC. The blood assays were funded by a British Heart Foundation grant (PG07/002). The Medical Research Council and University of Bristol provide core funding for Medical Research Council Centre for Causal Analyses in Translational Epidemiology. Dr Fraser is funded by a Medical Research Council research fellowship, and Dr Brion is funded by a Wellcome Trust Henry Wellcome research fellowship. Dr Hingorani is funded by a British Heart Foundation senior research fellowship (FS05/125).
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Variation in gestational weight gain (GWG) is associated with perinatal outcomes, but whether it is importantly associated with longer-term outcomes is unclear. In a prospective cohort of 5154 (for adiposity and blood pressure) and 3457 (for blood assays) mother-offspring pairs, we examined the association of GWG and prepregnancy weight with offspring cardiovascular risk factors at age 9 years. Women who gained more than 2009 Institute of Medicine–recommended amounts of weight during gestation were more likely to have offspring with greater body mass index, waist, fat mass, leptin, systolic blood pressure, C-reactive protein, and interleukin-6 levels and lower high-density lipoprotein cholesterol and apolipoprotein A levels. Detailed examination demonstrated that greater prepregnancy weight was also independently associated with greater offspring adiposity and adverse cardiovascular risk factors. Furthermore, women who gained weight before 14 weeks of gestation or who gained >500 g/wk from 14 to 36 weeks had offspring with greater adiposity. Greater GWG across the whole distribution between 14 and 36 weeks of gestation was associated with adverse lipid and inflammatory profiles in offspring, largely because of the association of GWG with offspring adiposity. Collectively, our findings support initiatives to maintain healthy weight in women of reproductive age and potentially to prevent excessive GWG, broadly in agreement with current Institute of Medicine recommendations. However, before guidelines on GWG are implemented, long-term follow-up of randomized controlled trials targeting GWG is needed to determine the effects of controlling GWG on a wide range of short- and long-term outcomes for both mother and infant.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.906081/DC1.