Summary
Background
Maternal caffeine intake during pregnancy is associated with an increased risk of childhood obesity. Studies in adults suggest that caffeine intake might also directly affect visceral and liver fat deposition, which are strong risk factors for cardio‐metabolic disease.
Objective
To assess the associations of maternal caffeine intake during pregnancy with childhood general, abdominal, and liver fat mass at 10 years of age.
Methods
In a population‐based cohort from early pregnancy onwards among 4770 mothers and children, we assessed maternal caffeine intake during pregnancy and childhood fat mass at age 10 years.
Results
Compared with children whose mothers consumed <2 units of caffeine per day during pregnancy, those whose mothers consumed 4‐5.9 and ≥6 units of caffeine per day had a higher body mass index, total body fat mass index, android/gynoid fat mass ratio, and abdominal subcutaneous and visceral fat mass indices. Children whose mothers consumed 4‐5.9 units of caffeine per day had a higher liver fat fraction. The associations with abdominal visceral fat and liver fat persisted after taking childhood total body fat mass into account.
Conclusions
High maternal caffeine intake during pregnancy was associated with higher childhood body mass index, total body fat, abdominal visceral fat, and liver fat. The associations with childhood abdominal visceral fat and liver fat fraction were independent of childhood total body fat. This suggests differential fat accumulation in these depots, which may increase susceptibility to cardio‐metabolic disease in later life.
Keywords: body mass index, caffeine, childhood, liver fat, pregnancy, visceral fat
1. INTRODUCTION
Caffeine is a methylxantine that occurs naturally in several food products. Caffeine‐containing beverages, including coffee and tea, are widely consumed by pregnant women. Caffeine crosses the placenta and enters the fetal circulation freely.1 The activity of the principal enzyme in caffeine metabolism, cytochrome CYP1A2, decreases progressively during pregnancy and is absent in placenta and fetus.2, 3, 4 As a consequence, fetal exposure to caffeine is prolonged and might adversely influence the development of organ systems. Consumption of caffeine‐containing beverages during pregnancy has been related to an increased risk of fetal death, impaired fetal growth, and low birth weight.5, 6, 7, 8, 9 In addition to these short‐term outcomes, maternal caffeine intake during pregnancy may also influence long‐term offspring body fat development. We previously observed among 7857 mothers and their children from the Netherlands that high maternal caffeine intake during pregnancy was associated with a higher childhood body mass index and total body fat mass at the age of 6 years.10 Similarly, studies among 615, 50 943, and 558 mothers and children from the United States, Norway, and Ireland, respectively, observed that any maternal caffeine intake during pregnancy was associated with an increased risk of obesity in childhood.11, 12, 13
In contrast, consumption of caffeine‐containing beverages by non‐pregnant adults seems to have beneficial effects on body fat accumulation and the risks of several diseases.14, 15, 16, 17, 18, 19 Previous studies suggest that consumption of caffeine‐containing beverages is associated with lower visceral fat accumulation and lower risks of non‐alcoholic fatty liver disease (NAFLD), possibly by influencing blood concentrations of adiponectin and pro‐inflammatory cytokines.15, 16, 17, 18, 19 Previous research suggests that blood concentrations of adipokines and cytokines in pregnant women are related to childhood body fat development.20, 21, 22 However, it is not known whether maternal caffeine intake during pregnancy is also related to offspring abdominal and liver fat accumulation. Thus far, only animal studies have shown that in utero exposure to caffeine increases intra‐hepatic fat content and the susceptibility to NAFLD.23, 24 As visceral and liver fat accumulation are related to the development of hypertension, type 2 diabetes, NAFLD, and the metabolic syndrome independent of excess body fat per se,25, 26 it is important to obtain further insight into whether maternal caffeine intake during pregnancy differentially affects offspring visceral and liver fat deposition.
Therefore, in a population‐based cohort among 4770 mothers and children from early pregnancy onwards, we assessed the associations of maternal caffeine intake during pregnancy with childhood general, abdominal, and liver fat at the age of 10 years, with the main focus on abdominal and liver fat.
2. METHODS
2.1. Study design
This study was embedded in the Generation R Study, a prospective population‐based cohort study from early pregnancy onwards performed in Rotterdam, the Netherlands.27 The study was approved by the Medical Ethical Committee of the Erasmus Medical Center, University Medical Center, Rotterdam (MEC 198.782/2001/31). Written informed consent was obtained from all mothers at enrolment in the study. The response rate at birth was 61%. Of the 8879 mothers that were prenatally included in the study, 8097 had information available on caffeine intake during pregnancy. Of their children, 7900 were singleton and live born. Of these children, 4770 participated in body composition follow‐up measurements at 10 years of age and were included in the analyses (Figure S1).
2.2. Maternal caffeine intake during pregnancy
As described previously, information on maternal caffeine intake from coffee and tea during pregnancy was obtained by postal questionnaires in the first, second, and third trimesters of pregnancy.7, 10 Response rates for these questionnaires were 91%, 80%, and 77%, respectively.7, 10 Mothers who reported to drink any coffee or tea were asked how many cups of coffee or tea they consumed on average per day and what type of coffee or tea they consumed (caffeinated, decaffeinated, or a combination of both). According to standard values for caffeine content, a regular coffee serving (125 mL) in the Netherlands contains ~90 mg caffeine, decaffeinated coffee contains ~3 mg, and black tea contains ~45 mg.28 To calculate the total caffeine intake in each trimester, the type of coffee or tea was weighted according to its caffeine content (caffeinated coffee = 1, caffeinated and decaffeinated coffee = 0.5, decaffeinated coffee = 0, caffeinated tea = 0.5, caffeinated and decaffeinated tea = 0.25, decaffeinated tea = 0, herbal tea = 0, and green tea = 0.5).7 Thus, in our analyses, each unit of caffeine intake reflects caffeine exposure based on one cup of caffeinated coffee (90 mg caffeine).10 Based on data availability, total caffeine intake was categorized into categories of <2, 2‐3.9, 4‐5.9, and ≥6 units per day (equivalent to <180, 180‐359, 360‐539, and ≥540 mg per day, respectively). For the main analyses using caffeine intake during the full pregnancy, caffeine intake of the trimesters was averaged.
2.3. Childhood body fat mass
At the age of 10 years, we measured height and weight without shoes and heavy clothing and calculated body mass index (kg/m2). We created age‐ and sex‐adjusted standard deviation scores (SDS) of body mass index using a Dutch reference chart.29 In addition, we defined childhood overweight/obesity according to the International Obesity Task Force cut‐offs.30 We measured total and regional body fat mass using dual‐energy X‐ray absorptiometry (DXA) (iDXA, General Electrics–Lunar, 2008, Madison, Wisconsin).31 Android/gynoid fat mass ratio was calculated and used as a measure of body fat distribution comparable with waist/hip ratio.31 Abdominal and organ fat were measured in a subgroup by magnetic resonance imaging (MRI), as described previously.27 Briefly, all children were scanned using a 3.0 Tesla MRI (Discovery MR750w, General Electric Healthcare, Milwaukee, Wisconsin). The MRI protocol included an axial 3‐point Dixon sequence for fat and water separation (IDEAL IQ) for liver fat measurements. This technique also enables the generation of liver fat fraction images.32 An axial abdominal scan from lower liver to pelvis and a coronal scan centred at the head of the femurs were also performed with a 2‐point Dixon acquisition (LavaFlex). The obtained fat scans were analysed by the Precision Image Analysis company (PIA, Kirkland, Washington), using the sliceOmatic (TomoVision, Magog, Canada) software package. All extraneous structures and any image artefacts were removed manually.33 Total subcutaneous and visceral fat volumes ranged from the dome of the liver to the superior part of the femoral head. Fat masses were obtained by multiplying the total volumes by the specific gravity of adipose tissue, 0.9 g/mL. Liver fat fraction was determined by defining four regions of interest of at least 4 cm2 in the central portion of the hepatic volume. Subsequently, the mean signal intensities were averaged to generate an overall mean liver fat fraction estimation. To create fat measures independent of child's height, we estimated the optimal adjustment by log‐log regression analyses and subsequently divided total and subcutaneous fat mass by height3 (total body fat mass index and subcutaneous fat mass index) and visceral fat mass by height4 (visceral fat mass index, Methods S1).34, 35
2.4. Covariates
Information on maternal age, pre‐pregnancy body mass index, parity, ethnicity, educational level, and folic acid supplementation use was obtained by questionnaire at enrolment in the study. Smoking and alcohol intake during pregnancy were repeatedly assessed by questionnaire. Information on gestational diabetes, gestational hypertensive disorders (gestational hypertension and pre‐eclampsia), date of birth, child's sex, and birth weight was obtained from midwife and hospital registries. Average television watching time was assessed by questionnaire at the age of 10 years.
2.5. Statistical analysis
First, we performed a non‐response analysis comparing participants included the analysis with those lost to follow up at the age of 10 years. Second, we assessed the associations of maternal caffeine intake during pregnancy with childhood general fat measures and the risk of overweight/obesity at age 10, using linear and logistic regression models. Third, we assessed the associations of maternal caffeine intake during pregnancy with childhood abdominal subcutaneous and visceral fat mass indices and liver fat fraction, using linear regression models. Non‐normally distributed outcome variables were log‐transformed. To enable comparison of effect estimates across the different outcomes, we calculated SDS for each of the outcomes. The models were first adjusted for child's age and sex only (basic models). Next, we additionally adjusted the models for maternal ethnicity, education, smoking during pregnancy, alcohol consumption during pregnancy, folic acid supplementation use, and childhood television watching time (confounder models). These confounders were selected based on existing literature, associations with the exposure and outcome in the study sample, and a change in effect estimates of >10%. Maternal age, pre‐pregnancy body mass index, parity, and gestational hypertensive disorders were also considered, but were not associated with either the exposure or the outcome or did not change the effect estimates with >10% and were therefore not included in the models. To explore whether any observed associations of caffeine intake during pregnancy with the outcomes were mediated by gestational age at birth and birth weight, we added these variables to the confounder models (mediator models). We performed tests for trend by adding the categorized caffeine intake variable to the models as continuous variable. Fourth, to further explore whether maternal caffeine intake during pregnancy was specifically associated with childhood abdominal fat mass and liver fat fraction, independent from total body fat mass, we used conditional regression analyses. We created measures of childhood abdominal subcutaneous fat mass, abdominal visceral fat mass, and liver fat fraction that are independent of total body fat mass by regressing these detailed childhood fat measures on childhood total body fat mass index. The standardized residuals from these models were used as an outcome for the regression models focused on the associations of maternal caffeine intake during pregnancy with conditional childhood abdominal and liver fat measures.36 Fifth, to identify potential critical periods, we assessed the associations of trimester‐specific maternal caffeine intake with childhood general, abdominal, and liver fat using linear regression models. As sex differences in childhood body fat development have been reported,37, 38 we tested for interactions between maternal caffeine intake during pregnancy and child's sex, but these interaction terms were not statistically significant (P values > .05). Missing values of covariates (maximum percentage of missing values: 20.8%) were imputed using Multiple Imputation, and pooled results from five imputed datasets were reported. All statistical tests were two‐sided, with a significance threshold of 0.05. The analyses were performed using the Statistical Package for the Social Sciences version 24.0 (IBM Corp, Armonk, New York, USA) and R version 3.3.4 (R Foundation for Statistical Computing).
3. RESULTS
3.1. Participants' characteristics
Table 1 shows that, of the 4770 women included, 2780 (58.3%), 1583 (33.2%), 329 (6.9%), and 78 (1.6%) consumed <2 units, 2‐3.9 units, 4‐5.9 units, and ≥6 units of caffeine per day, respectively, during pregnancy. Women who had higher caffeine intakes were older and were more likely to be higher educated, multiparous, and from European descent. They used less often folic acid supplementation and smoked and consumed alcohol more often during pregnancy. Table S1 shows that, as compared with women included in the analyses, those lost to follow up had slightly lower caffeine intakes and a lower pre‐pregnancy BMI, were younger, were more often multiparous, and were less often from European descent. These women used folic supplementation less often, smoked more often, and consumed alcohol less often during pregnancy.
Table 1.
Characteristics of the mothers and their children
| Total Group | <2 Units | 2‐3.9 Units | 4‐5.9 Units | ≥6 Units | P Value | |
|---|---|---|---|---|---|---|
| N = 4770 | N = 2780 (58.3%) | N = 1583 (33.2%) | N = 329 (6.9%) | N = 78 (1.6%) | ||
| Maternal characteristics | ||||||
| Caffeine intake during pregnancy, median (95% range), units | 1.6 (0.0‐5.2) | 1.0 (0.0‐1.8) | 2.6 (2.0‐3.8) | 4.5 (4.0‐5.7) | 6.7 (6.0‐10.3) | <.001 |
| Age, median (95% range), y | 31.2 (20.4‐39.6) | 30.4 (19.6‐39.1) | 32.0 (21.9‐40.1) | 32.9 (23.5‐39.8) | 33.7 (23.2‐40.8) | <.001 |
| Pre‐pregnancy BMI, median (95% range), kg/m2 | 22.6 (18.1‐34.5) | 22.6 (18‐34.6) | 22.4 (18.3‐34.1) | 22.8 (18.5‐34.5) | 22.7 (18.4‐31.5) | .242 |
| Education, N (%) | ||||||
| Primary | 340 (7.4) | 233 (8.7) | 87 (5.6) | 13 (4.0) | 7 (9.2) | <.001 |
| Secondary | 1944 (42.2) | 1247 (46.7) | 543 (35.3) | 116 (36.1) | 38 (50.0) | |
| Higher | 2324 (50.4) | 1191 (44.6) | 910 (59.1) | 192 (59.8) | 31 (40.8) | |
| Parity, nulliparous (%) | 2793 (58.8) | 1715 (62.0) | 873 (55.4) | 168 (51.1) | 37 (47.4) | <.001 |
| Ethnicity, European (%) | 3113 (65.8) | 1624 (59.1) | 1163 (73.8) | 264 (80.7) | 62 (80.5) | <.001 |
| Folic acid supplementation use, Yes (%) | 2955 (78.2) | 1663 (75.9) | 1039 (81.7) | 216 (82.4) | 37 (67.3) | <.001 |
| Smoking during pregnancy, Yes (%) | 1065 (24.3) | 493 (19.3) | 412 (28.3) | 116 (38.3) | 44 (58.7) | <.001 |
| Alcohol consumption during pregnancy, Yes (%) | 2495 (57.5) | 1271 (50.2) | 969 (67.3) | 203 (69.0) | 52 (70.3) | <.001 |
| Gestational hypertensive disorders, Yes (%) | 272 (5.9) | 166 (6.2) | 80 (5.2) | 22 (6.8) | 4 (5.3) | NA |
| Gestational diabetes, Yes (%) | 46 (1.0) | 26 (1.0) | 15 (1.0) | 5 (1.6) | 0 (0.0) | NA |
| Child characteristics | ||||||
| Males, No. (%) | 2361 (49.5) | 1410 (50.7) | 732 (46.2) | 176 (53.5) | 43 (55.1) | .009 |
| Gestational age at birth, median (95% range), wk | 40.1 (35.9‐42.3) | 40.1 (35.5‐42.3) | 40.3 (36.4‐42.3) | 40.3 (36.0‐42.4) | 40.3 (34.5‐42.4) | .023 |
| Birth weight, median (95% range), g | 3460 (2262‐4480) | 3450 (2250‐4430) | 3490 (2368‐4520) | 3530 (2392‐4534) | 3390 (1999‐4263) | .007 |
| Gestational age adjusted birth weight, mean (SD) | −0.1 (1.0) | −0.1 (1.0) | 0.0 (1.0) | 0.0 (1.1) | −0.3 (1.1) | .027 |
| Ever breastfeeding, Yes (%) | 3627 (92.6) | 2063 (92.3) | 1244 (93.3) | 266 (92.7) | 54 (91.5) | NA |
| Introduction of solid foods, before 6 mo (%) | 2800 (89.1) | 1569 (88.7) | 979 (89.4) | 214 (90.7) | 38 (90.5) | NA |
| Age at 10‐y follow‐up measurement, median (95% range), y | 9.7 (9.4‐10.7) | 9.7 (9.3‐10.8) | 9.7 (9.4‐10.7) | 9.7 (9.4‐10.4) | 9.7 (9.3‐10.3) | .650 |
| Television watching, More than 2 h/d (%) | 1168 (30.9) | 717 (33.3) | 346 (26.8) | 80 (28.7) | 25 (40.3) | <.001 |
| Body mass index at 10 y, median (95% range), kg/m2 | 17.0 (14.0‐24.8) | 17.0 (14.0‐25.1) | 16.8 (14.1‐24.2) | 17.2 (14‐24.1) | 17.8 (14.3‐24.0) | <.001 |
| Overweight, N (%) | 862 (3.7) | 556 (16.2) | 231 (11.8) | 54 (13.8) | 21 (22.0) | NA |
| Total body fat mass, median (95% range), kg | 8.5 (4.5‐22.0) | 8.6 (4.5‐22.2) | 8.4 (4.5‐21.7) | 8.5 (4.8‐21.9) | 9.7 (4.6‐20.9) | .044 |
| Android/gynoid fat mass ratio, median (95% range) | 0.2 (0.2, 0.5) | 0.2 (0.2, 0.5) | 0.2 (0.2, 0.5) | 0.2 (0.2, 0.5) | 0.3 (0.2, 0.5) | .023 |
| Abdominal subcutaneous fat, median (95% range), kg | 1.3 (0.6, 5.4) | 1.3 (0.6, 5.4) | 1.3 (0.6, 4.9) | 1.4 (0.7, 4.7) | 1.5 (0.8, 6.2) | .017 |
| Abdominal visceral fat, median (95% range), kg | 0.4 (0.2, 1.0) | 0.4 (0.2, 1.0) | 0.4 (0.2, 0.9) | 0.4 (0.2, 0.9) | 0.5 (0.2, 1.2) | .002 |
| Liver fat fraction, median (95% range), % | 2.0 (1.2, 5.2) | 2.0 (1.2, 5.3) | 2.0 (1.3, 4.6) | 2.1 (1.4, 5.4) | 2.1 (1.3, 8.4) | .444 |
Note: Values represent mean (SD), median (95% range) or number of participants (valid %). One unit of caffeine represents the equivalent of one cup of coffee (90 mg of caffeine). NA: Chi‐square test not available as a result of low expected cell counts.
3.2. Maternal caffeine intake during pregnancy and childhood general body fat mass
Figure 1 shows that in the confounder model, as compared with children whose mothers consumed <2 units of caffeine per day during pregnancy, those whose mothers consumed 4‐5.9 and ≥6 units of caffeine per day during pregnancy had a higher body mass index (differences: 0.12 standard deviation [SD] [95% confidence interval (CI), 0.01‐0.24] and 0.24 [95% CI, 0.01‐0.47], respectively), total body fat mass index (differences: 0.14 SD [95% CI, 0.04‐0.25] and 0.22 [95% CI, 0.02‐0.43], respectively), and android/gynoid fat mass ratio (differences: 0.16 SD [95% CI, 0.05‐0.27] and 0.22 [95% CI, 0.01‐0.44], respectively) at the age of 10 years (exact differences are given in Table S2). A dose‐response relationship was present for each of these outcomes (P‐values for trend < .05). Children whose mothers consumed ≥6 units of caffeine per day also tended to have a higher risk of overweight/obesity (odds ratio: 1.59 [95% CI, 0.92‐2.75], Figure 2). Results from the basic model were similar (Table S3). Additional adjustment for gestational age at birth and birth weight did not change the results (Table S4). Table S5 shows that no trimester‐specific associations were present, but rather that associations were similar across pregnancy.
Figure 1.
Associations of maternal caffeine intake during pregnancy with childhood general body fat mass. Values are regression coefficients (95% confidence intervals) from the confounder models that reflect the difference in childhood body mass index, total body fat mass index, android/gynoid fat mass ratio in children of mothers who consumed 2‐3.9, 4‐5.9, and ≥6 units of caffeine per day, as compared with those whose mothers consumed <2 units of caffeine per day. One unit of caffeine represents the equivalent of one cup of coffee (90 mg). The models are adjusted for child's sex, child's age at follow‐up measurement, maternal ethnicity, maternal education, maternal smoking, maternal alcohol use, folic acid supplementation, and television watching time. P values for trend were obtained from models in which the categorized caffeine intake variable (<2, 2‐3.9, 4‐5.9, and ≥6 units) was entered as continuous variable
Figure 2.
Associations of maternal caffeine intake during pregnancy with the risk of childhood overweight/obesity. Values are odds ratios (95% confidence intervals) from the confounder models that reflect the risk of overweight/obesity in children of mothers who consumed 2‐3.9, 4‐5.9, and ≥6 units of caffeine per day, as compared with those whose mothers consumed <2 units of caffeine per day. One unit of caffeine represents the equivalent of one cup of coffee (90 mg). The models are adjusted for child's sex, child's age at follow‐up measurement, maternal ethnicity, maternal education, maternal smoking, maternal alcohol use, folic acid supplementation, and television watching time. P values for trend were obtained from models in which the categorized caffeine intake variable (<2, 2‐3.9, 4‐5.9, and ≥ 6 units) was entered as continuous variable
3.3. Maternal caffeine intake during pregnancy and childhood abdominal fat mass and liver fat fraction
Figure 3A shows that in the confounder model, as compared with children whose mothers consumed <2 units of caffeine per day during pregnancy, those whose mothers consumed 4‐5.9 and ≥6 units of caffeine per day during pregnancy had a higher abdominal subcutaneous fat mass index (differences: 0.15 SD [95% CI, −0.01 to 0.30] and 0.35 SD [95% CI, 0.04‐0.65], respectively) and a higher abdominal visceral fat mass index (differences: 0.14 SD [95% CI, −0.03 to 0.30] and 0.43 SD [95% CI, 0.11‐0.76], respectively). Children whose mothers consumed 4‐5.9 units of caffeine per day also had a higher liver fat fraction, as compared with those whose mothers consumed <2 units per day during pregnancy (difference: 0.20 SD [95% CI, 0.04‐0.36]); exact differences are given in Table S6). A dose‐response relationship was present for each of the outcomes (P values for trend < .05). Results from the basic model were similar (Table S7). Additional adjustment for gestational age at birth and birth weight did not influence the observed estimates (Table S8). Table S9 shows that the associations for each trimester separately were comparable with those for the full pregnancy.
Figure 3.
Associations of maternal caffeine intake during pregnancy with childhood abdominal fat mass and liver fat fraction. Values are regression coefficients (95% confidence intervals) from the confounder models that reflect the difference in (A) childhood outcomes in SDS and (B) childhood outcomes in standardized residuals in children of mothers who consumed 2‐3.9, 4‐5.9, and ≥6 units of caffeine per day, as compared with those whose mothers consumed <2 units of caffeine per day. One unit of caffeine represents the equivalent of one cup of coffee (90 mg). The models are adjusted for child's sex, child's age at follow‐up measurement, maternal ethnicity, maternal education, maternal smoking, maternal alcohol use, folic acid supplementation, and television watching time. P values for trend were obtained from models in which the categorized caffeine intake variable (<2, 2‐3.9, 4‐5.9, and ≥6 units) was entered as continuous variable
Figure 3B shows that after conditioning on total body fat mass index to assess the effects of maternal caffeine intake during pregnancy on childhood abdominal fat and liver fat fraction independent of childhood total body fat, maternal caffeine intake during pregnancy of ≥6 units and 4‐5.9 units per day remained associated with abdominal visceral fat mass index and liver fat fraction, respectively (differences: 0.32 SD [95% CI, 0.00‐0.64] and 0.20 SD [95% CI, 0.04‐0.36]). A significant dose‐response relationship remained also present for these outcomes (P values for trend < .05). No associations were present with childhood abdominal subcutaneous fat mass index conditioned on childhood total body fat mass index.
4. DISCUSSION
In this population‐based prospective cohort study, high maternal caffeine intake during pregnancy was associated with higher childhood general body fat mass, abdominal fat mass, and liver fat fraction at the age of 10 years. The associations of high maternal caffeine intake with childhood abdominal visceral fat mass and liver fat fraction seemed to be independent from childhood total body fat mass.
4.1. Interpretation of main findings
Caffeine‐containing beverages are frequently consumed during pregnancy. Increasing evidence suggests that maternal caffeine intake during pregnancy might be related to long‐term offspring body fat development.10, 11, 12, 39 We previously showed among 7857 6‐year‐old children from the same cohort as the current study that maternal caffeine intake during pregnancy of ≥4 units per day was associated with a higher body mass index and total body fat mass. Maternal caffeine intake during pregnancy of ≥6 units per day was also associated with a higher android/gynoid fat mass ratio, reflecting a central body fat accumulation.10 A study among 272 mother‐child pairs from Brazil observed that any caffeine intake by women with an uncomplicated pregnancy was associated with a higher offspring sum of skinfold thicknesses at age 3 months.39 A study among 50 943 participants from Norway showed that any caffeine intake during pregnancy was associated with an increased risk of childhood overweight at ages 3 and 5, whereas at 8 years, this association was only present for high caffeine intakes.12 In an Irish study among 558 mother‐child pairs, higher maternal caffeine intake during pregnancy was associated with higher risks of overall and central obesity at the ages of 5 and 9 years.13 In line with these previous studies, we observed in the current study that higher maternal caffeine intake during pregnancy was associated with higher body mass index, total body fat mass, and android/gynoid fat mass ratio at the age of 10 years, as indicated by significant tests for trend. The strongest effects were present for maternal caffeine intake during pregnancy 4 or more units per day. For instance, as compared with children whose mothers consumed <2 units of caffeine per day, children whose mothers consumed ≥6 units of caffeine per day during their pregnancy had a 0.24 SD higher body mass index, corresponding to a difference of approximately 0.7 kg/m2. These effect sizes are comparable with those observed for well‐known determinants of childhood body mass index, such as maternal pre‐pregnancy overweight and smoking during pregnancy.40, 41, 42 These associations were similar across the trimesters of pregnancy. Mothers with high caffeine intakes during pregnancy also had higher alcohol intakes and smoked more often during their pregnancies. However, associations were present across the full range of maternal caffeine intake, and adjusting the models for these lifestyle‐related factors did not influence the results. We therefore do not consider it likely that the observed associations can be fully explained by differences in these factors. Thus, these findings suggest that maternal caffeine intake throughout pregnancy has long‐term consequences for offspring body fat development, as reflected by higher total body fat mass and a central body fat distribution.
Studies in adults suggest that consumption of caffeine‐containing beverages might also be associated with abdominal and ectopic fat deposition, although the direction of these associations might be different from the direction of the associations of maternal caffeine intake during pregnancy with offspring body fat development.15, 16, 17, 18, 19 A study among 364 Japanese men showed inverse associations of coffee consumption with visceral fat mass and visceral to subcutaneous fat mass ratio.15 A meta‐analysis of five studies showed that the risk of NAFLD was 30% lower in participants who consumed coffee as compared with those who did not.18 It is not known whether caffeine intake by pregnant women is also related to offspring fat deposition in these specific fat depots. Only one study, among 7857 participants from our cohort from the Netherlands, showed that maternal caffeine intake during pregnancy was not associated with pre‐peritoneal fat mass measured by abdominal ultrasound at age 6, which was used as proxy of visceral fat.10 In the current study, we observed that higher maternal caffeine intake during pregnancy was associated with higher childhood abdominal subcutaneous fat mass, abdominal visceral fat mass, and liver fat fraction measured by MRI at age 10. This inconsistency might be explained by differences in measures of abdominal visceral fat mass. Pre‐peritoneal fat mass provides an estimation of abdominal visceral fat mass, while MRI provides more precise measures and is the gold standard for the measurement of intra‐abdominal and organ fat deposition.33 Also, the associations of maternal caffeine intake during pregnancy might only become apparent at older childhood ages. The results for each of the trimesters separately were comparable with those for the full pregnancy. The associations with abdominal visceral fat mass and liver fat fraction persisted after taking total body fat mass into account. This suggests that maternal caffeine intake throughout pregnancy might differentially affect fat deposition in these depots in the offspring, independent of their total body fat development. As visceral and liver fat accumulation are related to the development of cardio‐metabolic disease independently of total body fat, these children might be at risk of later cardio‐metabolic disease.25, 26 The associations with abdominal subcutaneous fat mass were not independent from total body fat mass. This might be explained by subcutaneous fat being the main compartment of fat storage across the full body. Thus, maternal caffeine intake throughout pregnancy might affect offspring visceral and liver fat deposition, independent from their total amount of body fat.
The mechanisms underlying the observed associations are not well known. Studies in adults have suggested that consumption of caffeine‐containing beverages might increase adiponectin concentrations and decrease concentrations of pro‐inflammatory cytokines, subsequently influencing visceral and liver fat masses.15, 19 Although high maternal adiponectin concentrations during pregnancy have been related to a higher risk of childhood obesity,20 the role of adipokines and cytokines in the association of maternal caffeine intake during pregnancy with offspring fat deposition is unknown. We speculate that caffeine intake by pregnant women may affect adiponectin concentrations and the pro‐inflammatory state, which may affect fetal nutrient supply and subsequently lead to developmental adaptations in adipose tissue. Alternatively, animal studies have suggested that in utero exposure to caffeine may overexpose the developing fetus to glucocorticoids, leading to an altered development of the HPA‐axis.43, 44 High glucocorticoid concentrations have been related to increased central obesity. In addition, the concentration of glucocorticoid receptors is higher in visceral adipose tissue as compared with other fat depots, possibly resulting in differential fat deposition in these depots.45 Rats exposed to caffeine in utero had increased intra‐hepatic fat concentrations and increased susceptibility to NAFLD,23, 24 possibly by similar mechanisms. Finally, the associations might be explained by confounding by unhealthy lifestyle factors that are shared within families. However, a negative control analysis among 50 943 participants showed stronger associations for maternal caffeine intake during pregnancy with the risk of childhood overweight at the age of 3 years, as compared with those for paternal caffeine intake at the time of their partners pregnancy.12 Similarly, in another recent negative control analysis among 558 participants, maternal caffeine intake, but not paternal caffeine intake, was associated with childhood body mass index and waist circumference at ages 5 and 10 years.13 These results suggest that an intra‐uterine programming mechanism might at least partly underlie these associations. Further studies are needed to disentangle the mechanisms underlying the associations of maternal caffeine intake and childhood abdominal and liver fat deposition.
Our results are consistent with those of previous studies and further highlight the importance of limiting maternal caffeine intake during pregnancy with respect to its potential adverse effects on long‐term body fat development in the offspring. The current recommendations for maternal caffeine intake during pregnancy range between 200 and 300 mg per day and are based on the risks of adverse pregnancy and birth outcomes.46, 47, 48 The most pronounced effects observed in our study were for caffeine intakes above these guidelines. However, the dose‐response relationship in our and previous studies5, 6, 8, 9, 10, 11, 12, 13 suggest that the adverse effects of maternal caffeine intake with respect to both pregnancy outcomes and long‐term body fat development are not restricted to high caffeine intakes, but increase across the range of maternal caffeine intake. A review of randomized controlled trials had insufficient evidence to confirm that avoiding caffeine consumption during pregnancy is beneficial with respect to adverse pregnancy outcomes.49 Based on our findings and findings from other observational studies, further adequately powered randomized controlled trials are needed to assess whether avoiding caffeine consumption during pregnancy improves both pregnancy and long‐term offspring health outcomes, as compared with current recommendations. Our findings and findings from other observational studies need to be incorporated in future guidelines regarding maternal caffeine consumption during pregnancy, and these guidelines need to further emphasize potential beneficial effects on offspring health outcomes by further reducing caffeine intake during pregnancy below the current recommendations.
4.2. Strengths and limitations
This study was embedded in a large population‐based cohort from early pregnancy onwards, enabling us to prospectively study the associations of interest. Of all participants with information on maternal caffeine intake during pregnancy, 39.6% did not participate in the follow‐up measurements at age 10. This non‐response might have led to biased estimates if the associations of interest differ between participants included and lost to follow up. This seems unlikely as only a minor difference in maternal caffeine intake was observed between these groups. However, the selection towards a higher educated, healthier population might have affected the generalizability of our results. Maternal caffeine intake might have been underreported, possibly leading to misclassification of the caffeine intake categories and underestimation of the effect estimates. In accordance with the Dutch Nutrition Centre, we assumed that coffee and tea were consumed in cups of 125 mL.46 This might have differed between participants, which may have led to some misclassification of maternal caffeine intake. We only had data available about caffeine intake from coffee and tea and not from other sources, such as soft drinks, energy drinks, chocolate, and medications. However, at the time of data collection (2002‐2006), coffee and tea accounted for 70% and 26%, respectively, of all caffeine consumed.50 We had data available on many possible confounders. However, residual confounding might still be present, for example, by maternal and child's physical activity and dietary habits.
5. CONCLUSIONS
Our results suggest that high maternal caffeine intake during pregnancy is associated with higher general body fat, abdominal subcutaneous and visceral fat mass and liver fat fraction in childhood. The associations of maternal caffeine intake during pregnancy with childhood visceral fat mass and liver fat seem to be largely independent from childhood total body fat mass. This suggests differential fat accumulation in these depots, which may increase susceptibility to cardio‐metabolic disease.
CONFLICT OF INTEREST STATEMENT
No conflict of interest was declared.
AUTHORS' CONTRIBUTIONS
E.V., M.E.H., and R.G. designed and conducted the research and wrote the paper. E.V. and M.E.H. performed the statistical analysis. V.W.V.J. and E.H.G.O. coordinated data acquisition and critically reviewed and revised the manuscript. E.V. and R.G. had primary responsibility for the final content. All authors approved the final manuscript and agree to be accountable for all aspects of the work.
Supporting information
Data S1. Supporting Information
ACKNOWLEDGEMENTS
The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam, and the Stichting Trombosedienst and Artsenlaboratorium Rijnmond (STAR), Rotterdam. We gratefully acknowledge the contribution of participating mothers, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The Generation R Study is financially supported by the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development. V.W.V.J. received a grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw‐VIDI 016.136.361) and a European Research Council Consolidator Grant (ERC‐2014‐CoG‐648916). R.G. received funding from the Dutch Heart Foundation (grant number 2017T013), the Dutch Diabetes Foundation (grant number 2017.81.002), and the Netherlands Organization for Health Research and Development (ZonMW, grant number 543003109).
Voerman E, Jaddoe VW, Hulst ME, Oei EH, Gaillard R. Associations of maternal caffeine intake during pregnancy with abdominal and liver fat deposition in childhood. Pediatric Obesity. 2020;15:e12607 10.1111/ijpo.12607
Funding information Diabetes Fonds, Grant/Award Number: 2017.81.002; Erasmus Medisch Centrum; Erasmus Universiteit Rotterdam; European Research Counsil, Grant/Award Number: ERC‐2014‐CoG‐648916; Hartstichting, Grant/Award Number: 2017T013; ZonMw, Grant/Award Numbers: 543003109, ZonMw‐VIDI 016.136.361
REFERENCES
- 1. Goldstein A, Warren R. Passage of caffeine into human gonadal and fetal tissue. Biochem Pharmacol. 1962;11:166‐168. [DOI] [PubMed] [Google Scholar]
- 2. Yu T, Campbell SC, Stockmann C, et al. Pregnancy‐induced changes in the pharmacokinetics of caffeine and its metabolites. J Clin Pharmacol. 2016;56(5):590‐596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Brent RL, Christian MS, Diener RM. Evaluation of the reproductive and developmental risks of caffeine. Birth Defects Res B Dev Reprod Toxicol. 2011;92(2):152‐187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Aldridge A, Aranda JV, Neims AH. Caffeine metabolism in the newborn. Clin Pharmacol Ther. 1979;25(4):447‐453. [DOI] [PubMed] [Google Scholar]
- 5. Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM. Maternal caffeine intake during pregnancy and risk of pregnancy loss: a categorical and dose‐response meta‐analysis of prospective studies. Public Health Nutr. 2016;19(7):1233‐1244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. CARE Study Group . Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ. 2008;337:a2332. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Bakker R, Steegers EA, Obradov A, Raat H, Hofman A, Jaddoe VW. Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: the Generation R Study. Am J Clin Nutr. 2010;91(6):1691‐1698. [DOI] [PubMed] [Google Scholar]
- 8. Sengpiel V, Elind E, Bacelis J, et al. Maternal caffeine intake during pregnancy is associated with birth weight but not with gestational length: results from a large prospective observational cohort study. BMC Med. 2013;11:42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Chen LW, Wu Y, Neelakantan N, Chong MF, Pan A, van Dam RM. Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose‐response meta‐analysis. BMC Med. 2014;12:174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Voerman E, Jaddoe VW, Gishti O, Hofman A, Franco OH, Gaillard R. Maternal caffeine intake during pregnancy, early growth, and body fat distribution at school age. Obesity (Silver Spring). 2016;24(5):1170‐1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Li DK, Ferber JR, Odouli R. Maternal caffeine intake during pregnancy and risk of obesity in offspring: a prospective cohort study. Int J Obes (Lond). 2014;39(4):658‐664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Papadopoulou E, Botton J, Brantsaeter AL, et al. Maternal caffeine intake during pregnancy and childhood growth and overweight: results from a large Norwegian prospective observational cohort study. BMJ Open. 2018;8(3):e018895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Chen LW, Murrin CM, Mehegan J, Kelleher CC, Phillips CM, Cross‐Generation Cohort Study for the Lifeways . Maternal, but not paternal or grandparental, caffeine intake is associated with childhood obesity and adiposity: the Lifeways Cross‐Generation Cohort Study. Am J Clin Nutr. 2019;109(6):1648‐1655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Coffee consumption and health: umbrella review of meta‐analyses of multiple health outcomes. BMJ. 2017;359:j5024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Mure K, Maeda S, Mukoubayashi C, et al. Habitual coffee consumption inversely associated with metabolic syndrome‐related biomarkers involving adiponectin. Nutrition. 2013;29(7–8):982‐987. [DOI] [PubMed] [Google Scholar]
- 16. Hino A, Adachi H, Enomoto M, et al. Habitual coffee but not green tea consumption is inversely associated with metabolic syndrome: an epidemiological study in a general Japanese population. Diabetes Res Clin Pract. 2007;76(3):383‐389. [DOI] [PubMed] [Google Scholar]
- 17. Marventano S, Salomone F, Godos J, et al. Coffee and tea consumption in relation with non‐alcoholic fatty liver and metabolic syndrome: a systematic review and meta‐analysis of observational studies. Clin Nutr. 2016;35(6):1269‐1281. [DOI] [PubMed] [Google Scholar]
- 18. Wijarnpreecha K, Thongprayoon C, Ungprasert P. Coffee consumption and risk of nonalcoholic fatty liver disease: a systematic review and meta‐analysis. Eur J Gastroenterol Hepatol. 2017;29(2):e8. [DOI] [PubMed] [Google Scholar]
- 19. Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeine is protective in patients with non‐alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012;35(1):76‐82. [DOI] [PubMed] [Google Scholar]
- 20. Li LJ, Rifas‐Shiman SL, Aris IM, et al. Associations of maternal and cord blood adipokines with offspring adiposity in Project Viva: is there an interaction with child age? Int J Obes (Lond). 2018;42(4):608‐617. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Gaillard R, Rifas‐Shiman SL, Perng W, Oken E, Gillman MW. Maternal inflammation during pregnancy and childhood adiposity. Obesity (Silver Spring). 2016;24(6):1320‐1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Englich B, Herberth G, Rolle‐Kampczyk U, et al. Maternal cytokine status may prime the metabolic profile and increase risk of obesity in children. Int J Obes (Lond). 2017;41(9):1440‐1446. [DOI] [PubMed] [Google Scholar]
- 23. Wang L, Shen L, Ping J, et al. Intrauterine metabolic programming alteration increased susceptibility to non‐alcoholic adult fatty liver disease in prenatal caffeine‐exposed rat offspring. Toxicol Lett. 2014;224(3):311‐318. [DOI] [PubMed] [Google Scholar]
- 24. Hu S, Xia L, Luo H, et al. Prenatal caffeine exposure increases the susceptibility to non‐alcoholic fatty liver disease in female offspring rats via activation of GR‐C/EBPalpha‐SIRT1 pathway. Toxicology. 2019;417:23‐34. [DOI] [PubMed] [Google Scholar]
- 25. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007;116(1):39‐48. [DOI] [PubMed] [Google Scholar]
- 26. Britton KA, Fox CS. Ectopic fat depots and cardiovascular disease. Circulation. 2011;124(24):e837. [DOI] [PubMed] [Google Scholar]
- 27. Kooijman MN, Kruithof CJ, van Duijn CM, et al. The Generation R Study: design and cohort update 2017. Eur J Epidemiol. 2016;31(12):1243‐1264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.NEVO‐tabel 2006. Dutch Food Composition Table 2006. The Hague, Netherlands: Voedingscentrum; [Netherlands Nutrition Center] 2006. (in Dutch).
- 29. Fredriks AM, van Buuren S, Burgmeijer RJ, et al. Continuing positive secular growth change in The Netherlands 1955‐1997. Pediatr Res. 2000;47(3):316‐323. [DOI] [PubMed] [Google Scholar]
- 30. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320(7244):1240‐1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Helba M, Binkovitz LA. Pediatric body composition analysis with dual‐energy X‐ray absorptiometry. Pediatr Radiol. 2009;39(7):647‐656. [DOI] [PubMed] [Google Scholar]
- 32. Reeder SB, Cruite I, Hamilton G, Sirlin CB. Quantitative assessment of liver fat with magnetic resonance imaging and spectroscopy. J Magn Reson Imaging. 2011;34(4):729‐749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Hu HH, Nayak KS, Goran MI. Assessment of abdominal adipose tissue and organ fat content by magnetic resonance imaging. Obes Rev. 2011;12(5):e504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. VanItallie TB, Yang MU, Heymsfield SB, Funk RC, Boileau RA. Height‐normalized indices of the body's fat‐free mass and fat mass: potentially useful indicators of nutritional status. Am J Clin Nutr. 1990;52(6):953‐959. [DOI] [PubMed] [Google Scholar]
- 35. Wells JC, Cole TJ. Steam as. Adjustment of fat‐free mass and fat mass for height in children aged 8 y. Int J Obes Relat Metab Disord. 2002;26(7):947‐952. [DOI] [PubMed] [Google Scholar]
- 36. 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(12):1320‐1324. [DOI] [PubMed] [Google Scholar]
- 37. Karastergiou K, Smith SR, Greenberg AS, Fried SK. Sex differences in human adipose tissues—the biology of pear shape. Biol Sex Differ. 2012;3(1):13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Fuente‐Martin E, Argente‐Arizon P, Ros P, Argente J, Chowen JA. Sex differences in adipose tissue: it is not only a question of quantity and distribution. Adipocyte. 2013;2(3):128‐134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. de Medeiros TS, Bernardi JR, de Brito ML, Bosa VL, Goldani MZ, da Silva CH. Caffeine intake during pregnancy in different intrauterine environments and its association with infant anthropometric measurements at 3 and 6 months of age. Matern Child Health J. 2017;21(6):1297‐1307. [DOI] [PubMed] [Google Scholar]
- 40. Voerman E, Santos S, Patro Golab B, et al. Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: an individual participant data meta‐analysis. PLoS Med. 2019;16(2):e1002744. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Riedel C, Fenske N, Muller MJ, et al. Differences in BMI z‐scores between offspring of smoking and nonsmoking mothers: a longitudinal study of German children from birth through 14 years of age. Environ Health Perspect. 2014;122(7):761‐767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Grzeskowiak LE, Hodyl NA, Stark MJ, Morrison JL, Clifton VL. Association of early and late maternal smoking during pregnancy with offspring body mass index at 4 to 5 years of age. J Dev Orig Health Dis. 2015;6(6):485‐492. [DOI] [PubMed] [Google Scholar]
- 43. Xu D, Wu Y, Liu F, et al. A hypothalamic‐pituitary‐adrenal axis‐associated neuroendocrine metabolic programmed alteration in offspring rats of IUGR induced by prenatal caffeine ingestion. Toxicol Appl Pharmacol. 2012;264(3):395‐403. [DOI] [PubMed] [Google Scholar]
- 44. Xu D, Zhang B, Liang G, et al. Caffeine‐induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic‐pituitary‐adrenal axis inhibition in fetal rats. PloS One. 2012;7(9):e44497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Lee MJ, Pramyothin P, Karastergiou K, Fried SK. Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity. Biochim Biophys Acta. 2014;1842(3):473‐481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Cafeïne. [Caffeine]. Voedingscentrum. [The Netherlands Nutrition Center] (in Dutch). Available from: http://www.voedingscentrum.nl/encyclopedie/cafeine.aspx. Accessed March 11, 2019.
- 47. Efsa Panel on Dietetic Products N, Allergies . Scientific opinion on the safety of caffeine. EFSA J. 2015;13(5):4102. [Google Scholar]
- 48. World Health Organization . Restricting caffeine intake during pregnancy. 2019; https://www.who.int/elena/titles/caffeine-pregnancy/en/. Accessed March 11, 2019.
- 49. Jahanfar S, Jaafar SH. Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes. Cochrane Database Syst Rev. 2015;6:CD006965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50. Clausson B, Granath F, Ekbom A, et al. Effect of caffeine exposure during pregnancy on birth weight and gestational age. Am J Epidemiol. 2002;155(5):429‐436. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information