eine intake during pregnancy in different...
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Vol.:(0123456789)1 3
Matern Child Health J DOI 10.1007/s10995-016-2230-7
Caffeine Intake During Pregnancy in Different Intrauterine Environments and its Association with Infant Anthropometric Measurements at 3 and 6 Months of AgeThamíris Santos de Medeiros1,6 · Juliana Rombaldi Bernardi2,5,6 · Mariana Lopes de Brito4,6 · Vera Lucia Bosa2,3,6 · Marcelo Zubaran Goldani3,5,6 · Clécio Homrich da Silva3,5,6
© Springer Science+Business Media New York 2017
3 and 6 months. Linear regression was used to analyze the interaction between caffeine intake and skinfold thick-ness. Results Overall, 272 mother–child pairs were investi-gated (41 DM, 26 HYP, 68 SMO, 25 SGA, and 112 CTL). There were no differences in anthropometric measurements between infants born to mothers who had and had not con-sumed caffeine during pregnancy (P > 0.05). Children of mothers in the DM group had the highest adjusted average skinfold thicknesses at 3 months. An interaction between maternal caffeine intake during pregnancy and the sum of skinfolds at age 3 months was found in the DM and CTL groups (P < 0.05). However, significant differences were not observed at 6 months. Conclusions Maternal caffeine intake influenced infants skinfold thickness measurements at 3 months of age. This parameter was reduced in infants born to mothers with DM and increased in those born to healthy control mothers.
Keywords Caffeine · Pregnancy · Infants · Anthropometry
Significance
Experimental research shows that exposure to caffeine in utero interferes with the formation of the hypothalamic-pituitary-adrenal (HPA) axis of the fetus. It is known these changes persist in postnatal life. Longitudinal studies found an association between the consumption of this substance by the mother in pregnancy and increased risk of obesity in childhood to early adolescence (Li et al. 2015; Voer-man et al. 2016). This study investigated the association between maternal caffeine intakes during pregnancy in dif-ferent intrauterine environments with the development of adiposity in an early period of life.
Abstract Objective To investigate the association between maternal caffeine intake during pregnancy and infant anthropometric measurements at age 3 and 6 months. Methods Longitudinal observational study of mother–child pairs stratified into five groups: diabetic women (DM), hypertensive women (HYP), smoking mothers (SMO), mothers of infants small for gestational age (SGA), and controls (CTL). Pairs were recruited from three public hos-pitals in Porto Alegre, Brazil, from 2011 to 2015, using a convenience sampling strategy. The Food Frequency Ques-tionnaire (FFQ) was administered on postpartum day 7 to evaluate maternal caffeine intake during pregnancy. The anthropometric measurements of interest (weight, length, and skinfold thickness) were assessed at birth and at age
* Thamíris Santos de Medeiros [email protected] Master of Sciences in Child and Adolescent Health,
Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
2 Department of Nutrition, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
3 Department of Pediatrics, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
4 Graduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
5 Department of Pediatrics and Graduate Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
6 Center for the Study of Child and Adolescent Health, Hospital de Clínicas de Porto Alegre, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2nd floor, 2350, CEP 90035-903 Porto Alegre, RS, Brazil
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Introduction
The intrauterine environment is considered a critical period of exposure to exogenous and endogenous factors, which may trigger metabolic disorders during fetal programming. Caffeine consumption is highly prevalent among women, including during pregnancy (Chen et al. 2014; Li et al. 2015), and is thus a common exogenous factor. Caffeine reaches the fetus immediately after ingestion and absorp-tion by the mother. The lack of an efficient enzymatic detoxification apparatus in the fetus leads to greater expo-sure and caffeine accumulation in fetal tissue (Chen et al. 2014).
Maternal metabolic diseases can antagonize or potenti-ate the action of caffeine on the fetus (Hinkle et al. 2015). High levels of this substance reduce maternal blood per-fusion in the intervillous spaces of the placenta, reducing nutrient supply to the fetus and leading to inadequate intra-uterine growth (Chen et al. 2014). Furthermore, maternal smoking increases clearance of caffeine by enzyme induc-tion in the liver (Grosso et al. 2008). A previous study showed that children of pregnant smokers exposed to caf-feine have lower birth weight than children of non-smokers in the same condition (Care 2008).
In experimental studies, exposure to caffeine in utero can interfere with fetal development of the hypotha-lamic–pituitary–adrenal (HPA) axis, which is responsi-ble for homeostatic reactions, due to fetal overexposure to maternal glucocorticoids and increased metabolic activa-tion in the offspring hypothalamus (Tan et al. 2012). This susceptibility occurs secondary to a decrease in expression of the placental enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) or by a direct inhibitory effect of caffeine on the same enzyme in the fetal hypothalamus. Conse-quently, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and glucocorticoid receptors are overexpressed in the fetal hypothalamus; this, in turn, inhibits HPA axis function and alters regulation of glucose and lipid metabolism in the fetus 8. These effects can modify the crucial role of central nervous system homeostasis in the regulation of appetite and other metabolic processes [Li et al.2015]. Furthermore, it is known that these effects can be partially inherited by the next generation (Zhang et al. 2014).
On the other hand, comparatively few studies have investigated the relationship between maternal caffeine intake during pregnancy and adiposity, especially in infants (Li et al. 2015; Klebanoff and Keim 2015; Voerman et al. 2016). Two recent longitudinal studies found an association between consumption of this substance during pregnancy and increased risk of obesity in childhood (Li et al. 2015; Voerman et al. 2016). Within this context, the aim of our study was to investigate the association between mater-nal caffeine intake during pregnancy and anthropometric
measures in offspring at 3 and 6 months of age, considering the possible interactions between caffeine consumption and different intrauterine environments.
Methods
This longitudinal, observational study is nested in a larger birth cohort, the Impact of Perinatal Different Intrauter-ine Environments on Child Growth and Development in the First Six Months of Life (IVAPSA) Project. This study was conducted with a convenience sample of mother–child pairs stratified into groups according to various maternal exposures during pregnancy (Bernardi et al. 2012).
The sample was recruited from three public hospitals in Porto Alegre, state of Rio Grande do Sul, Brazil, from Sep-tember 2011 to August 2015 (Hospital de Clínicas de Porto Alegre, Hospital Femina, and Hospital Nossa Senhora da Conceição, the last two of which belong to the same hos-pital network, Grupo Hospitalar Conceição). A conveni-ence sample was chosen due to the difficulty of obtain-ing mother–child pairs who met the inclusion criteria for the different groups. However, these hospitals are located at strategic points in the city, are university-affiliated, and all are referral centers for high-risk pregnancies. This ensures that the selected facilities would receive pregnant women from different districts of the city but with similar characteristics.
Participants
The mother–child pairs were divided into five groups: dia-betic mothers (DM group), hypertensive mothers (HYP group), smoking mothers (SMO group), mothers of infants small for gestational age (SGA group), and controls (CTL group). The inclusion criteria were that pairs lived in the city of Porto Alegre and infants had been born at the partic-ipating hospitals. We excluded mothers who tested positive for HIV, preterm newborns, twin pregnancies, and infants with congenital diseases and/or birth defects.
The DM group included women who had been diag-nosed with diabetes mellitus (type 1, type 2, or gestational). The HYP group included women diagnosed with hyper-tensive disorders (preeclampsia, eclampsia, preeclampsia superimposed on chronic hypertension, chronic hyperten-sion, or gestational hypertension). For these two groups, conditions were defined as gestational if diagnosed during the current pregnancy and as chronic if diagnosed during that period or earlier. The SMO group included mothers who reported having smoked during pregnancy, regard-less of the duration of exposure or the number of cigarettes smoked. The SGA group included newborns who had a birth weight below the 5th percentile for fetal growth,
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according to the curve proposed by Alexander et al. (1996) (Alexander et al. 1996). Finally, the control group included mothers who did not have any of the defining conditions of the other intrauterine exposure groups. These clinical con-ditions were diagnosed by physicians during the prenatal/birth and obtained from hospital records. Participants in each group had the defining condition alone; for this study, we did not analyze mixed groups (i.e., mothers who had more than one of the conditions of interest simultaneously) or pairs in which the mother had any other clinical condi-tions or diseases.
Data Collection
The mother–child pairs were recruited on the day of deliv-ery. At this time, the investigators posed the first questions to the mother and collected information from medical records to confirm that pairs met the inclusion criteria. Data were also collected on maternal age, maternal pre-gesta-tional body mass index (BMI), mode of delivery, and infant birth weight and length. The pairs were evaluated at 7 days, 3, and 6 months by means of home visits. A brief descrip-tion of the methods used in the present study is provided in Table 1. More details have been published elsewhere (Bernardi et al. 2012). The anthropometric measurements of interest were weight, length, and triceps and subscapular skinfold thickness. Weight and length were measured at all visits and skinfolds only at 3 and 6 months. Measurements were always obtained in duplicate.
Food Consumption
The food frequency questionnaire (FFQ) was administered on postpartum day 7 to evaluate maternal caffeine intake during pregnancy. This questionnaire had been validated previously for a population of pregnant women in a city from the same region of Brazil (Giacomello et al. 2008).
The instrument consists of 96 items and 8 options for intake frequency, ranging from “more than three times a day” to “never or almost never.” The amount consumed was deter-mined by standard measurements.
The caffeinated foods included coffee, sodas, and choco-late. These were selected because they have the highest caf-feine content among the foods listed in the FFQ, as demon-strated by an analysis of chemical composition tables. We calculated the average amount of caffeine among the dif-ferent types of each food. For coffee (serving size in cups), reconstituted instant coffee, espresso, and coffee infusion were considered; for sodas (serving size in glasses), cola, guarana, and lemon-lime soda were considered; and for chocolate (serving size in pieces), dark, milk, and white were considered. We calculated the level of caffeine in mil-ligrams by converting serving sizes as needed and check-ing the U.S. nutritional tables (United States Department of Agriculture 2013). We did not use the Brazilian nutritional table because it does not report caffeine content. We then divided these analyses into two variables, caffeinated foods or coffee only, and found a positive correlation between the two (r = 0.852). Based on previous studies (Li et al. 2015; Sengpiel et al. 2013), we limited our analysis of caffeine intake to caffeine from coffee only.
Breastfeeding was investigated by a 24-h diet recall, and a basic structured questionnaire developed specifically for this study was used to record the type of food given to the child. These instruments were administered in all interviews.
Anthropometric Data
Two trained investigators obtained anthropometric meas-urements. To reduce interobserver and interobserver vari-ability, we used standardized techniques and calibrated equipment. Body weight in kg was measured using a port-able digital electronic scale (Marte®, Scientific, São Paulo,
Table 1 Overview of data collection
IVAPSA cohort, Porto Alegre, September 2011–August 2015
Interview Immediate postpartum 7 days 3 months 6 months
Site Hospital Home Home HomeInformation Pregnancy and birth data Maternal dietary habits during
pregnancyInfant feeding and anthropo-
metric parametersInfant feeding and anthropo-
metric parametersVariables Maternal age, education, fam-
ily income, marital status, ethnicity, pre-gestational Body Mass Index, parity, gestational age, mode of delivery; infant sex, weight, and length at birth
Caffeine intake during preg-nancy
Breastfeeding, complementary food introduction, weight, length, skinfold thickness
Breastfeeding, complementary food introduction, weight, length, skinfold thickness
Instrument Medical and hospital records Validated Food Frequency Questionnaire
24-h dietary recall, basic ques-tions, direct measurements
24-h dietary recall, basic ques-tions, direct measurements
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Brazil) that was accurate to within 50 g. Each infant’s weight was calculated by subtracting the mother’s weight from the total weight of mother and child combined. Infant length in cm was measured using a portable stadiometer (Alturexata®, Belo Horizonte, Brazil), with the infant in supine position on a flat and stable surface, such as a table. Skinfold thicknesses in mm were measured using a skin-fold caliper (Lange®, Ann Arbor, Michigan, USA). Triceps skinfold thickness was measured at the midpoint between the acromion and the olecranon; subscapular skinfold thickness, at the inferior angle of the scapula, in the skin-fold axis.
Sample Size
The sample size for the IVAPSA study was calculated to detect a difference of 0.5 standard deviations in mean body-weight Z score in the first 6 months of life, with a signifi-cance level of 5% and a statistical power of 80%. Based on these criteria, the size was calculated as 72 mother–child pairs in each group, if double in the control group, for a total of 432 pairs (Bernardi et al. 2012). For the present study, we checked the IVAPSA database and we included only pairs for which caffeine intake data were available and complete.
Statistical Analysis
The primary outcome of interest consisted of anthropo-metric measurements according to maternal caffeine intake during pregnancy. The Kolmogorov–Smirnov test was used to assess normality. Variables were described as mean and standard deviation if distributed parametrically and as median and interquartile range if nonparametric.
We performed analysis of variance (ANOVA) with Tuk-ey’s post-hoc test and the Kruskal–Wallis test with Dunn’s post-hoc procedure to compare means among continuous variables. We used the Chi square test with adjusted stand-ardized residuals analysis to test for associations between categorical variables. To evaluate the association of mater-nal and gestational variables with caffeine intake during pregnancy (characterized dichotomously as any intake/no intake), we performed a univariate Poisson regression. For analysis of correlation between the two caffeine source var-iables (only coffee/caffeinated foods), we used Pearson cor-relation coefficients. Finally, we performed a Students t-test and Mann–Whitney test for analysis of anthropometric measurements stratified by intrauterine environment groups and maternal caffeine intake (intake/no intake).
Multiple linear regression was used to assess the inter-action between maternal caffeine intake during pregnancy in the different intrauterine environment groups and anthro-pometric measurements in the infant. Variables based on
previous studies (pre-gestational maternal BMI, mode of delivery, birth weight, and exclusive breastfeeding) were used as an adjustment to verify the actual effects of the intrauterine groups and caffeine (Baker et al. 2004; Goldani et al. 2011). The significance level was set at 5%, and all analyses were performed in PASW Statistics Version 18.0.
Ethical Aspects
The IVAPSA project was approved by the Research Ethics Committees of Hospital de Clínicas de Porto Alegre and Grupo Hospitalar Conceição. The protocol numbers were 110,097 and 11,027, respectively.
Results
This sample included 272 mother–child pairs. Of these, 41 were allocated to the DM group, 26 to the HYP group, 68 to the SMO group, and 25 to SGA; 112 composed the CTL group.
The distribution of sociodemographic, perinatal, and anthropometric variables across groups is shown in Table 2. Mean maternal age was significantly higher in the HYP group (30.1 years) than in SGA (23.6 years) and CTL (26.0 years) (P < 0.05). Mothers in the SGA group had a significantly higher median educational attainment (11.0 years) than in the SMO group (8 years) (P < 0.01). The SMO group had a significantly lower mean family income (R$ 1352.80) than the SGA group (R$ 2275.10) (P < 0.05). Most women (86.6%) who were cohabiting were in the CTL group, while most unmarried women belonged to the SMO group (61.8%) (P < 0.01). Primiparity was significantly more prevalent in the SGA group (72.0%), whereas multiparity was higher in the SMO group (70.6%) (P < 0.05). There was no difference in ethnicity among the five groups. Mothers in the DM and HYP groups had sig-nificantly higher median pre-gestational BMI (27.6 and 27.4 kg/m², respectively) than those in SMO, SGA, and CTL (23.4, 20.9, and 23.7 kg/m², respectively) (P < 0.01). Cesarean section was significantly more frequent in the HYP group (76.9%) than in any other (P < 0.01). Infant sex distribution was similar across the study groups. Children in the DM group had a higher birth weight (3402 g) than children in the HYP, SMO, and SGA groups (3146, 3104, and 2542 g, respectively) (P < 0.01). However, children in the SGA group had the shortest birth length (46.2 cm) (P < 0.01).
At age 3 months, 25.9% of children were receiving exclusive breastfeeding. Only one child was still receiving exclusive breast milk at 6 months. The prevalence of exclu-sive breastfeeding was similar across all different intrau-terine environment groups. However, proportionally, the
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SMO group had a substantial rate of early weaning (data not shown).
Despite not significant, mothers belonging to the DM group had a higher prevalence of caffeine intake (80.5%) when compared to mothers in the other groups (P < 0.05) (Table 3). Maternal caffeine intake during pregnancy was statistically different among the different intrauter-ine environment groups (P < 0.05). Specifically, the aver-age mean intake in the SMO group (150.3 ± 18.5 mg)
was significantly higher than in the CTL group (91.3 ± 9.4 mg) (P = 0.01) (Table 3).
Table 4 shows a crude analysis of mothers stratified by caffeine intake and the anthropometric measurements obtained in infants, considering intrauterine groups. Maternal caffeine consumption was not significantly associated with anthropometric measurements in infants at birth, in age 3 and 6 months (Table 4).
Table 2 Maternal and perinatal characteristics stratified by intrauterine environment
The information of italics shows the significant results into categoryIVAPSA cohort, Porto Alegre, September 2011–August 2015SD standard deviation, IQR interquartile range, DM diabetes mellitus, HYP hypertension, SMO tobacco smoking, SGA small for gestational age, CTL control groupǂ Missing data points: Family income (n = 27), pre-gestational BMI (n = 22), gestational age (n = 45). ANOVA with Tukey’s post-hoc test for parametric variables, Kruskal–Wallis test with Dunn’s post-hoc procedure for nonparametric variables, Chi square test for categorical variables
DM (41) HYP (26) SMO (68) SGA (25) CTL (112) Overall (272) p
Maternal Age (years),
mean ± SD27.8ab ± 5.9 30.1a ± 6.6 25.0ab ± 5.9 23.6b ± 5.3 26.0b ± 7.4 26.2 ± 6.7 0.002
Education (years), median [IQR]
10.0ab [3.0] 10.5ab [4.0] 8.0b [4.0] 11.0a [2.0] 10.0ab [3.0] 10.0 [3.0] 0.010
Family incomeǂ (reais), mean ± SD
2014.9ab ± 2004.8 1789.9ab ± 1487.3 1352.8a ± 715.3 2275.1b ± 1854.9 2079.9ab ± 1355.7 1881.8 ± 1467.2 0.020
Marital status, n (%)
<0.001
Cohabiting 36 (87.8) 20 (76.9) 42 (61.8) 23 (92.0) 97 (86.6) 218 (80.1) Single 5 (12.2) 6 (23.1) 26 (38.2) 2 (8.0) 15 (13.4) 54 (19.9)
Ethnicity, n (%) 0.612 White 26 (63.4) 18 (69.2) 40 (58.8) 12 (48.0) 68 (60.7) 164 (60.3) Nonwhite 15 (36.6) 8 (30.8) 28 (41.2) 13 (52.0) 44 (39.3) 108 (39.7)
Pre-gestational BMIǂ (kg/m²), median [IQR]
27.6a [7.0] 27.4a [9.9] 23.4b [4.9] 20.9b [3.9] 23.7b [3.9] 24.4 [6.6] <0.001
Parity, n (%) 0.002 Primiparous 15 (36.6) 7 (26.9) 20 (29.4) 18 (72.0) 52 (46.4) 112 (41.2) Multiparous 26 (63.4) 19 (73.1) 48 (70.6) 7 (28.0) 60 (53.6) 160 (58.8)
Perinatal Gestational age
(weeks), median [IQR]
39 [2] 38 [2] 39 [2] 39 [0] 39 [2] 39 [2] 0.007
Mode of delivery, n (%)
<0.001
Vaginal 24 (58.5) 6 (23.1) 49 (72.1) 18 (72.0) 82 (73.2) 179 (65.8) Cesarean 17 (41.5) 20 (76.9) 19 (27.9) 7 (28.0) 30 (26.8) 93 (34.2)
Infant sex, n (%) 0.983 Female 21 (51.2) 14 (53.8) 34 (50.0) 14 (56.0) 60 (53.6) 143 (52.6) Male 20 (48.8) 12 (46.2) 34 (50.0) 11 (44.0) 52 (46.4) 129 (47.4)
Birth weight (g), mean ± SD
3402a ± 409 3146b ± 486 3104b ± 397 2542b ± 164 3332ab ± 439 3196 ± 472 <0.001
Birth length (cm), mean ± SD
49.0a ± 2.0 48.0a ± 2.0 47.9a ± 2.3 46.2b ± 1.7 49.2a ± 2.1 48.5 ± 2.3 <0.001
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On adjusted analysis, women who did not consume cof-fee during pregnancy were not been included in the inter-action analysis. In general, caffeine consumption during pregnancy was associated with increase in skinfolds in total sample, even after adjustment [0.0015 (CI 0.000–0.029) P < 0.047]. There were statistically significant differ-ences among the groups at 3 months (P < 0.05). The sum of triceps and subscapular skinfolds in the DM group was higher in absolute terms than in the other groups. This dif-ference remained after adjusting for potential confounders (P = 0.017). Moreover, there was an interaction between maternal caffeine intake and the sum of infant skinfold thicknesses. This interaction was mediated by intrauterine environments and remained significant after adjustments (P = 0.034). At 6 months, measures were no longer statisti-cally different (P > 0.05) (Table 5).
Figure 1 shows the dose-dependent relationship of caf-feine intake during pregnancy and skinfold thicknesses according to intrauterine environment group. The results were only significant at age 3 months and for groups DM (P = 0.010) and CTL (P = 0.016).
Discussion
In the present study, we observed an interaction between maternal caffeine intake during pregnancy and offspring adiposity at 3 months of age. The dose-dependence of con-sumption showed a negative relationship in the DM group.
Birth weight results were as expected in our sample. Children of women with DM during pregnancy are more likely to develop macrosomia (Alberico et al. 2014). Infants with intrauterine growth restriction have lower weight and shorter length at birth than other groups (Victora et al. 2015). Exclusive breastfeeding rates were far below national and international recommendations. According to WHO, infants should receive breast milk exclusively
until the 6th month of life, for its countless health benefits (World Health Organization 2002). Equally concerning was the high rate of early weaning observed in infants from the SMO group. These children are thus particularly highly exposed to risk factors, given the harmfulness of smok-ing to the fetus and child. This situation may be made even worse by the high maternal caffeine intake during preg-nancy found in this group and in other studies (Chen et al. 2014; Sengpiel et al. 2013).
Women in the SGA group also had substantial caffeine intake levels. Children included in our sample were born underweight for gestational age without a specific cause. Several previous publications have demonstrated the corre-lation between low birth weight and maternal consumption of caffeine during gestation (Chen et al. 2014; Care 2008; Sengpiel et al. 2013). In addition, the odds of insufficient weight at birth are higher in children of heavy caffeine con-sumers (>300 mg per day) (Rhee et al. 2015; Hoyt et al. 2014). This phenomenon is believed to involve damage to placental angiogenesis caused by exposure to caffeine in utero, a mechanism proposed in an investigation of human placentas and demonstrated in an experimental study with chick embryos (Kirkinen et al. 1983; Ma et al. 2015).
On the other hand, longitudinal observational study showed a positive odds ratio for higher weight through-out childhood among children exposed to caffeine in utero (Li et al. 2015). Another investigation measured maternal levels of paraxanthine (the main metabolite of caffeine in vivo) during pregnancy and its effects on offspring, and found a positive relative risk for developing obesity in chil-dren between ages 48 and 84 months. (Klebanoff and Keim 2015).
In total sample, the existence of a positive dose-depend-ent relationship between maternal caffeine intake dur-ing pregnancy and infant adiposity supports the previous hypothesis in which caffeine consumption during preg-nancy has been associated with higher proportion of fat
Table 3 Maternal caffeine intake from coffee during pregnancy, stratified by intrauterine environment
IVAPSA cohort, Porto Alegre, September 2011–August 2015SD standard deviation, IQR interquartile range, DM diabetes mellitus, HYP hypertension, SMO tobacco smoking, SGA small for gestational age, CTL control group*Significant difference across groups (P < 0.05); ANOVA with Tukey’s post-hoc test for mean and Kruskal–Wallis test with Dunn’s post-hoc procedure for median caffeine intake
DM (41) HYP (26) SMO (68) SGA (25) CTL (112)
Coffee intake during pregnancy, n (%) Yes 33 (80.5) 17 (65.4) 47 (69.1) 20 (80.0) 71 (63.4) No 8 (19.5) 9 (34.6) 21 (30.9) 5 (20.0) 41 (36.6)
Caffeine intake from coffee (mg)* Mean ± SD 96.4 ± 17.4 136.6 ± 20.4 150.3 ± 18.5 128.2 ± 19.6 91.3 ± 9.4 Median [IQR] 46.3 [165.4] 92.7 [101.9] 92.7 [139.0] 92.7 [92.7] 92.7 [62.1]
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Table
4 M
atern
al ca
ffeine
intak
e dur
ing pr
egna
ncy a
nd an
thro
pome
tric m
easu
remen
ts of
infan
ts at
3 and
6 mo
nths
of li
fe, st
ratifi
ed by
intra
uterin
e env
ironm
ent.
IVAP
SA co
hort,
Por
to Al
egre,
Se
ptemb
er 20
11–A
ugus
t 201
5
There
was
no si
gnifi
cant
differe
nce b
etwee
n caff
eine c
onsu
mptio
n gro
ups a
t birt
h, 3 o
r 6 m
onth
s (M
ann–
Whit
ney t
est)
SD st
anda
rd de
viatio
n, SK
skinf
old th
ickne
ss, M
mon
ths,
DM
diab
etes m
ellitu
s, H
YP hy
perte
nsion
, SM
O to
bacc
o smo
king,
SGA
small
for g
estat
ional
age,
CTL
contr
ol gr
oup
DMHY
PSM
OSG
ACT
L
At bi
rth3 M
6 MAt
birth
3 M6 M
At bi
rth3 M
6 MAt
birth
3 M6 M
At bi
rth3 M
6 M
n Yes
3327
2117
1110
4637
2520
1614
7156
46 N
o8
64
98
821
1613
54
341
3227
Weig
ht (g
) Y
es33
97 ±
409
6489
± 84
884
37 ±
1178
3055
± 45
762
70 ±
714
7772
± 91
631
47 ±
391
6012
± 80
676
52 ±
969
2561
± 15
355
55 ±
659
7516
± 79
532
80 ±
429
6214
± 62
781
20 ±
750
No
3458
± 49
361
76 ±
489
7987
± 45
033
19 ±
520
5893
± 45
677
22 ±
734
3009
± 40
558
42 ±
1031
7511
± 11
6624
68 ±
206
5394
± 24
969
50 ±
1430
3423
± 44
663
37 ±
1110
7845
± 10
82Le
ngth
(cm)
Yes
48.8
± 2,0
60.6
± 2.5
68.2
± 4.9
47.5
± 1.8
59.8
± 1.5
66.8
± 1.9
48.3
± 2.2
60.4
± 2.3
66.5
± 2.1
46.4
± 1.5
59.2
± 2.6
66.3
± 2.9
49.2
± 2.2
60.8
± 2.0
67.9
± 2.1
No
49.6
± 2.1
60.4
± 1.3
65.9
± 2.0
49.0
± 2.2
60.7
± 1.9
67.0
± 2.3
47.3
± 2.6
59.1
± 3.3
65.5
± 3.5
45.6
± 2.3
58.6
± 2.3
66.6
± 2.1
49.2
± 1.9
61.0
± 2.3
67.0
± 2.2
Trice
ps S
K (m
m) Y
es–
10.8
± 2.2
10.7
± 2.5
–9.8
± 2.
39.3
± 2.
2–
9.4 ±
2.5
9.8 ±
2.6
–9.9
± 1.
911
.0 ±
2.9–
9.9 ±
2.0
10.5
± 3.2
No
–9.7
± 2.
29.9
± 1.
9–
11.0
± 2.3
10.1
± 2.1
–9.2
± 1.
79.6
± 2.
1–
9.7 ±
1.5
9.7 ±
3.0
–9.8
± 2.
29.8
± 2.
3Su
bsca
pular
SK
(mm)
Yes
–8.8
± 1.
79.0
± 2.
6–
7.9 ±
1.2
7.7 ±
2.2
–8.1
± 2.
47.5
± 2.
0–
8.4 ±
2.6
8.5 ±
1.9
–8.3
± 2.
07.9
± 1.
9 N
o–
7.3 ±
2.3
8.4 ±
0.9
–8.6
± 1.
87.8
± 3.
2–
8.2 ±
2.1
8.2 ±
2.1
–8.9
± 2.
17.7
± 2.
3–
8.1 ±
2.5
8.6 ±
2.8
Sum
of S
Ks (m
m) Y
es–
19.7
± 3.4
19.6
± 4.3
–17
.7 ±
2.916
.8 ±
3.6–
17.5
± 4.7
17.3
± 4.2
–18
.3 ±
3.819
.5 ±
4.3–
18.3
± 3.3
18.4
± 4.6
No
–17
.0 ±
4.118
.2 ±
2.0–
19.7
± 3.3
17.9
± 4.6
–17
.4 ±
3.617
.8 ±
3.8–
18.6
± 3.2
17.3
± 4.2
–17
.8 ±
4.418
.3 ±
4.5
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mass later in life. Our results showed a precocious effect of caffeine on lipogenesis during the prenatal period. The mechanism of the effects of caffeine on fetal HPA axis programming has its basis on overexposure of the fetus to maternal glucocorticoids. In this case, the intrauterine environment exposed the fetus to a hyperglycemic status in pregnancy (Tan et al. 2012; Xu et al. 2012).
Nonetheless, the dose–response relationship seen in women in the DM group confronts our initial assumption. Research in this context is scarce. Nevertheless, a study of pregnant women suggested a protective effect of moder-ate coffee consumption in the first trimester of pregnancy against gestational DM (Hinkle et al. 2015). Other studies have reported prevention of type 2 DM by regular caffeine intake in adulthood. The effect is not due to caffeine, but
rather to micronutrients and other phenolic constituents of coffee (Tunnicliffe and Shearer 2008; Huxley et al. 2009).
However, the effects observed in this study occurred at 3 months and were not confirmed at 6 months of age. The first years of life constitute a very sensitive period that is closely correlated with occurrences in the intrauterine and early postnatal environments (Wells 2010). Thus, rapid, intense changes in growth and development in this phase are possible. Observing effects in early age means that other exogenous factors, such as food, culture, socializa-tion, and physical inactivity or sedentary lifestyle, are less likely to have been involved. However, these factors may also influence the outcome investigated herein (Pergher et al. 2010). Follow-up of these children through child-hood will be necessary for a better understanding of these results.
The limitations of this study include the lack of assess-ment of consumption of tea (a beverage with considerable caffeine content) during pregnancy. However, other studies have shown that effects from coffee only are more signifi-cant (Li et al. 2015; Sengpiel et al. 2013). In addition, this study used the FFQ to obtain the main variable of interest, i.e., consumption of caffeine. This is a limitation because this questionnaire is long and recall bias may occur. How-ever, the investigators were trained to remind mothers often that their responses should focus on consumption during the last pregnancy. Moreover, the pregnant women included in the sample had similar socioeconomic backgrounds and were users of public hospitals. As there was no difference in dietary pattern among the different groups, feeding did not influence the study results. Dietary recall referred to the day preceding the interview. Another aspect to be consid-ered as a limitation is the sample size, due to the difficulties of obtaining and following the initial sample of a longitudi-nal observational study.
Among the strengths of this study, we highlight the sample inclusion criteria. We recruited mothers and their infants from hospitals soon after delivery. The selection of newborns at term avoids confounding factors related to prematurity. Moreover, while the majority of studies ana-lyze low birth weight or pregnancy outcomes at birth, no studies had ever investigated the effects of caffeine intake during pregnancy in the early stages of extrauterine life. This study was also the first to combine, in the same anal-ysis, mother–child pairs with similar demographic and socioeconomic conditions but different intrauterine envi-ronments. In addition, we compared outcomes between pairs grouped by mother or infant health condition, which provides a good platform to distinguish how effect esti-mates differ between these groups and which groups will be best to target for preconception and prenatal health interventions.
Table 5 Analysis of interaction between maternal caffeine consump-tion, intrauterine environment, and sum of skinfold thicknesses in the infant
IVAPSA cohort, Porto Alegre, September 2011–August 2015Multiple linear regression. P-value of the interaction at 3 months = 0.034. P-value of the interaction at 6 months = 0.202. CI confidence interval, DM diabetes mellitus, HYP hypertension, SMO tobacco smoking, SGA small for gestational age, CTL control group. Model adjusted for maternal pre-gestational body mass index, mode of delivery, birth weight, and exclusive breastfeeding*Bonferroni-corrected
n Β 95%CI p*
3 months DM 25 2.647 [0.176;5.118] 0.036 HYP 10 −1.990 [−8.544;4.563] 0.552 SMO 29 −2.315 [−4.843;0.212] 0.073 SGA 15 1.467 [−1.977;4.911] 0.404 CTL 48 0 Caffeine 0.014 [0.003;0.025] 0.016 DM × caffeine 25 −0.022 [−0.040;−0.005] 0.010 HYP × caffeine 10 −0.004 [−0.052;0.044] 0.868 SMO × caffeine 29 0.003 [−0.014;0.019] 0.755 SGA × caffeine 15 −0.015 [−0.037;0.007] 0.174 CTL × caffeine 48 0
6 months DM 18 1.955 [−1.798;5.709] 0.307 HYP 6 2.786 [−4.407;9.979] 0.448 SMO 22 0.142 [−3.308;3.592] 0.936 SGA 12 2.946 [−1.583;7.475] 0.202 CTL 40 0 Caffeine 0.015 [0.000;0.029] 0.047 DM × caffeine 18 −0.014 [−0.039;0.011] 0.272 HYP × caffeine 6 −0.050 [−0.107;0.007] 0.088 SMO × caffeine 22 −0.016 [−0.039;0.006] 0.161 SGA × caffeine 12 −0.025 [−0.052;0.002] 0.069 CTL × caffeine 40 0
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Therefore, our results provide important inputs for inves-tigating the hypothesis of development of overweight in childhood secondary to fetal programming. This study can also foster an expansion of practices and protocols used
during antenatal care; namely, it suggests that adding anal-ysis of coffee consumption to standard maternal nutritional assessments can be highly relevant.
Fig. 1 Interaction between dose of caffeine consumed by the mother during pregnancy and estimated sum of skinfolds at 3 and 6 months of the child
** 3 MONTHSHYPDM SMO SGA CTL
DM HYP SMO SGA CTL
Adj
uste
d su
m o
f ski
nfol
ds (m
m)
A)
mm(sdlofniksfo
musdetsujd
Caffeine during pregnancy (mg)
Caffeine during pregnancy (mg)
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Conclusions
This study found no difference in anthropometric measure-ments between children exposed or not exposed to caffeine in utero as a result of maternal coffee consumption during pregnancy. Among children born to caffeine consumers, we found an interaction between maternal caffeine intake during pregnancy and the sum of skinfold thicknesses at 3 months of age. On analysis of dose dependence, an increase in caffeine levels was found to be associated with decreased skinfold thickness in children born to mothers with diabetes and increased in children born to control mothers, but only at 3 months.
Substance use by during pregnancy and its relation to child development and growth is a relevant topic in the area of maternal and child health. The potential relation-ship between caffeine consumption by pregnant women and adiposity in infants reveals a need for further research on this subject. Future studies should seek to elucidate the bio-chemical mechanisms responsible for the effects observed and their duration through longer follow-up assessments.
The effects of excess weight gain in early childhood may continue into adulthood, leading to other chronic dis-eases and complications in the future. Early identification and intervention are essential to interrupting this cycle, as obesogenic environments are also a risk factor for later generations.
Compliance with Ethical Standards
Conflict of interest The authors report no conflicts of interest.
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