Norwegian, Swedish and Dutch researchers examining a large Norwegian population-based cohort recently reported in European Journal of Nutrition that daily maternal intake of sweetened carbonated beverages (SCB) in pregnancy was associated with an increase in ADHD symptoms among offspring at eight years of age.
The magnitude of associations in the study was weak (typically 15–21 percent increased relative risk of offspring having six or more ADHD symptoms), suggesting SCB only play a minor role in the etiology of ADHD.
However, further research into causal agents is warranted, as SCB are common exposures, and even a little reduction of risk may still be of importance for children’s ADHD symptoms at the population level.
ADHD is a complex multifactorial disorder where both genes and environment contribute to its development. However, the exact cause of the disorder is still elusive.
Data from national MoBa-study
This study was based on data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). MoBa is a large prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health. Participants were recruited from across Norway during 1999–2008.
The women consented to participation in 41 percent of the invited pregnancies. Participating women answered three questionnaires during pregnancy, of which the second was a food frequency questionnaire, introduced in 2002, and completed during mid-pregnancy.
After delivery, questionnaires were forwarded to the family when the child was six months, 18 months, and at three, five, seven and eight years, as well as further questionnaires when the child is a teenager. The cohort now includes 114,500 children, 95,200 mothers and 75,200 fathers.
For theMoBa pregnancies, data are routinely linked to the MBRN, a national health registry based onmandatory reporting of information on pregnancies and birth outcomes for all births in Norway since 1967.
The study population consisted of 39,870 mother-child pair of mothers who responded to the food frequency questionnaire and a questionnaire when their child was eight years of age. The exposure was defined as maternal intake (daily servings) of SCB (sugar- and artificially sweetened), using no daily intake as reference.
The outcome in the study was offspring ADHD symptoms, evaluated as a continuous standardized ADHD score and as a binary outcome of six or more ADHD symptoms vs. five symptoms or less.
More research needed
Associate professor Liv Grimstvedt Kvalvik at the University of Bergen is first author of the study. She explains that the authors adjusted for possible factors that could explain the associations such as maternal educational level, maternal pre-pregnancy body mass index, maternal depression and anxiety, maternal ADHD symptoms, other components of the maternal diet, maternal age at delivery, parity, birth year and season.
This study is an observational study and conclusions about causality cannot be drawn with certainty, and residual confounding by for instance life-style factors or medical conditions not accounted for may be present.
On the other hand, the longitudinal design with prospectively collected data, strengthens the results and their interpretation. While this study suggests that daily maternal intake of SCBs could be linked to a small increase in ADHD symptoms in offspring at eight years of age, further research is needed to explore this association.
Effects of consuming sugars and alternative sweeteners during pregnancy on maternal and child health: Evidence for a secondhand sugar effect
While research is limited, there is some evidence to suggest that drinking sugar-sweetened beverages in pregnancy can increase a woman’s risk of preeclampsia. A large study conducted in Norway that examined the diets of over 32 000 pregnant women showed that increased consumption of sugar-sweetened carbonated and noncarbonated drinks was associated with a higher risk for preeclampsia, after adjustment for total energy intake and other confounding variables (OR for the comined beverages 1·27 (95 % CI 1·05, 1·54) for high intake (>125 ml/d) compared with no intake)(24).
In contrast, eating fresh or dried fruit was associated with a lower risk, perhaps due to their ﬁbre content. Interestingly, the authors found that while the positive association between sugar-sweetened beverage consumption and pre-eclampsia was signiﬁcant in both normal and overweight women, the risk was higher in women with a BMI <25 as compared with 25 or above (crude OR 1·32 v. 1·28). A smaller Norwegian study (n 3133) also showed a positive relationship between high sucrose consumption (>25 % of total energy) and preeclampsia(25). While potential relationships with other types of sugars were not pre-sented, the authors did evaluate speciﬁc food items and found that consumption of sugar-sweetened soft drinks was related to increased risk.
While many factors can contribute to risk for premature delivery, and often times the cause for its occurrence is unknown, maintaining a healthy diet in pregnancy can serve as an additional safeguard(26). There is speciﬁc evidence to suggest that increased intake of sweetened beverages is related to risk for premature delivery. For example, Englund-Ogge et al. examined the relationship between sweetened beverage consumption in pregnancy and preterm delivery in 60 000 women in Norway(27). They found that one daily serving of sugar-sweetened beverages increased the risk of preterm delivery by 25 %. In addition, daily one serving of diet beverages increased the risk by 11 %. In a study of the same size from Denmark, researchers found that just one daily serving of diet beverage consumption increased the risk of a preterm delivery by 38 %, and four daily servings increased the risk by 78 %(28). Interestingly, in this study, which used slightly different methods, there was no effect of regular sugar-sweetened beverages on preterm delivery. In contrast, a smaller study from the UK showed that con- sumption of sugar-sweetened cola beverages did increase the risk of preterm delivery, but did not show a relation- ship with artiﬁcial sweeteners(29).
Possible mechanisms that could explain the observed effects of sugar-sweetened beverages on the pregnancy complications presented here include pathways related to insulin sensitivity and inﬂammation. Normal pregnancy is characterised by reduced maternal insulin sensitivity in peripheral tissues, but this is more pronounced in overweight individuals or those with gestational diabetes(30). These effects can be exacerbated by a high sugar diet. Decreased insulin sensitivity can lead to glucose intolerance, which is a known risk factor for pre- eclampsia and preterm delivery and the deﬁning feature of GDM(31–33).
Additionally, increased sugar consumption is associated with increased circulating pro-inﬂammatory cytokine concentrations, particularly in individuals with impaired glucose tolerance(34). Increased circulating pro-inﬂammatory cytokine concentrations, in turn, are associated with GDM, preeclampsia and preterm delivery(35). Interestingly, in the study discussed in the previous paragraph, Englund-Ogge et al.(27) found that the consumption of sugar-sweetened beverages was more highly correlated with early preterm delivery, while consumption of artiﬁcially sweetened beverages was correlated with late preterm delivery. The authors hypothesised that this could be due to the fact that younger fetuses are more sensitive to inﬂammatory interleukins.
In terms of alternative sweeteners, the exact mechan-ism of how they may contribute to preterm delivery is not known. One possible explanation is the way these compounds are broken down by the body. Aspartame, for example, is metabolised into aspartic acid, phenylalanine and methanol.
The methanol is then converted into formaldehyde and formic acid, which is toxic in high doses. In animal studies, exposure to even a low dose of methanol can result in pregnancy complications including preterm delivery(36). Another possible explanation relates to how these alternative sweeteners affect the gut microbiome.
Animal studies have demonstrated that artiﬁcial sweeteners disrupt the normal/healthy composition of bacteria that reside in the gut(37). Alteration of gut bacteria can increase numbers of unhealthy bacteria that promote inﬂammation and increased gut permeability and reduce numbers of healthy bacteria that assist in fermentation and satiety hormone production(38,39). However, it must be noted that this evidence is reliant on animal studies and its applicability to human biology remains unknown.
Effects of sugar consumption before pregnancy on fetal development and offspring health
While the majority of this review focuses on the impact of maternal diet during pregnancy on maternal and offspring outcomes, there is mounting evidence for a role of diet prior to conception(40). Animal studies have demonstrated that overfeeding prior to pregnancy (and not during pregnancy) can have long-lasting programming effects on offspring(41).
For example, sheep embryos from dams overfed in the periconceptional period and transferred to the wombs of non-obese dams show increased fat mass at 4 months(42). While it is more difﬁcult to separate the effects of preconception and prenatal nutrition in human subjects, some researchers have developed methods of doing so. Dominguez-Salas et al. used seasonal differences in nutrition in Gambian women to pinpoint the inﬂuence of the preconception period. They reported that maternal nutrition around the time of conception inﬂuenced DNA methylation in lymphocytes and hair follicles from infants postnatally(43) Another study found that maternal lipid proﬁle at conception successfully predicted preterm birth, regardless of whether the women were provided essential fatty acid supplementation during pregnancy(44).
Indeed, it may be the case that by the time sugar-related pregnancy complications are realised, the optimal window for intervention has passed. Therefore, pre-pregnancy sugar intake may be just as or more inﬂuential than intake during pregnancy. Importantly, the relevance of preconception nutrition does not appear to be limited to mothers. There are now a series of animal studies to show that poor diet quality in fathers can be transmitted to offspring through the germline. Carone et al., demonstrated that a high sucrose, low protein diet consumed by male mice affects the expression of key metabolic genes in offspring, including upregulation of cholesterol biosynthesis genes.
The mechanisms underlying this appear to be epigenetic, as paternal diet was highly correlated with cytosine methylation of the enhancer of lipid transcription factor Ppara(45). However, direct examination of sperm methylation patterns did not show an effect of diet, suggesting alternative epigenetic information carriers such as RNA. Indeed, a subsequent study reported that direct injection of naive one-cell embryos with sperm or testis RNA from high sugar/high fat-fed donors induced obes- ity and metabolic dysfunction in the resulting progeny(46).
To the best of our knowledge, there do not yet exist studies examining the impact of preconception maternal and paternal alternative sweetener intake on offspring health. However, these existing studies suggest that both maternal and paternal preconception diet are important contributors to the health of offspring, and if possible, nutritional interventions should not be limited to pregnancy alone.
Effects of sugar consumption in pregnancy on fetal development and offspring health
Transfer of regular sugars across the placenta and effects on fetal development
While studies conducted in human subjects are limited due to ethical issues, it is well established that both glucose and fructose cross the human placenta(47), and therefore reach and can affect the developing baby. Human studies also suggest that fructose concentrations are higher in the fetal bloodstream relative to that of the mother, suggesting active transport of fructose across the placenta(48) and animal studies have conﬁrmed this(15). For example, one study in rats showed that gestational exposure to fructose led to pups who were hyperglycemic at birth(49).
The developing fetus lacks the ability to undergo gluconeogenesis, and thus relies on the transport of glucose from the maternal bloodstream(50). One key player in the placental transport of both glucose and fructose is facilitative GLUT-9, which consists of the isoforms GLUT-9a and 9b(51). GLUT-9 is unique in that it can also transport fructose and uric acid. The protein expression of GLUT-9 is directly associated with blood glucose concentrations; hyperglycemia increases expression and hypoglycemia decreases expression(51).
Thus, insulin-resistant and
diabetic individuals will tend to have increased expression of GLUT-9. This increased expression has also been observed in the placental tissue of pregnant diabetic women(50). This has been suggested as playing a key role in fetal pathologies frequently seen in diabetic pregnancies, likely due to increased placental and fetal exposure to glucose and fructose(50).
The exact effects of exposure to increased fructose levels on placental and embryonic tissue are not fully understood. Rodriquez et al. demonstrated that fetuses from fructose-fed pregnant rats had hypertriglyceridemia and higher hepatic TAG content(52). These fetuses also had higher expression of genes related to lipogenesis and a low expression of genes related to fatty acid catabolism. Additionally, it was noted that these fetuses had an impairment in the leptin signalling pathway. Vickers et al. similarly demonstrated markers of impaired metabolic function including hyperglycemia and hyperleptinemia in fetuses and neonates of fructose-fed mothers, particularly in female offspring(53). Together, these effects could predispose pups to obesity early in life. Further studies are necessary to determine if similar outcomes hold true in human subjects. Additionally, it has been demonstrated that elevated fructose levels are assaciated with increased levels of reactive oxygen species, In fact, it has been suggested that reactive oxygen species-related oxidative damage could be a ‘unifying mechanism’ to explain diabetic complications(54).
Maternal transfer of alternative sugars and their by-products to the fetus
It is known that saccharin crosses the placenta(55), as do the breakdown products of aspartame(56), and it is hypothesised that sucralose and acesulfame-K cross the placenta as well(57,58). While animal studies have not found these products to have toxic effects on the fetus(59), research has been limited and results from animal studies must be interpreted with caution due to differences in physiology as compared with human subjects.
Therefore, the complete effects of these products in human subjects are not known. It has been previously concluded that moderate consumption of artiﬁcial sweeteners is safe during pregnancy(59). However, given the observational research we describe in this review that suggests negative effects of maternal consumption on outcomes such as premature birth(27,28) and future offspring adiposity(60,61), it is possible that there are mechanistic links and risks that are not yet fully understood. Studies on the effects of other alternative sweeteners such as stevia and sugar alcohols are also lacking.
Effects of maternal sugar and alternative sweetener intake on future childhood obesity
Regular sugars. A variety of studies conducted in human subjects have shown that excess maternal sugar consumption during pregnancy can increase the chances that a child will become overweight or obese(62–65). For example, a study conducted in Singapore with 910 mother/child pairs found that higher sugar and carbohydrate intakes during late pregnancy were associated with the higher BMI in the children at ages 2–4 years, whereas fat and protein intake were not related to these markers(63).
Another study, conducted in the Netherlands, evaluated 3312 mother–child pairs and found that daily one additional serving of a sugar- sweetened beverage during pregnancy resulted in a 0.05 standard deviation score higher fat mass index in the child at age 6 years.
Furthermore, when types of drinks were evaluated separately, intakes of 100 % fruit juice, but not of soda or sweetened juice concentrate drinks, were associated with a higher child fat mass.
These ﬁndings were independent of gestational weight gain, birth weight, and children’s insulin concentrations. Similarly, an American study conducted with 1078 mother–child pairs found that maternal sugar-sweetened beverage consumption was related to future childhood obesity.
Speciﬁcally, each serving of sugar-sweetened beverage consumed daily during the second trimester was related to measures of child overweight at age 7 years, including BMI, fat mass index and waist circumference(65). Finally, a smaller study in the USA of 285 mothers/children found that in overweight or obese mothers, consumption of sweets was a predictor of birthweight, such that each 1 % increase in percentage of energy consumed from sweets early in pregnancy increased the odds of macrosomia by 10 % and weight for age >90th percentile by 20 %(62). Also, in the overweight or obese group, at 6 months, the strongest predictors of higher weight for age z-scores were a greater percentage of energy from sweets early in pregnancy. In normal-weight women, higher intake of sugary drinks was the strongest predictor of birth weight but was not related to infant weight at 6 months.
In addition to dietary sugar content, the overall glycemic load of the maternal diet during pregnancy has been linked to increased risk of offspring obesity. A study conducted in the UK with 906 mother–child pairs found that both maternal dietary glycemic index and glycemic load in early pregnancy (11 weeks) were positively associated with child fat mass at age 4 and 6 years, whereas maternal glycemic index during late pregnancy (34 weeks) was not(66). Another study that evaluated the effects of the maternal glycemic index on neonatal adiposity in 542 mother–child pairs in the UK found that maternal glycemic load in the second trimester was associated with neonatal central adiposity as measured by waist to length ratio(67).
Additional studies are required to help clarify the role of the maternal glycemic index on parameters of offspring obesity and in particular which trimester of pregnancy is the most inﬂuential.
Alternative sweeteners. The effects of maternal consumption of alternative sweeteners during pregnancy on infant and child outcomes have not been extensively studied. One detailed study in 3033 mother–infant dyads in Canada showed that 30 % of women consumed artiﬁcial sweeteners during pregnancy(61). Women who consumed artiﬁcial sweeteners daily had a 2-fold higher risk of an infant being overweight by age 1 year.
Another study conducted in Denmark with 918 mother–child dyads found that approximately half of the mothers consumed artiﬁcially sweetened beverages and 9 % consumed them on a daily basis. Compared with those participants who never consumed artiﬁcial sweeteners, the daily consumers were more likely to have children who were large for gestational age at birth (relative risk 1·57;95 % CI 1·05, 2·35) and who were overweight or obese by age 7 years (relative risk 1·93; 95 % CI 1·24, 3·01).
Furthermore, they found that substituting artiﬁcially sweetened beverages with water reduced risk for overweight at age 7 years, but substituting regular sweetened beverages with artiﬁcially sweetened alternatives did not confer a reduced risk.
Effects of maternal sugar consumption on future child feeding behaviours and metabolism. One of the ways that exposure to excess sugars during gestation can promote future obesity is through fetal programming(68). While the brain, vital organs and adipose tissue are developing in utero, they are particularly vulnerable to nutritional insults. As we will explain later, a maternal diet that is high in sugar may lead to structural and functional alterations that can predispose a child to poor feeding behaviours and a metabolism that favours fat storage.
During early gestation, the structures and pathways of the brain that are responsible for feeding behaviour are already developing. The hypothalamus, which begins to develop as early as 9 weeks gestation, plays a key role in energy and glucose homeostasis and disruption of its healthy development is thought to create a predisposition for metabolic diseases(69). Although research in human subjects has been limited, studies in animals suggest that a maternal diet that is high in sugar is associated with altered gene expression, hyperphagia and disrupted glucose homeostasis in the offspring(69).
The central reward system is also important in determining feeding behaviour. Studies in human subjects, while limited, suggest that dopamine and opioids are expressed in the fetal striatum by 12 weeks gestation and their associated receptors can be detected by about 20 weeks gestation(70).
A maternal diet that is high in sugars stimulates the synthesis and release of these compounds that are related to pleasure and reward and can predispose a child to prefer sweet tastes and even to become addicted to them(70).
While much of the evidence for the association between a high sugar diet and alterations in feeding behaviours and metabolism come from animal studies, there have been observational studies conducted in human subjects that support the same conclusions. For example, Brion et al. evaluated maternal dietary data both during pregnancy and at 47 weeks postpartum, paternal dietary data at 47 weeks and child dietary data at age 10 years(71).
They found that maternal gestational intakes of protein, fat and carbohydrates were positively associated with the child’s intakes at age 10 years, whereas paternal diet was not strongly associated. Furthermore, for protein and fat intake, maternal prenatal diet was more strongly associated with the child’s future intakes than were the mother’s postnatal intakes. These results suggest a programming effect and that the in utero food environmental may have a larger inﬂuence on the child’s diet than the eventual family food environment.
There has also been research to suggest that a child’s taste preferences are shaped in utero by the maternal diet(72). In a classic study, it was shown that when infants were tested before weaning, those infants who were exposed to carrot ﬂavour via maternal consumption in pregnancy exhibited more liking for carrot ﬂavour compared with those infants who were not exposed in utero(73).
While to our knowledge, a similar study has not been conducted with a maternal exposure to sugar, we do know that a preference for sweet tastes is present at birth and probably before(74). For example, a study in preterm infants found they sucked stronger and more frequently on a nipple that had been soaked in sucrose compared with one that had not(75). One potential reason for this is that an innate desire for sweetness is advantageous in evolutionary terms.
Of the various types of sugars, fructose, in particular, should be considered as a prenatal exposure that has the potential for negative programming effects on offspring metabolism(76). There is only limited data available on the long-term effects of high fructose exposure during gestation. However, there are some studies, mostly in animals that suggest that high fructose consumption in pregnancy can lead to persistent neuroendocrine and metabolic alterations in the baby related to the development of feeding behaviour and propensity to develop obesity later in life(15,76).
Several potential mechanisms could explain the adverse effects of high fructose exposure during these periods. For example, we know that even very low levels of fructose can directly promote the process of building new fat cells during critical periods of development(77).
High fructose intake during development might also promote obesity by disrupting the normal signalling that occurs between the brain and adipose tissue(15,52,76,78). Results from a well-controlled human study evaluated changes in appetite-related hormone concentrations over 24 h in response to meals containing either glucose or fructose.
Levels of insulin and leptin were signiﬁcantly lower after the fructose meal than after the glucose meal, and fructose failed to suppress post-meal ghrelin levels as effectively as glucose, which suggests that consumption of fructose could disrupt energy balance signalling to the brain and result in excess energy consumption and obesity(78).
Alternative sugars are also important to consider in terms of their effects on fetal programming of feeding behaviours and future metabolic health(79). In animals, prenatal exposure to artiﬁcial sweeteners leads to higher selection and taste preference for sweet foods in adulthood(58,80). Beyond inﬂuencing behaviour, these exposures also can have metabolic consequences. Chronic exposure to aspartame in mice in utero and early life has also been shown to be associated with elevated fasting blood glucose as well as reduced insulin sensitivity in later life(81).
A summary diagram of the secondhand effects of sugars and alternative sweeteners is depicted in Fig. 1.
reference link DOI: 10.1017/S002966511800263X
Original Research: Open access.
“Association of sweetened carbonated beverage consumption during pregnancy and ADHD symptoms in the offspring: a study from the Norwegian Mother, Father and Child Cohort Study (MoBa)” by Liv Grimstvedt Kvalvik et al. European Journal of Nutrition