Impact of artificial sweeteners on fertility, reproductive, pregnancy and offspring health outcomes

The use of non-natural sweeteners, interchangeably known as artificial or intense sweeteners, is broad both geographically and in terms of the multitude of ingested substances they are incorporated in. Characterised as low caloric additives that act as sugar substitutes in predominantly ‘low-energy’ or ‘low sugar’ foods and drinks, their extensive and increasing use in recent decades is attributed to the increased prevalence of obesity and metabolic pathologies and consequent shift towards low carbohydrate/low sugar dietary patterns. [1-4] However the widespread application of these substances is not without controversy, with ongoing debate regarding the short- and long-term health consequences associated with chronic intake. [2] One area of concern is the potential impact of ingestion of artificial sweeteners on fertility, reproductive, pregnancy and offspring health outcomes.

Types of sweeteners

There are a wide range of artificial sweeteners that are approved for use in foods and drinks in Australia, specifically acesulphame potassium, advantame, alitame, aspartame, aspartame-acesulphame salt, cyclamate, neotame, saccharin, sucralose, thaumatin and sugar alcohols. [1] These substances are also widely used internationally along with cyclamate in the European Union, with each having distinctive characteristics pertaining to sweetness intensity, persistence of sweet taste and aftertaste. [4] Along with their primary role as sweeteners, artificial sweeteners also have stabilising and texturizing properties in certain food and drinks. The predominant dietary source of artificial sweeteners at a population level is via the ingestion of soft drinks. [2,4]

Health effects in general population

The controversy and debate over potential health consequences associated with acute and chronic intake of artificial sweeteners in both general and sub-population groups is largely due to mixed research results, with beneficial, harmful and neutral effects observed in different studies conducted over the last few decades. [5]

While the majority of research indicates that artificial sweeteners are generally safe in regards to the risk of acute toxicity, preclinical data points to potential toxicity associated with non-metabolised compounds from the ingestion of artificial sweeteners. [6]

In particular, it is the overall safety profile associated with the chronic ingestion of artificial sweeteners that is questioned. A comprehensive 2015 meta-analysis that assessed the potential risks and benefits associated with the intake of artificial and intense sweeteners was unable to rule out potential long-term risks with daily intake, and also concluded the absence of evidence justifying the substitution of sugars with artificial or intense sweeteners on the basis of nutritional benefit. [2,4]

In the general population, some evidence has observed adverse physiological effects with the long-term ingestion of artificial sweeteners while other data demonstrates beneficial or neutral effects.

Adverse physiological effects observed in such data include increased weight and incidence of obesity [3-6]; compositional and functional alterations in the gut microbiome [6,8]; metabolic effects on glucose and insulin levels [4,6]; increased risk of type 2 diabetes mellitus [4, 5]; elevated risks of bladder and breast cancer [4,6]; increased incidence of dental caries [4]; and neuropsychological symptoms (i.e. headaches, migraines, mood changes, anxiety, insomnia, depression) [4].

Conversely, other data has demonstrated beneficial effects in relation to weight loss [3-6] and neutral effects on glucose and insulin levels and risk of type 2 diabetes mellitus [4,6], and cancer [4,6] with the regular intake of artificial sweeteners. While the evidence is inconclusive, there are particular concerns regarding the health effects of artificial sweeteners in certain population groups, including those with diabetes, obesity, epilepsy, a predisposition to migraines, children and pregnant and lactating women. [6]

Health impacts on reproductive health and fertility outcomes

While there aren’t a significant number of studies pertaining to the impact of regular intake of artificial sweeteners on reproductive health and fertility outcomes, the existing evidence points to a cause for concern and further research. [2]

Preclinical mechanistic studies have observed a range of physiological effects with oral exposure to artificial sweeteners, particularly saccharine, sorbitol and aspartame.

In female animal models these artificial sweeteners were shown to significantly increase the percentage of abnormal estrous cycles, serum progesterone levels and apoptosis in granulosa, oocyte and corpus luteum cells, and adversely influence the quality of human oocytes and embryo development. [2,9] In pregnant animal models, artificial sweeteners resulted in significant decreases in circulating progesterone levels, placenta diameter and embryo glutathione concentrations, induced glucose-intolerance and a pro-oxidative environment in the endometrium. The adverse influence of artificial sweeteners on glucose is independent of their low-caloric status. [2,10] Consequently, offspring exposed to artificial sweeteners in utero had reduced gestational lengths and foetal weights and increased chromosomal aberrations, foetal congenital malformations and embryo toxicity and decreased embryo development scores. The latter mechanism has been partly attributed to the impact of the aspartame metabolite formic acid and is one of the mechanism suggested to be a potential factor involved in the increased risk of preterm birth observed in human clinical trials. [2,10-13]

Male animal models have also observed negative effects associated with exposure to artificial sweeteners on sperm parameters and an increased rate of sperm DNA fragmentation and apoptosis. [14] The importance of local taste receptors in sperm maturation in the concentration of fertilisation-competent sperm is one recent area of investigation which may be a mechanism influencing the impact of artificial sweeteners on sperm health. [15]

Some of these physiological mechanisms associated with artificial sweeteners ingestion in animals have been also observed in human clinical trials. [2,16]

Impact on menstrual characteristics

A 2016 cross-sectional clinical trial investigated the impact of regular soft drink consumption versus abstaining from soft drinks on menstrual characteristics in 639 nulliparous females aged 16-40 years of age. [16] Specific menstrual characteristics assessed were duration and heaviness of menstrual bleeding, incidence of menstrual pain and cycle length. Subjects in the regular soft drink consumption group (n=392) were observed to have significant increases in duration (51.53% of subjects; mean = 4.38+0.02 days; p=0.002) and heaviness (85.71% subjects) of menstrual bleeding as well as incidence of abdominal pain during menstruation (89.54% of subjects), compared with non-consumers. (n=247). The effect of soft drinks on cycle length was not significant (p>0.05). The authors concluded that the data demonstrated that soft drink consumption adversely influenced menstrual characteristics, potentially via neuroendocrine and reproductive-associated mechanisms. [16]

Impact on reproductive outcomes

Consistent with data observed in preclinical research, a 2017 cross-sectional trial assessed the potential link between regular intake of artificially- or sugar- sweetened soft drinks (ASB, SSB) or coffee on fertility and pregnancy outcomes. [2] In particular, the primary aims of the study where to determine whether daily ingestion of these substances by males and females influenced oocyte quality and intracytoplasmic sperm injection (ICSI), specifically embryo quality on days 2 and 3, chances of blastocyst formation, pregnancy, implantation and miscarriage.
Subjects were couples undergoing ICSI due to female-factor or unexplained infertility (n=524, mean age of f: 36.4 ± 5.0 years, m: 37.5 ± 5.8 years).

Associations were found between regular consumption of ASB or coffee and oocyte morphology (ooplasm central granulation, vacuoles, smooth endoplasmic reticulum clusters [SERc], large perivitelline space, fragmented polar body, zona pellucida and shape abnormalities) and oocyte quality (>3 servings/day, granulation, vacuoles and SERc). They were also associated with dose-dependent negative effects on day 2 embryo quality and chances of blastocyst formation, implantations and pregnancy (2-3 servings/day). Interestingly, the ingestion of SSB had no effect on any measured parameter regardless of dose. Potential mechanisms suggested by the authors requiring further investigations were gene activation and obesity-induced metabolic effects. [2]

Two large separate cohort analyses also indicate a potential association between regular intake of artificial sweeteners and risk of preterm birth. [11,12]

In 2010 the Danish National Birth Cohort (1996–2002) investigated the association between intakes of and ASB and SSB and preterm delivery (<37 weeks’ gestation, which was the primary outcome) in 59 334 women. [11] Compared with no intake of ASB during pregnancy, consumption of 1-4/day of these drinks increased the risk of preterm delivery (1: adjusted odds ratio = 1.38 95% CI: 1.15, 1.65; 4: 1.78 (95% CI: 1.19, 2.66) in both normal-weight and overweight women. A stronger risk was observed for early (<32 weeks) and moderately early preterm (32-34 weeks) versus late preterm (34-37 weeks) delivery. While the authors stated it was difficult to attribute such results to a specific sweetener due to the mix of sweeteners present in such drinks, suggested mechanisms included the effects of methanol on either the foetal hypothalamic–pituitary–adrenal axis and/or on the maternal uterine environment. [11]

Similar results were observed in the 2012 Norwegian Mother and Child Cohort Study on 60,761 pregnant women that aimed to replicate the results from the Danish Cohort. [12] Following similar methodology and primary outcomes as used in the prior study, the Norwegian Cohort found that compared to non-consumers, ingesting 4 ASB daily was associated with significantly higher risk of preterm delivery (adjusted OR: 1.37; 95% CI: 1.08, 1.74), while daily consumption of 1/day was significantly associated with late preterm delivery (34-26+6 weeks) (adjusted OR: 1.14, 95% CI: 1.00, 1.29) and spontaneous preterm delivery (aOR: 1.15; 95% CI: 1.01; 1.32; p-trend=0.07).

The downstream impact of the detrimental effects of regular consumption of artificial sweeteners on oocyte and sperm quality, conception processes and birth outcomes is also demonstrated in offspring health outcomes.

Impact on offspring health outcomes

Clinical investigations into the influence of artificial sweeteners during pregnancy on offspring health parameters have found potential links between their ingestion and offspring body composition, metabolic health and risk of atopy. [17-22]

In a sub-analysis of 918 women with gestational diabetes in the Danish National Birth Cohort, daily intake of >1 ASB during pregnancy was positively associated with large for gestational age offspring (adjusted RR 1.57; 95% CI: 1.05, 2.35 at birth), BMI scores (0.59 SD increase; 95% CI: 0.23, 0.96) and overweight/obesity (aRR 1.93; 95% CI; 1.24, 3.01) at 7 years of age, compared with non-consumers. [17] Notably, maternal obesity status, offspring physical activity, beverage consumption and dietary patterns were not significantly associated with the observed impact of ASB on offspring body composition parameters.

The 2016 Canadian Healthy Infant Longitudinal Development study observed similar results, with daily maternal intake of ASB during pregnancy associated with 0.20-unit increase in infant BMI scores at 1 year of age. [20] As with the Danish Cohort, these effects were not explained by maternal BMI, diet quality, total energy intake or other obesity risk factors.

Potential mechanisms suggested by the research include ASB exacerbating glucose intolerance via dysregulation and activation of sweet taste receptors subsequently promoting excessive intake and increased intestinal glucose absorption (upregulation of expression of Na+-dependent glucose transporter SGLT1  increase of intracellular Ca2+ concentrations  translocation of GLUT2 in the brush border membrane of the enterocyte); gut microbiota alterations (reduction in the number of commensal bacteria i.e. Bifidobacterium, Lactobaccillus and Bacteroidetes  correlated with insulin resistance and adiposity); and induction of oxidative stress (downregulation of glutathione/glutathione peroxidase antioxidant system). [17,19]

The Danish National Birth Cohort also found that intake of > 1 ASB daily during pregnancy were 1.23 times more likely to report a child asthma diagnosis and child wheeze vs non-consumers, and 1.74 times more likely to report a child with allergic rhinitis during the first 7 years. No association was found for SSB. [22]

The absence of definitive evidence demonstrating the safety of regular ingestion of artificial sweeteners during pregnancy and the findings from both the mechanistic and clinical evidence clearly highlight the need for further investigations. Currently the research highlights concerns regarding the impact of artificial sweeteners on fertility, reproductive, pregnancy and offspring health outcomes.

References

Food Standards Australia New Zealand. Intense sweeteners. July 2019. Accessed 3 September 2019 [Source]
Setti AS, Braga DPAF, Halpern G, Figueira RCS, Iaconelli A Jr, Borges E Jr. Is there an association between artificial sweetener consumption and assisted reproduction outcomes? Reprod Biomed Online 2018 Feb; 26 (2): 145-153. [Abstract]
Olivier B, Serge AH, Catherine A, Jacques B, Murielle B, Marie-Chantal CL et al. Review of the nutritional benefits and risks related to intense sweeteners. Arch Pub Health 2015 Oct 1; 73: 41. [Full Text]
Lohner S, Toews I, Meerpohl JJ. Health outcomes of non-nutritive sweeteners: an analysis of the research landscape. Nutrition J 2017; 16: 55. [Full Text]
Swithers SE. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends Endocrinol Metab Sep; 24 (9): 431-441. [Abstract]
Sharma A, Amarnath S, Thulasimani M, Ramaswamy S. Artificial sweeteners as a sugar substitute: are they really safe? Indian J Pharmacol 2016 May-Jun; 48 (3): 237-40. [Abstract]
Ngekure K, Jiang J, Enayatullah H, Ennab W, Mustafa S, Rodeni S, Wei Q, Shi F. Sweet taste receptor agonists alter ovarian functions and ovarian cycles in aged mice. Reprod Biol Aug 2019; doi: 10.1016/repbio.2019.07.007. [Abstract]
Suez J, Koren T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014; 514 (7521): 181-186. [Abstract]
Ngekure K, Jiang J, Enayatullah H, Ennab W, Mustafa S, Rodeni S, Wei Q, Shi F. Sweet taste receptor agonists alter ovarian functions and ovarian cycles in aged mice. Reprod Biol Aug 2019; doi: 10.1016/repbio.2019.07.007. [Abstract]
Al-Qudsi F, Al-Hasan MM. In utero exposure to commercial artificial sweeteners affects mice development and mammary gland structure. Environ Sci Poll Res. 2019. Doi: 10.1007/s11356-018-3935-5. [Abstract]
Halldorsson TI, Strom M, Petersen SB, Olsen SF. Intake of artificially sweetened soft drinks and risk of preterm delivery: a prospective cohort study in 59 334 Danish pregnant women. The Am J Clin Nutr 2010; 92 (3): 626-633. [Abstract]
Englund-Ogge L, Brantsaeter AL, Haugen M, Sengpiel V, Khatibi A, Myre R, Myking S, Meltzer HM, Kacerovsky M et al. Association between intake of artificially sweetened beverages and preterm delivery: a large prospective cohort study. Am J Clin Nutr 2012 Sep; 96 (3): 552-9. [Full Text]
Saben JL, Asghar Z, Rhee JS, Drury A, Scheaffer S, Moley KH. Excess maternal fructose consumption increases foetal loss and impairs endometrial decidualisation in mice. Endocrinol 2016 Feb; 157 (2): 956-68. [Full Text]
Rahimipour M, Talebi AR, Anvari M, Sarcheshmeh AA, Omidi M. Saccharin consumption increases sperm DNA fragmentation and apoptosis in mice. Iran J Reprod Med 2014 May; 12 (5): 307-312. [Abstract]
Luddi A, Governini L, Wilmskotter D, gudermann T, Boekhoff I, Piomboni P. Taste receptors: new players in sperm biology. Int J Mol Sci 2019; 20 (4): 967. [Full Text]
Adienbo OM, Hart VO, Ajah AA. Assessment of menstrual characteristics among nulliparous female consumers of carbonated soft drinks. Int J Reprod, Contracept, Obstet Gynecol 2016 Jan; 5 (1): 194-197. [Full Text]
Zhu Y, Olsen SF, Mendola P, Halldorsson TI, Rawal S, Hinkle SN et al. Maternal consumption of artificially sweetened beverages during pregnancy, and offspring growth through 7 years of age: a prospective cohort study. Int J Epidemiol 2017 Oct 1; 46 (5): 1499-1508. [Abstract]
Reid AE, Chauha BF, Rabbani R, Lys J, Copstein L, Mann A, Abou-Setta AM et al. Early exposure to non-nutritive sweeteners and long-term metabolic health: a systematic review. Pediatrics 2016 Mar; 137 (3): e20153603. [Abstract]
Araujo JR, Martel F, Keating E. Exposure to non-nutritive sweeteners during pregnancy and lactation: impact in programming of metabolic diseases in the progeny later in life. Reproductive Toxicology 2014; 49: 196-201. [Abstract]
Azad MB, Sharma AK, de Souza RJ, Dolinsky VW, Becker AB, Mandhane PJ, Turvey SE, Subbarao P, Lefebvre DL, Sears MR, Canadian Healthy Infant Longitudinal Development Study Investigators. Association between artificially sweetened beverage consumption during pregnancy and infant body mass index. JAMA Pediatr 2016 Jul 1; 170 (7): 662-70. [Abstract]
Archibald AJ, Dolinsky VW, Azad MB. Early-life exposure to non-nutritive sweeteners and the developmental origins of childhood obesity: global evidence from human and rodent studies. Nutrients 2018 Feb 10; 10 (2): pii: E194. [Abstract]
Maslova E, Strom M, Olsen SF, Halldorsson TI. Consumption of artificially sweetened soft drinks in pregnancy and risk of child asthma and allergic rhinitis. PLoS One 2013; 8 (2): e57261 [Abstract]

DISCLAIMER:

The information provided on FX Medicine is for educational and informational purposes only. The information provided on this site is not, nor is it intended to be, a substitute for professional advice or care. Please seek the advice of a qualified health care professional in the event something you have read here raises questions or concerns regarding your health.