Thorhallur I. Halldorsson PhD Center for Fetal Programming, Statens Serum Institut, Copenhagen,Denmark Unit for Nutrition Research, Faculty of Food Science and Nutrition, University of Iceland Intake of Artificially Sweetened Soft Drinks and Risk of Preterm Delivery

Background (1) - A quick internet search - Pubmed.com search (animal and human studies) –Antioxidants + pregnancy = 8452 hits –Fish oil + pregnancy = 972 –Dioxins + pregnancy = 842 –Diet soft drinks+ pregnancy = 17 –Aspartame + pregnancy = 40 –Acesulfame-K + pregnancy = 1 The same picture does not repeated when repeating the same search on Google.com Given the increasing use of artificial sweeteners there appears to be room for more studies (observational and experimental).

Background (1) - A quick internet search - Pubmed.com search (animal and human studies) –Antioxidants + pregnancy = 8452 hits –Fish oil + pregnancy = 972 –Dioxins + pregnancy = 842 –Diet soft drinks+ pregnancy = 17 –Aspartame + pregnancy = 40 –Acesulfame-K + pregnancy = 1 Almost opposite results when repeating the same search on Google.com Given the increasing use of artificial sweeteners there appears to be room for more studies (observational and experimental).

Background (2) Previous epidemiologic studies had reported positive associations between soft drink consumption and –Hypertensive disorders –Individual attributes of the metabolic syndrome …in middle aged non-pregnant subjects Hypertensive disorders are an independent risk factor for preterm delivery

Setting (1) The Danish National Birth Cohort – –≈ women enrolled ( ) –Information on diet for women Soft drink consumption –Food frequency questionnaire (4 variables) –Carbonated and non-carbonated sugar sweetened and artificially sweetened soft drinks

Setting (2) A total of women with singleton pregnancies Preterm delivery (<37 weeks) ≈ 4.6% Adjustment for: –pre-pregnancy BMI, parity, age, height, cohabitant status, smoking, total energy intake and familial socio-occupational status

Results

Carbonated soft drinks vs. preterm sugar sweetened (none) artificially sweetened (↑)

Pre-pregnancy body mass index same effect size and strength of association for normal-weight and overweight women

Type of preterm delivery The association with preterm delivery was primarily driven by medically induced deliveries

Summary of Results (1) Artificially sweetened carbonated soft drinks –38% increase in is risk for ≥1 serving/day vs. no intake Artificially sweetened non-carbonated soft drinks: –20% increase is risk for ≥1 serving/day vs. no intake No association for sugar sweetened carbonated and non-carbonated soft drinks

Summary of Results (2) Stable with respect to pre-pregnancy BMI No strong indication of confounding by atributes of lifestyle and socio-economical status. Driven by medically induced deliveries

Limitations (1) Medically induced preterm delivery may suggest that the association we observe is an iatrogenic phenomenon. However, range of potential disturbing factors were examined including: –Pregnancy hypertension –Preeclampsia –Gestational diabetes –Maternal weight gain –Macrosomia –Use of various medication –Intake of alcohol There was no strong indication suggesting that the observed association might be driven by these factors

Limitations (1) Medically induced preterm delivery may suggest that the association we observe is an iatrogenic phenomenon. However, range of potential disturbing factors were examined including: –Pregnancy hypertension –Preeclampsia –Gestational diabetes –Maternal weight gain –Macrosomia –Use of various medication –Intake of alcohol There was no strong indication suggesting that the observed association might be driven by these factors

Limitations (2) Drinking artificially sweetened soft drinks results in exposures to complex mix of sweeteners: Sweeteners from non-alcoholic beverages in Denmark, 2005 Food Addit Contam Part A Jun;25(6):662-8.

Possible explanation (1) - methanol exposure - ≈3-9 fold increase in dietary methanol exposure due to aspartame sweetened foods

Possible explanation (2) - methanol exposure -

Possible explanation (3) - dietary methanol exposure - Methanol exposure –0, 200, 600 and 1800ppm (2h/day) –11-12 animals per group Significant shortening of gestation in all exposed animals No other adverse effects were observed 5 exposed animals delivered by C-section No C-section among controls

Conclusions Intake of artificially sweetened soft drinks may increase risk of preterm delivery Possibly due to low dose methanol exposure However, the plausibility of this mechanism can be debated … … and the role of bias and unadjusted confounding can not be excluded Further testing in another independent data is therefore needed