The effect of nicotine-containing products and fetal sex on placenta-associated circulating midpregnancy biomarkers

Biol Sex Differ. 2022 Jul 15;13(1):39. doi: 10.1186/s13293-022-00443-1.


Background: In utero exposure to nicotine, largely assessed by smoking, is a risk factor for impaired offspring health, while potential effects of non-combustible nicotine use such as snus (oral moist tobacco), are less well-known. Maternal serum concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) may be viewed as "placenta health markers", known to differ by fetal sex. Maternal smoking during pregnancy has been associated with lower levels of circulating sFlt-1, while the effect of snus on placenta-associated angiogenic factors is unknown. Our aim was to explore if snus and/or smoking exposure was associated with midpregnancy maternal levels of sFlt-1, PlGF and sFlt-1/PlGF ratio if these associations were modified by fetal sex.

Methods: Midpregnancy (16-22 gestational weeks) serum from 2603 Scandinavian women enrolled in the population-based multi-center PreventADALL (Preventing Atopic Dermatitis and ALLergies in children) study was analysed for sFlt-1 and PlGF concentrations by electrochemiluminescence, deriving the sFlt-1/PGF ratio. Nicotine use was assessed by electronic questionnaires at enrollment in 2278 of the women. Univariable and multivariable linear regression models on log transformed outcomes were used to assess the association between nicotine use and biomarker levels. Interaction terms were included to identify whether the associations were modified by fetal sex.

Results: Median sFlt-1, PlGF and sFlt-1/PlGF ratios among women with nicotine exposure information were similar to those of all included women and differed by fetal sex. Current snus use was significantly associated with reduced maternal circulating PlGF levels in adjusted analyses [β - 0.12, (95% CI - 0.20; 0.00) compared to never use, p = 0.020]. A significant interaction between fetal sex and snus exposure was observed for PIGF (p = 0.031). Prior or periconceptional snus use was significantly associated with PIGF in male fetus pregnancies [β - 0.05 (95% CI - 0.09 to (- 0.02)) and β - 0.07 (95% CI - 0.12 to (- 0.02)) compared to never use, p = 0.002]. Smoking was not significantly associated with any circulating biomarkers levels.

Conclusions: Midpregnancy maternal angiogenic profile differed by periconceptional snus use and fetal sex. Snus exposure, perceived as "safe" by users, before or during pregnancy seems to affect midpregnancy placental health in a sex dimorphic manner.

Keywords: Angiogenic proteins; Fetal sex; Moist tobacco; Nicotine; Placenta; PreventADALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Child
  • Female
  • Humans
  • Male
  • Nicotine* / adverse effects
  • Placenta / metabolism
  • Placenta Growth Factor
  • Pregnancy
  • Vascular Endothelial Growth Factor Receptor-1* / metabolism


  • Biomarkers
  • Placenta Growth Factor
  • Nicotine
  • Vascular Endothelial Growth Factor Receptor-1