Causes and consequences of stress and tobacco exposure in utero on birth size, asthma and academic achievement

The objective of this thesis was to further the understanding of the consequences of stress and smoking during pregnancy, the causes of intrauterine growth and asthma as well as the consequences of asthma on school performance and to explore explanations of observed associations.

In Study I we investigated the associations between four measures of subjective distress and cortisol levels in early and late pregnancy and perinatal outcomes. All estimated associations were small and most statistically non-significant. However, for birth weight by gestational age the estimated associations with subjective distress were statistically significant, indicating higher birth weight with higher distress. Results were similar in early and late pregnancy.

In Study II we explored an intergenerational effect of smoking during pregnancy (SDP) on the grandchildren’s intrauterine growth. The grandchildren of maternal grandmothers who smoked during pregnancy had a slightly higher risk of being large for gestational age, which may be partly explained by a higher obesity rate among their daughters (grandchild’s mother). In contrast, the grandchildren of paternal grandmothers who smoked during pregnancy had slightly higher risk of being small for gestational age, which may be partly explained by a higher SDP rate among their daughters-in-law (grandchild’s mother). Sensitivity analysis with regard to unmeasured confounding indicated that this may explain the associations.

In Study III, we explored the association between tobacco use during pregnancy and offspring asthma/wheeze and the potential role of nicotine and familial factors such as genes and environment shared within the family. We found that SDP was associated with a higher risk of asthma/wheeze in the first two years of life, but not at higher ages. Analysis of the association between oral snuff use in pregnancy, i.e. exposure to nicotine without combustion toxins, and asthma/wheeze indicated no clear association. The sibling comparisons showed lower estimates. Taken together this indicates that the role of nicotine in the association between SDP and asthma/wheeze may be limited, while familial factors seem important.

In Study IV we examined if adolescents with asthma in school Grades 7-8 and 9 perform worse in school compared to adolescents without asthma. Our results indicated that school performance of adolescents with asthma was somewhat better than among those without asthma, but also that asthma severity and control were important. Adolescents with severe, but controlled asthma, performed somewhat better than those without asthma, while children with uncontrolled asthma performed somewhat worse. Sibling analyses indicated familial factors explained most associations, with the exception of an association between uncontrolled asthma in Grade 9 and slightly lower school performance.

In conclusion, considering other known detrimental effects of the risk factors investigated in this thesis, our findings of no or very modest associations, should not in any way be interpreted as excuses for ignoring stress in pregnant women, continue smoking during pregnancy or give up the strife for asthma control in children and adolescents.

List of scientific papers

I. Lundholm C, Rejnö G, Brew BK, Smew A, Saltvedt S, Almqvist C. Associations between maternal distress, cortisol levels and perinatal outcomes. [Submitted]

II. Lundholm C, Öberg S, D’Onofrio BM, Larsson H, Brew BK, Almqvist C. The role of maternal obesity and smoking during pregnancy in the transgenerational association between grandmaternal smoking during pregnancy and grandchild’s foetal growth. [Submitted]

III. Lundholm C, Gunnerbeck A, D'Onofrio BM, Larsson H, Pershagen G, Almqvist C. Smoking and snuff use in pregnancy and the risk of asthma and wheeze in pre-schoolchildren - A population-based register study. Clinical & Experimental Allergy. 2020, 50(5):597-608.
https://doi.org/10.1111/cea.13593

IV. Lundholm C, Brew BK, D'Onofrio BM, Osvald EC, Larsson H, Almqvist C. Asthma and subsequent school performance at age 15-16 years: A Swedish population-based sibling control study. Scientific Reports. 2020, 10(1):7661.
https://doi.org/10.1038/s41598-020-64633-w