Cigarette smoking during pregnancy is common and adversely affects fetal neurodevelopment through modulation of brain nicotinic acetylcholine receptors. Previous studies of maternal smoking as a risk factor for schizophrenia have yielded contradictory findings, potentially as a result of methodological limitations, such as small sample size, or smoking data based on maternal interviews rather than objective biomarkers.
Niemela and colleagues1 examined whether maternal smoking during pregnancy was associated with schizophrenia in the Finnish Prenatal Study of Schizophrenia. They utilized maternal cotinine levels (the primary metabolite of nicotine) in prospectively drawn, biobanked maternal blood specimens obtained during the first or early second trimester of pregnancy. These results were linked with a national registry of cases of schizophrenia.
The authors performed a nested case-control study from a sample of all births in Finland from 1983 to 1998 (from the Finnish Maternity Cohort, which consists of almost all pregnancies in Finland, with over 1 million archived prenatal blood samples drawn since 1983). Subjects were followed up until 2009.
A diagnosis of schizophrenia or schizoaffective disorder in the offspring was identified through the Finnish Hospital and Outpatient Discharge Registry, which includes all recorded diagnoses for psychiatric hospitalizations and outpatient treatment.
Nine hundred seventy-seven women with schizophrenia or schizoaffective disorder had maternal blood samples with sufficient volume for the cotinine assays. Cases were matched 1:1 to controls without a history non-affective psychosis or bipolar disorder, based on date of birth, sex, and residence in Finland.
Potential covariates considered in the analyses included sex, parental age, maternal education, province of birth, parental history of psychiatric disorders, previous births, weight for gestational age, maternal C-reactive protein, and gestational week of the blood draw. The mean age of subjects was 22.
Data were analyzed using conditional logistic regression. Cotinine levels were analyzed as both a continuous and categorical measure (reference, < 20 ng/mL; moderate exposure, 20 - 50 ng/mL; and heavy exposure, > 50 ng/mL). After controlling for maternal age, province of birth, and parental psychiatric disorder, increasing (log-transformed) maternal cotinine levels were associated with a significant, 3.41-fold increased odds (95% confidence interval [CI], 1.86 - 6.24) of schizophrenia in the offspring.
In the categorical analyses, heavy nicotine exposure was associated with a significant, 1.38-fold increased odds (95% CI, 1.05 - 1.82) of schizophrenia in the offspring after controlling for the same covariates. The pattern of results was similar when restricted to only subjects with schizophrenia, and the association was not mediated by low weight for gestational age or parental psychiatric disorders.
The authors note that there is extensive evidence for an association between prenatal smoking and neurocognitive impairments in offspring, which have also been related to schizophrenia.2,3 Potential mechanisms by which nicotine alters fetal brain development include apoptotic processes affecting the neuronal numbers, fetal hypoxia, and epigenetic changes.
The bottom line
This is the first (and largest) study to report an association between maternal smoking and schizophrenia in the offspring using biomarker data for maternal exposure.
Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.
1. Niemela S, Sourander A, Sucel H-M, et al. Prenatal nicotine exposure and risk of schizophrenia among offspring in a national birth cohort. Am J Psychiatry. Published online May 24, 2016. doi: 10.1176/appi.ajp.2016.15060800.
2. Clifford A, Lang L, Chen R. Effects of maternal cigarette smoking during pregnancy on cognitive parameters of children and young adults: a literature review. Neurotoxicol Teratol. 2012;34:560-570.
3. Kalkstein S, Hurford I, Gur RC. Neurocognition in schizophrenia. Curr Top Behav Neurosci. 2010;4:373-390.