Genetic epidemiological studies of adverse pregnancy outcomes and the role of schizophrenia

The purposes of this thesis were to investigate the importance of genetic and environmental factors in the development of adverse pregnancy outcomes and to investigate the role of schizophrenia as a risk factor for and a consequence of adverse pregnancy outcomes.

In the first study we investigated the importance of genetic and environmental factors for pre-eclampsia and gestational hypertension and whether the diseases share genetic etiology. Swedish population-based registers were used and 1,188,207 births were included. We found that full sisters and mother-daughters were more similar for pre-eclampsia and gestational hypertension than half-sisters. Moreover, a full sister to a woman with pre-eclampsia had a significantly increased risk of gestational hypertension. The heritability estimates were 31% for pre-eclampsia, 20% for gestational hypertension, and 28% for pregnancy-induced hypertension. In sum, we found a genetic component in the liability of both pre-eclampsia and gestational hypertension. The co-morbidity indicates that pre-eclampsia and gestational hypertension may share parts of their genetic etiology.

The aims of the second and third studies were to examine risks of adverse pregnancy outcomes among mothers and fathers with schizophrenia and to investigate if the increased risks among women with schizophrenia were due to maternal, paternal, genetic and/or environmental factors. Two million births from Swedish population-based registers were included. Maternal factors (e.g., smoking) explained most of the risks for adverse pregnancy outcomes and women with an episode of schizophrenia during pregnancy had the highest risks. Increased risks for low birth weight, small-for-gestational age, and infant death among offspring to fathers with schizophrenia were observed. In conclusion, mothers with schizophrenia have increased risks for adverse pregnancy outcomes. The risks were highest for women admitted to psychiatric care during pregnancy. The increased risks among offspring to fathers with schizophrenia suggest that, in addition to maternal risk behavior, non-optimal social and/or economical circumstances are of importance.

In the fourth study we investigated if the previously found association between low birth weight and subsequent development of schizophrenia is mediated by familial factors. We used data from obstetric records in a cohort analysis of 11,360 same-sexed twins, and conducted co-twin control analyses on 90 pairs discordant for schizophrenia. The results from the cohort analyses showed that low birth weight and small head circumference were associated with later development of schizophrenia. The associations remained in the within-pair analyses. We concluded that the association between low birth weight and schizophrenia is partly a function of reduced fetal growth and that fetal growth restriction seems to be associated with risk of schizophrenia independently of familial factors.

This thesis has examined adverse pregnancy outcomes using register-based samples and genetic epidemiological methods. We found a genetic comorbidity between pre-eclampsia and gestational hypertension, which should be considered in the future search for susceptibility genes and in the identification of intervention strategies. Maternal as well as paternal schizophrenia influence the risk of adverse pregnancy outcomes. These results prompt for better surveillance of families at risk. Further, we found that fetal growth restriction is an independent risk factor for subsequent development of schizophrenia. Adverse pregnancy outcomes represent some of the most challenging targets in epidemiology and elucidation of the underlying mechanisms and identification of markers of early insult that predisposes to adult diseases are important.

List of scientific papers

I. Nilsson E, Salonen Ros H, Cnattingius S, Lichtenstein P (2004). The importance of genetic and environmental effects for pre-eclampsia and gestational hypertension: a family study. BJOG. 111(3): 200-6.
https://doi.org/10.1111/j.1471-0528.2004.00042.x

II. Nilsson E, Lichtenstein P, Cnattingius S, Murray RM, Hultman CM (2002). Women with schizophrenia: pregnancy outcome and infant death among their offspring. Schizophr Res. 58(2-3): 221-9.
https://doi.org/10.1016/S0920-9964(01)00370-X

III. Nilsson E, Hultman CM, Cnattingius S, Otterblad Olausson P, Lichtenstein P (2006). Schizophrenia and adverse pregnancy outcomes - maternal, paternal and genetic influences. [Submitted]

IV. Nilsson E, Stalberg G, Lichtenstein P, Cnattingius S, Olausson PO, Hultman CM (2005). Fetal growth restriction and schizophrenia: a Swedish twin study. Twin Res Hum Genet. 8(4): 402-8.
https://doi.org/10.1375/1832427054936727