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Gestation Matters: Preterm Birth Raises Risk for Psychiatric Illness

13 June 2012. Babies born prematurely have an increased risk of developing a psychiatric illness in adulthood, according to a new study published online June 1 in the Archives of General Psychiatry. The study, led by Chiara Nosarti, of King’s College London, U.K., examined the hospital records of 1.3 million Swedes, and found that preterm birth significantly raised the risk of later psychiatric illness. However, neither low birth weight for gestational age nor a low newborn health score immediately after birth showed the same relationship with later mental illness.

According to the Centers for Disease Control (CDC), about 13 percent of all babies born in the U.S. are premature, defined as less than 37 weeks of gestation. Premature babies have an elevated risk of a host of immediate health problems, as well as an increased chance of other illnesses later in life, including diabetes, heart disease, and high blood pressure (Thomas et al., 2011). A host of studies have implicated perinatal complications (including preterm birth, low birth weight, and delivery-related hypoxia) in later risk for psychiatric illness, with the majority of studies focusing on schizophrenia (Jones et al., 1998). Although one study examining perinatal complications and bipolar disorder found no association between the two (Scott et al., 2006), the question of whether perinatal complications raise the risk of other psychiatric illnesses besides schizophrenia remains largely unanswered.

A challenge in defining the role of perinatal complications in later risk for psychiatric illness is identifying the specific factors that may play a role, since babies often have two or more risk factors concurrently (e.g., infants born premature are usually underweight). The studies that have attempted to parse out the differences are mixed, with some finding that premature birth, but not low birth weight, raise the risk, while others report that smallness for gestational age or hypoxia confer the greatest risk (Geddes et al., 1999; Hultman et al., 1999).

In the current study, researchers examined the relationship between multiple perinatal risk factors and several mental illnesses using data from the Swedish Medical Birth Register on individuals born between 1973 and 1985. Three main pregnancy variables were assessed: 1) gestational age, grouped as follows: very preterm (<32 weeks), moderately preterm (32-36 weeks), term (37-41 weeks), and post-term (≥42 weeks); 2) birth weight for gestational age (measured in standard deviations from a Swedish birth weight curve); and 3) Apgar (newborn health) score at five minutes after birth.

Using the Swedish National Hospital Discharge Register, which records diagnoses according to the World Health Organization’s International Classification of Diseases (ICD), the researchers then identified the subjects (aged 16-29) who were subsequently hospitalized for nonaffective psychosis (which includes schizophrenia and schizoaffective disorder), depressive disorder, bipolar affective disorder, eating disorder, drug dependency, or alcohol dependency.

Preterm birth is risky
Preterm birth was significantly associated with increased risk of hospitalization for a number of psychiatric illnesses, including nonaffective psychosis, bipolar affective disorder, and depressive disorder. Importantly, the effect remained when a number of factors—smallness for gestational age; Apgar score; sex; and mother’s number of previous children, age at delivery, education level, and psychiatric family history—were controlled for, suggesting that the observed effect is specific for premature birth.

In addition, the risk for all three illnesses was greater in babies born very preterm (<32 weeks) than those classified as moderately preterm (32-36 weeks), with the largest effect in the former group being an over sevenfold increase in risk for bipolar disorder (compared to a 2.7-fold increase in the moderately premature group). The risk for developing nonaffective psychosis and major depression was 2.5 and 2.9 times higher, respectively, in the very premature group, compared to 0.6- and 0.3-fold increases in risk that were seen in moderately preterm babies. Very premature birth was also associated with an increased risk for eating disorders, and moderately premature birth was associated with an increased risk for drug and alcohol dependency.

In contrast to the preterm data, babies that were small for their gestational age did not exhibit an increased risk for nonaffective psychosis, major depression, or bipolar disorder, although an association with later drug and alcohol dependency was observed. In addition, there was no relationship between a low Apgar score and later risk for nonaffective psychosis and bipolar disorder, although an increase in risk for major depression was observed. No significant interaction among the three variables (preterm birth, low weight for gestational age, and low Apgar score) was observed.

Making sense of the data
Nosarti and colleagues’ findings that preterm birth is associated with increased risk for psychiatric illnesses suggests that abnormalities in early brain development can produce changes that last into adulthood. In fact, alterations in a number of brain networks implicated in psychiatric illness, such as frontostriatal and frontoparietal, have been found in adults who were born prematurely (Nosarti et al., 2009; Narberhaus et al., 2009).

Although preterm birth has previously been implicated in risk for schizophrenia, the link between premature birth and major depression and bipolar disorder reported here is a first. These data also suggest that diverse psychiatric illnesses may share a common etiological mechanism, consistent with previous studies demonstrating overlap in both risk genes and cognitive endophenotypes between schizophrenia and bipolar disorder (Owen et al., 2007; MacCabe et al., 2008). The authors speculate that preterm birth may be one of the environmental factors that confer risk for later psychiatric illness, perhaps interacting with genetic factors. A gene-environment interaction may push an individual over the threshold to develop a psychiatric illness, although neither factor alone is sufficient (Mittal et al., 2008).

Maternal genetic factors have previously been implicated in the etiology of preterm birth (Svensson et al., 2009). In the present study, however, the increased risk of later psychiatric illness was similar when the statistical models used in analysis did and did not control for additional maternal factors, including family psychiatric history, suggesting that premature birth may not share genetic factors in common with maternal psychiatric illness.

Although the results of the current study are bolstered by its large sample size and broad range of mental illnesses examined, the use of hospital registries is one limitation. Only the most severe patients that required hospitalization were included in the psychiatric illness groups, while those having less severe forms of mental illness were included in the control group. Thus, whether the results are generalizable to individuals with less severe forms of mental illness remains to be seen.

The hope is that, someday, information on the role of perinatal complications in later development of psychiatric illness will lead to better early detection strategies. According to the authors, the findings suggest that “future longitudinal research combining gene-environment information, including gestational age, may represent a useful investigative tool with potential for early identification of individuals who may be particularly vulnerable to develop a variety of psychiatric disorders in late adolescence and young adulthood.”—Allison Curley.

Nosarti C, Reichenberg A, Murray RM, Cnattingius S, Lambe MP, Yin L, Maccabe J, Rifkin L, Hultman CM. 2012. Preterm Birth and Psychiatric Disorders in Young Adult Life. Arch Gen Psychiatry June 1:610-617. Abstract

Comments on News and Primary Papers
Comment by:  Marit S Indredavik
Submitted 6 July 2012
Posted 6 July 2012

This study provides important and partly new information on long-term psychiatric outcomes after preterm birth. It is a historical, population-based cohort study using data from Swedish national registers, showing increased risk for severe psychiatric disorders—nonaffective psychosis, depressive, bipolar, and even eating disorders—in the very preterm population. The risk was also increased, although to a lesser degree, for the moderately preterm group (except for eating disorders). Maternal psychiatric history, socioeconomic or perinatal factors could not explain the findings. Interestingly, being small for gestational age increased the risk for drug and alcohol dependency.

This expands present knowledge, and supplements the emerging evidence of increased risk for adult psychiatric disorders in low-birth-weight populations (Moster et al., 2008; Walshe et al., 2008; Hack, 2009; and Lund et al., 2011). The study takes care of several aspects that usually limit other studies: a large sample size, inclusion of the moderately preterm group, maternal psychiatric morbidity, and a range of prenatal and perinatal factors. As such, this well-performed study deserves credit. The results underline the concern that psychiatric morbidity is one of the major health issues after preterm birth.

The authors suggest impaired neurodevelopment as a plausible biological basis for psychiatric disorders associated with preterm birth. They propose that similar etiologies may lead to a variety of different outcomes, although non-optimal fetal growth may represent other or additional risk factors. Future studies combining advanced cerebral MRI techniques, and clinical, genetic/epigenetic, and environmental data, may provide new knowledge on the etiology. A better understanding of the mechanisms involved may point to improved prevention and intervention aiming to reduce the psychiatric morbidity for low-birth-weight individuals.


Hack M. Adult outcomes of preterm children. J Dev Behav Pediatr 2009;30(5):460-70. Abstract

Lund LK, Vik T, Skranes J, Brubakk AM, Indredavik MS. Psychiatric morbidity in two low birth weight groups assessed by diagnostic interview in young adulthood. Acta Paediatr 2011;100:598-604. Abstract

Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med 2008;359:262-273. Abstract

Walshe M, Rifkin L, Rooney M, Healy E, Nosarti C, Wyatt J, Stahl D, Murray RM, Allin M. Psychiatric disorder in young adults born very preterm: Role of family history. European Psychiatry 2008;23:527-531. Abstract

View all comments by Marit S Indredavik