At the Lieber Institute for Brain Development (LIBD), I am investigating the implication of obstetric complications in the development of schizophrenia.
In the study, a postmortem analysis of subjects diagnosed with schizophrenia was cross-referenced with subjects who experienced obstetric complications. It was hypothesized that subjects with a history of obstetric complications would positively correlate with subjects that developed schizophrenia. This would suggest that obstetric complications may influence the risk of schizophrenia through the gene-environment interaction.
The deck below illustrates the progress made in the study. It is this kind of work that I'm most passionate about-- creating comprehensive and inviting visuals to share complex ideas.
Introduction:
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves, causing them to lose touch with reality (Forsyth, 2013). This disease of unknown etiology is found in approximately 7 or 8 individuals out of 1,000 (NIH, 2017). While schizophrenia can be inherited, causing the disease to resurface throughout families, that isn’t the only context of its development. There is significant evidence supporting the role of genetics as a risk factor for schizophrenia. More importantly, an individual’s genetic risk may cause vulnerability to environmental cues such as psychosocial factors or obstetric/perinatal complications (Newman, 2016). By understanding the etiology of schizophrenia, we can begin understanding early indicators where we can better treat or even prevent its pathogenesis.
The goal of this study is to identify trends correlating the diagnosis of schizophrenia with the history of obstetric complications to identify significant gene-expression. It was hypothesized that subjects with a history of obstetric complications would positively correlate with the diagnosis of schizophrenia. When paired, an individual’s genetic makeup and their perinatal environment can instigate the changes in the brain that will eventually lead to schizophrenia (Forsyth, 2013). How obstetric complications, such as hypoxia (oxygen deficiency), contribute to schizophrenia is rooted in the dependence of fetal brain growth on glucose and oxygen supply (Nicodemus, 2008). Any complications regarding the in-utero environment may compromise healthy development. Certain studies have gone on to say that individuals at genetic risk may be consequently vulnerable and less equipped to combat the perinatal stress of glucose and oxygen deprivation (Forsyth, 2013). Examples of obstetric complications associated with schizophrenia would be bleeding, diabetes, prematurity, preeclampsia (characterized by high blood pressure) and abnormal fetal growth (Boog, 2017). It’s important to note that while obstetric complications have become widely associated with the development of schizophrenia, a specific complication has yet to be determined as the main environmental trigger, suggesting that the role of obstetric complications in developing schizophrenia should be further explored (Laurens, 2015).
Methods:
To frame the study, our lab referenced our collection of post-mortem tissue, which served as the pool of subjects to be analyzed. The criteria, or basis of categorization, within that pool was the diagnosis of schizophrenia versus alternative psychiatric disorders and control cases. Each case is diagnosed separately by psychiatrists within LIBD, Dr. Kleinman and Dr. Bigelow, after reviewing the medical records and interviews with decedent's family members. If they provide contradicting diagnoses and fail to reconcile a unanimous diagnosis, an external third opinion is brought in.
Prospective obstetric complication cases were then derived from our in-house library of schizophrenic and case-control subjects through survey and clinical data. First, cases where the decedent’s mother is next of kin were prioritized from the initial pool. Such cases would provide the opportunity to speak directly with the mother who would have the most vivid and reliable recollection of the pregnancy, as birth records are not readily available. The mother’s recollection holds a lot of weight in determining the nature of the obstetric complications. In the survey, obstetric complications were temporally distinguished: complications during the pregnancy, during delivery, and during the first postnatal month. To obtain this information, we have surveyed the mothers of decedents via a written questionnaire. As of now, there has been about a 50% response rate, totaling 112 responses, which is fairly successful given the sensitive nature of the topic. While the process has been underway, we have identified opportunities to improve our survey’s level of detail and accessibility to the next of kin. Some of the cases included in the table below will not be considered in the ultimate analysis due to either incompletion, someone other than the mother completed the survey, or other criteria.
The survey and clinical data will be used to analyze the pool of cases. The McNeil-Sjöström Scale for obstetric complications (OCs) is a survey designed to gauge the severity and classification of obstetric complications recalled by the mother. Confidence level of the mother’s recollection is integrated into the survey to account for the margins of error. The scoring system will be applied to the survey data our lab collects to indicate the frequency of obstetric complications in our pool of cases.
Prevalence and severity of obstetric complications will be noted in cases with schizophrenia versus other neuropsychiatric disorders and control-cases. We are examining cases where the subject has schizophrenia with and without a history of obstetric complications, as well as subjects with and without development of schizophrenia that have a history of obstetric complications (Preti, 2000). Through the McNeil-Sjöström Scale, we will focus on the prevalence of three prospective indicators of schizophrenia: fetal malnutrition, extreme
prematurity, and hypoxia (Dalman, 1999). Fetal malnutrition is when there is a critically insufficient supply of nutrients to the fetus, leading to growth impairments (Dalman, 1999). Extreme prematurity is when a baby is born alive before reaching the 28 week mark of pregnancy (Dalman, 1999). Hypoxia is when there is a deficiency in oxygen and glucose made available to the prenatal tissue (Dalman, 1999).
Through the lens of neuropathology, a breadth of information can be explored in investigating the pathology of psychiatric disorders like schizophrenia. The Neuropathology Laboratory uses postmortem human brain tissue to investigate the anatomic and molecular perturbations associated with schizophrenia. Cases with a history of obstetric complications will be examined to identify similarities in gene expression. The procedure for such analysis follows in line with that carried out in the Nicodemus study in 2008. While there is no clear link between any one gene and the etiology of schizophrenia, our study will hone in on hypoxic genes as schizophrenia candidate genes. Hypoxic genes (AKT1, BDNF, and NRG1) targeted in the Nicodemus study were related to high obstetric complication scores as well as the development of schizophrenia (Nicodemus, 2008). Hypoxic genes are being targeted because the hypoxia-inducible factor (HIF) is regulated by the HIF-1a protein (and ultimately oxygen supply) so when there is an oxygen deficiency, HIF initiates a cascade of mechanisms that hinder normal growth and development (Nicodemus, 2008). Such abnormal development may generate the individual’s susceptibility to schizophrenia.
Results:
From the data, we can derive a pattern of gene-expression in cases with a positive correlation between the frequency of scores and the diagnosis. Our study is currently in the stage of acquiring and processing surveys from the mothers of the decedents. Therefore, we have yet to collect sufficient data to warrant statistically relevant results. The results would however support or negate the notion that an individual’s genetic makeup predisposes them to a vulnerability of an environmental trigger: obstetric complication.
Discussion:
In correlational studies such as ours, discussion of the results cannot continue without noting that correlation does not mean causation. There is a breadth of alternative causes for the development of schizophrenia in cases with a history of obstetric complications. The sole environmental cue of obstetric complications isn’t the end-all be-all of schizophrenia pathogenesis. A series of environmental triggers such as drug use or traumatic life experiences may also be implicated in the pathogenesis of schizophrenia.
In correlational studies such as ours, discussion of the results cannot continue without noting that correlation does not mean causation. There is a breadth of alternative causes for the development of schizophrenia in cases with a history of obstetric complications. The sole environmental cue of obstetric complications isn’t the end-all be-all of schizophrenia pathogenesis. A series of environmental triggers such as drug use or traumatic life experiences may also be implicated in the pathogenesis of schizophrenia.
Moving forward, determining the role of obstetric complications in genetically predisposed individuals will be key to building awareness and establishing preventative measures in the future. In the near future, this study could substantiate the notion that psychiatric disorders are developmental, rather than caused by a later environmental factors. Research in this field can help debunk stigmas surrounding neuropsychiatric disorders. Further down the line, a pregnant woman could have her child’s genetic makeup screened for specific gene expression that indicates a susceptibility to abnormal neuropsychiatric developments. Insights into schizophrenia from this research can prompt discussions on related affective disorders.
From the work done on this study so far, I am interested in understanding the role of genetics as the cause of obstetric complications (Suvisaari, 2013). How does the maternal mental state and genetic makeup predispose the mother to a likelihood of obstetric complications? Would we see that obstetric complications are more common in mothers with schizophrenia? Could we determine that obstetric complications are an indicator for schizophrenia prevalence, rather than an environmental trigger?
Citations:
Boog, G. "[Obstetrical Complications and Further Schizophrenia of the Infant: A New Medicolegal
Threat to the Obstetrician?]." Journal De Gynecologie, Obstetrique Et Biologie De La Reproduction. U.S. National Library of Medicine, 03 Dec. 2003. Web. 20 Apr. 2017.
Dalman, MD Christina. "Obstetric Complications and the Risk of Schizophrenia." Archives of General Psychiatry . American Medical Association, 01 Mar. 1999. Web. 20 Apr. 2017.
Forsyth, Jennifer K., Lauren M. Ellman, Antti Tanskanen, Ulla Mustonen, Matti O. Huttunen, Jaana Suvisaari, and Tyrone D. Cannon. "Genetic Risk for Schizophrenia, Obstetric Complications, and Adolescent School Outcome: Evidence for Gene-Environment Interaction." Schizophrenia Bulletin . Oxford University Press, Sept. 2013. Web. 20 Apr. 2017.
Haukvik, U. K., and I. Agartz. "[Do Obstetric Complications Increase the Risk of Schizophrenia?]." Tidsskrift for Den Norske Laegeforening : Tidsskrift for Praktisk Medicin, Ny Raekke. U.S. National Library of Medicine, 11 Feb. 2010. Web. 20 Apr. 2017.
Karin Sjöström, McNeil, Thomas F. and Elizabeth Cantor-Graae. "Obstetric Complications as Antecedents of Schizophrenia." Journal of Psychiatric Research . N.p., Nov. 1994. Web. 20 Apr. 2017.
Laurens, Kristin R., Luming Luo, Sandra L. Matheson, Vaughan J. Carr, Alessandra Raudino, Felicity Harris, and Melissa J. Green. "Common or Distinct Pathways to Psychosis? A Systematic Review of Evidence from Prospective Studies for Developmental Risk Factors and Antecedents of the Schizophrenia Spectrum Disorders and Affective Psychoses." BMC Psychiatry . BioMed Central, 25 Aug. 2015. Web. 20 Apr. 2017.
National Institutes of Health . U.S. Department of Health and Human Services. Web. 20 Apr. 2017.
Newman, Louise, Fiona Judd, Craig A. Olsson, David Castle, Chad Bousman, Penelope Sheehan, Christos Pantelis, Jeffrey M. Craig, Angela Komiti, and Ian Everall. "Early Origins of Mental Disorder - Risk Factors in the Perinatal and Infant Period." BMC Psychiatry . BioMed Central, 2016. Web. 20 Apr. 2017.
Nicodemus, K. K., S. Marenco, A. J. Batten, R. Vakkalanka, M. F. Egan, R. E. Straub, and D. R. Weinberger. "Serious Obstetric Complications Interact with Hypoxia-regulated/vascular-expression Genes to Influence Schizophrenia Risk." Molecular Psychiatry. U.S. National Library of Medicine, Sept. 2008. Web. 20 Apr. 2017.
Preti, A., L. Cardascia, T. Zen, M. Marchetti, G. Favaretto, and P. Miotto. "Risk for Obstetric Complications and Schizophrenia." Psychiatry Research. U.S. National Library of Medicine, 30 Oct. 2000. Web. 20 Apr. 2017.
Suvisaari, J. M., V. Taxell-Lassas, M. Pankakoski, J. K. Haukka, J. K. Lönnqvist, and L. T. Häkkinen. "Obstetric Complications as Risk Factors for Schizophrenia Spectrum Psychoses in Offspring of Mothers with Psychotic Disorder." Schizophrenia Bulletin. U.S. National Library of Medicine, Sept. 2013. Web. 20 Apr. May 2017.