Significant outcomes
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OCs are associated with more severe psychopathology.
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Difficulties during delivery are specifically associated with worse psychopathology.
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OCs are heterogeneous, and timing description is essential.
Limitations
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The OCs included come from a clinical scale, so some others may be missing.
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OCs were not analysed individually but as groups according to specific characteristics.
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OCs were recorded through a familiar interview.
Introduction
First episode of psychosis (FEP) can be the initial event of a wide variety of diagnoses and eventually lead to schizophrenia, bipolar disorder, major depression disorder and other clinical entities (Salvatore et al., Reference Salvatore, Baldessarini, Tohen, Khalsa, Perez Sanchez-Toledo, Zarate, Vieta and Maggini2009). Regardless of diagnostic heterogeneity, genetic and environmental factors interact with the risk pathway. Among the environmental factors, obstetric complications (OCs) or abnormalities during the prenatal and perinatal period have been historically described as major risk contributors (Cannon et al., Reference Cannon, Jones and Murray2002; Davies et al., Reference Davies, Segre, Estradé, Radua, De Micheli, Provenzani, Oliver, Salazar de Pablo, Ramella-Cravaro, Besozzi, Dazzan, Miele, Caputo, Spallarossa, Crossland, Ilyas, Spada, Politi, Murray, McGuire and Fusar-Poli2020). However, current evidence suggests that OCs in psychosis are a risk factor not only for the later development of psychosis but also for other effects that range from neuroanatomical (Costas-Carrera et al., Reference Costas-Carrera, Garcia-Rizo, Bitanihirwe and Penadés2020), neurocognitive (Amoretti et al., Reference Amoretti, Rabelo-da-Ponte, Garriga, Forte, Penadés, Vieta, Parellada, Ramos-Quiroga, Gama, Verdolini, Bitanihirwe and Garcia-Rizo2022), metabolic abnormalities (Garcia-Rizo et al., Reference Garcia-Rizo, Fernandez-Egea, Bernardo and Kirkpatrick2015) to clinical psychopathology (Mezquida et al., Reference Mezquida, Fernández-Egea, Treen, Mané, Bergé, Savulich, García-Álvarez, García-Portilla, Bobes, Bernardo and García-Rizo2021). Moreover, some specific clinical features, such as childhood attention deficit hyperactivity disorder symptoms in schizophrenia-spectrum disorders, seem to be associated with OCs (Peralta et al., Reference Peralta, de Jalón, Campos, Zandio, Sanchez-Torres and Cuesta2011), while higher ratings of parkinsonism, catatonia and dyskinesia have been associated with OCs in neuroleptic-naïve psychotic patients (Peralta et al., Reference Peralta, Cuesta and Serrano2006; Peralta & Cuesta, Reference Peralta and Cuesta2010). However, there remains much inconsistency between studies on how OCs are measured, as some authors include OCs as a discrete entity while others specify the timing and the nature of the obstetric event (Mezquida et al., Reference Mezquida, Fernandez-Egea, Treen, Mane, Berge, Savulich, Garcia-Alvarez, Garcia-Portilla, Bobes, Bernardo, Garcia-Rizo, Mané, Bergé, Savulich, Garcia-Alvarez, García-Portilla, Bobes, Bernardo and Garcia-Rizo2018).
The perinatal origins of psychosis model are receiving increasing attention (Garcia-Rizo & Bitanihirwe, Reference Garcia-Rizo and Bitanihirwe2020), particularly within the realm of metabolism (i.e. logic and theory). This field of enquiry in general medicine originated as the “Barker hypothesis”, where the relationship between foetal growth and later type 2 diabetes mellitus (T2DM) (Hales & Barker, Reference Hales and Barker1992) established a theoretical basis for the developmental origins of health and disease model (Gluckman & Hanson, Reference Gluckman and Hanson2006). This model suggests that “undesirable conditions” during the perinatal period can have long-lasting metabolic consequences. Indeed, recent research showed that birth weight (BW), an indirect measure of the intrauterine milieu, is related to weight gain (Garcia-Rizo et al., Reference Garcia-Rizo, Bioque, Mezquida, Amoretti, Cuesta, Díaz-Caneja, Mas, Lobo, González-Pinto, Fraguas, Corripio, Vieta, Baeza, Bergé, Fernandez-Egea, Garriga, Bernardo, Parellada, Meseguer, Moreno, Pina-Camacho, Alonso-Solís, Rabella, Zorrilla, López, Barcones, De-la-Cámara, Sanjuan, Cañete, Mané, Morro, Salagre, Hidalgo-Matezzi, Castro-Fornielles, de la Serna, Contreras, Saiz-Masvidal, Bobes, García-Portilla, Gutiérrez-Fraile, Segarra, Fares-Otero, Rodriguez-Jimenez, Butjosa, Usall, Sarró, Pomarol-Clotet, Ibañez, Sánchez-Torres and Selva-Vera2020; Garriga et al., Reference Garriga, Fernandez-Egea, Mallorqui, Serrano, Oliveira, Parellada, Kirkpatrick, Vieta, Bernardo and Garcia-Rizo2019a) and glucose values in FEP (Garcia-Rizo et al., Reference Garcia-Rizo, Cabrera, Bioque, Mezquida, Lobo, Gonzalez-Pinto, Diaz-Caneja, Corripio, Vieta, Baeza, Garcia-Portilla, Gutierrez-Fraile, Rodriguez-Jimenez, Garriga, Fernandez-Egea and Bernardo2022), with T2DM in schizophrenia (Fernandez-Egea et al., Reference Fernandez-Egea, Walker, Ziauddeen, Cardinal and Bullmore2020) and in affective disorders (Garriga et al., Reference Garriga, Wium-Andersen, Wium-Andersen, Nordentoft and Osler2019b).
However, the study of OCs and their relationship with clinical presentation in psychiatric patients has received less attention. OCs taken as a whole were associated with more prominent negative symptoms in patients with chronic schizophrenia and early onset in adolescence (Kotlicka-Antczak et al., Reference Kotlicka-Antczak, Gmitrowicz, Sobów, Rabe-Jabłonska and Rabe-Jabłońska2001). OCs were associated with negative symptoms in less affluent patients with schizophrenia (Jones et al., Reference Jones, Gallagher, Moss and McFalls2011). Similar outcomes were observed in an African cohort, where OCs were associated with negative symptomatology (Mechri et al., Reference Mechri, Mrad, Mokni, Gaddour, Letaif and Gaha2008). Interestingly negative symptoms were also associated with OCs in the adolescent with psychotic-like experiences (Cardno et al., Reference Cardno, Selzam, Freeman and Ronald2021), while also in adolescents, adverse events during early development (both prenatal and perinatal) lead to an increased risk of developing non-clinical psychosis-like symptoms (Zammit et al., Reference Zammit, Odd, Horwood, Thompson, Thomas, Menezes, Gunnell, Hollis, Wolke, Lewis and Harrison2009).
When specifically evaluating the type of OCs, previously published work by Kotlicka-Antczak and colleagues has described more prominent negative symptomatology to be associated with abnormalities in delivery evaluated with the Apgar score (Kotlicka-Antczak et al., Reference Kotlicka-Antczak, Gmitrowicz, Sobów, Rabe-Jabłonska and Rabe-Jabłońska2001) while a recent cross-sectional study in patients with chronic schizophrenia with predominant negative symptomatology described an association between difficulties during delivery assessed with the Lewis–Murray scale and measures of anxiety, guilt feelings and unusual thought content (Mezquida et al., Reference Mezquida, Fernández-Egea, Treen, Mané, Bergé, Savulich, García-Álvarez, García-Portilla, Bobes, Bernardo and García-Rizo2021).
BW, an indirect marker of the prenatal environment, has been studied in a Finnish schizophrenia study sample, where both low and high BW were associated with more severe symptoms, especially in terms of “bizarre” behaviour, affective flattening and attentional impairment (Wegelius et al., Reference Wegelius, Pankakoski, Lehto, Suokas, Häkkinen, Tuulio-Henriksson, Lönnqvist, Paunio and Suvisaari2013). In addition, the same study found low BW to be associated with more severe formal thought disorder (Wegelius et al., Reference Wegelius, Pankakoski, Lehto, Suokas, Häkkinen, Tuulio-Henriksson, Lönnqvist, Paunio and Suvisaari2013). However, another study stratifying the study cohort into deficit and non-deficit schizophrenia did not find any association with low BW (Alabaf et al., Reference Alabaf, Kirkpatrick, Chen, Cardinal and Fernandez-Egea2022). Maternal smoking, an indirect marker of an adverse intrauterine environment, has been correlated with lower BW (Abraham et al., Reference Abraham, Alramadhan, Iniguez, Duijts, Jaddoe, Dekker, Den Crozier, Godfrey, Hindmarsh, Vik, Jacobsen, Hanke, Sobala, Devereux and Turner2017) and also with more negative symptomatology (Stathopoulou et al., Reference Stathopoulou, Beratis and Beratis2013). Indeed, a later study found that maternal smoking was associated with more severe deficit symptoms (Bernardini et al., Reference Bernardini, Wan, Crisafio, Massey and Compton2015). Additionally, recent research evaluating the effect of maternal cortisol during pregnancy highlights the importance not only of timing but also of foetal sex (Ellman et al., Reference Ellman, Murphy, Maxwell, Calvo, Cooper, Schaefer, Bresnahan, Susser and Brown2019). Indeed, in a large schizophrenia hospital cohort, OCs were associated with negative symptomatology only in females (Gallagher et al., Reference Gallagher, Jones and Eaton2014).
Nevertheless, negative findings have also been described. No association was described between OCs and clinical psychopathology neither in a Nigerian cohort of patients diagnosed with schizophrenia (Onu & Ohaeri, Reference Onu and Ohaeri2020) nor in a cohort of severely ill schizophrenia patients (Smith et al., Reference Smith, Honer, Kopala, MacEwan, Altman and Smith1995).
OCs have been related to clinical symptomatology not only in schizophrenia but also in affective disorders (Serati et al., Reference Serati, Bertino, Malerba, Mucci, Barkin, Grassi, Altamura and Buoli2020; Solé et al., Reference Solé, Roca, Torres, Hernández, Fernández, Díaz, Vieta and Garcia-Esteve2020; Sagué-Vilavella et al., Reference Sagué-Vilavella, Amoretti, Garriga, Mezquida, Williams, Serra-Navarro, Forte, Varo, Montejo, Palacios-Garran, Madero, Sparacino, Anmella, Fico, Giménez-Palomo, Pons-Cabrera, Salgado-Pineda, Montoro Salvatierra, Sánchez Gistau, Pomarol-Clotet, Ramos-Quiroga, Undurraga, Reinares, Martínez-Arán, Pacchiarotti, Valli, Bernardo, Garcia-Rizo, Vieta and Verdolini2022). In a longitudinal study, hypomania with previous psychotic experiences was initially associated with gestational influenza; however, later analysis did not confirm the association (Anderson et al., Reference Anderson, Hoath, Zammit, Meyer, Pell, Mackay and Smith2016). Nevertheless, in the general population, a study evaluating a wide range of psychopathology measures in offspring suggested that the association between prenatal and postnatal factors and psychopathology of offspring during adulthood was mediated by familial factors (Essau et al., Reference Essau, Sasagawa, Lewinsohn and Rohde2018). Beyond this, recent research focussing on FEP highlights the effect of other environmental factors in later life related to psychopathological profile at onset of psychiatric illness, such as childhood adversity (Butjosa et al., Reference Butjosa, Usall, Vila-Badia, Mezquida, Cuesta, Rodríguez-Toscano, Amoretti, Lobo, González-Pinto, Espliego, Corripio, Vieta, Baeza, Bergé, Bernardo, Bioque, García-Rizo, Mayoral, Merchan, Alonso-Solís, Rabella, López, Zorrilla, De-la-Cámara, Barcones, Sanjuan, Dolores Moltó, Morro, Monserrat, Verdolini, Salagre, de la Serna, Castro-Fornieles, Contreras Fernández, Saiz Masvidal, Paz Garcia-Portilla, Bousoño, Gutiérrez Fraile, Zabala Rabadán, Dompablo, Rodriguez-Jimenez, Rubio-Abadal, Pardo, Sarró, Pomarol-Clotet, Ibanez, Sánchez-Torres and Selva-Vera2022) and cannabis use (González-Blanco et al., Reference González-Blanco, García-Portilla, Gutiérrez, Mezquida, Cuesta, Urbiola, Amoretti, Barcones, González-Pinto, Pina-Camacho, Corripio, Vieta, Baeza, Toll, Sáiz, Bobes, Bernardo, Bioque, Sagué, Alonso-Solís, Grasa, González-Ortega, Zorrilla, Santabárbara, De-la-Cámara, Aguilar, Nacher, Bergé, Mané, Montejo, Anmella, Castro-Fornieles, de la Serna, Contreras, Sáiz-Masvidal, García-Álvarez, Bobes-Bascarán, Zabala-Rabadán, Segarra-Echevarría, Sanchez-Pastor, Rodriguez-Jimenez, Usall, Butjosa, Sarró, Guerrero-Pedraza, Ibañez, Ribeiro and Balanzá-Martínez2021; Safont et al., Reference Safont, Garriga, Amoretti, Cuesta, Parellada, González-Pinto, Bergé, Rodriguez-Jimenez, Bejarano, Sarró, Ibáñez, Usall, Gutiérrez, Vieta, Arranz, Berrocoso, Verdolini and Bernardo2022).
Built on the rationale described above, in this paper, we aimed to evaluate the clinical presentation and characteristics of a cohort of FEP according to their profile of OCs.
Material and methods
Study setting
This study is part of the multicentre Project ‘Phenotype–genotype interaction: application of a predictive model in first psychotic episodes’, the PEPs study, which is a longitudinal cohort study examining gene–environment (G×E) interactions on the pathway to psychosis. A complete description of the PEPs protocol has been published previously (Bernardo et al., Reference Bernardo, Cabrera, Arango, Bioque, Castro-Fornieles, Cuesta, Lafuente, Parellada, Saiz-Ruiz and Vieta2019, Reference Bernardo, Bioque, Parellada, Ruiz, Cuesta, Llerena, Sanjuán, Castro-Fornieles, Arango and Cabrera2013).
The PEPs Project incorporates clinical parameters from various assessments/visits: baseline, 2-month, 6-month, 1-year and 2-year follow-up. For the present study, we have focussed on baseline visits.
Subjects
Three-hundred thirty-five FEP patients were included in the PEPs Project, running between 2009 and 2011 at 16 Spanish hospitals that participated in the Biomedical Research Networking Center for Mental Health (CIBERSAM) (Salagre et al., Reference Salagre, Arango, Artigas, Ayuso-Mateos, Bernardo, Castro-Fornieles, Bobes, Desco, Fañanás, González-Pinto, Haro, Leza, Mckenna, Meana, Menchón, Micó, Palomo, Pazos, Pérez, Saiz-Ruiz, Sanjuán, Tabarés-Seisdedos, Crespo-Facorro, Casas, Vilella, Palao, Olivares, Rodriguez-Jimenez and Vieta2019), which is following up a cohort of patients with FEP (Fraguas & Díaz-Caneja, Reference Fraguas and Díaz-Caneja2021). From those 335 patients recruited initially, due to missing data required for the analyses, only 277 were included in the study.
Patients were included if they met the following inclusion criteria: aged between 7 and 35 years old at recruitment; presence of psychotic symptoms of less than 12-month duration; the ability to speak Spanish correctly and providing written informed consent. The exclusion criteria were an Intelligent Quotient (IQ) lower than 70 and with significant difficulties or malfunctioning with adaptive processes, history of head trauma with loss of consciousness and the presence of an organic disease. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and adhered to Good Clinical Practice guidelines. Ethics committees of all participating centres approved the current study. As inclusion criteria, informed consent was obtained from all participants or from parents or legal guardians of under-age subjects.
Antipsychotic treatment
As most of the participating centers were tertiary university hospitals, a large majority of the patients included in the study were recruited during their first hospitalisation, when the first anti-psychotic treatment was initiated. In the whole sample recruited, the majority of the patients (n = 304, 90.7%) were taking antipsychotic treatment by the time they were included in the study, with a mean 54.08 days of treatment (Bioque et al., Reference Bioque, Llerena, Cabrera, Mezquida, Lobo, González-Pinto, Díaz-Caneja, Corripio, Aguilar, Bulbena, Castro-Fornieles, Vieta, Lafuente, Mas, Parellada, Saiz-Ruiz, Cuesta, Bernardo, Gassó, Amoretti, García Bernardo, Tapia-Casellas, Alonso-Solís, Grasa, Hernández, González, Ruiz, Modrego, Escartí, Mané, Torrent, Baeza, Contreras, Albacete, Bobes, García-Portilla, Zabala Rabadán, Segarra Echevarría, Rodriguez-Jimenez, Morales-Muñoz, Butjosa, Landin-Romero, Sarró, Ibáñez, Sánchez-Torres and Balanzá-Martínez2016). Only a small proportion (n = 49, 14.6% of the sample) had been taking antipsychotic for more than 3 months before the inclusion. A previous report gave a full description of the psychopharmacological treatment used in this study (Bioque et al., Reference Bioque, Llerena, Cabrera, Mezquida, Lobo, González-Pinto, Díaz-Caneja, Corripio, Aguilar, Bulbena, Castro-Fornieles, Vieta, Lafuente, Mas, Parellada, Saiz-Ruiz, Cuesta, Bernardo, Gassó, Amoretti, García Bernardo, Tapia-Casellas, Alonso-Solís, Grasa, Hernández, González, Ruiz, Modrego, Escartí, Mané, Torrent, Baeza, Contreras, Albacete, Bobes, García-Portilla, Zabala Rabadán, Segarra Echevarría, Rodriguez-Jimenez, Morales-Muñoz, Butjosa, Landin-Romero, Sarró, Ibáñez, Sánchez-Torres and Balanzá-Martínez2016). The prescribed daily dose (PDD) for a drug was defined as the daily dose of a drug formulation, oral or injectable, calculated separately for each treatment day of an individual patient who was treated with this drug formulation for at least three consecutive days (irrespective of the dose). To compare the different antipsychotics, the PDDs doses of antipsychotics were converted to an estimated daily equivalent doses of chlorpromazine (CPZ) following the international consensus (Gardner et al., Reference Gardner, Murphy, O’Donnell, Centorrino and Baldessarini2010).
Clinical assessments
At baseline, a complete psychiatric personal and family history was performed in a systematic interview, including OCs registration, substance use and traumatic experiences.
Clinical symptomatology was assessed using the Spanish-validated version of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) (Peralta & Cuesta, Reference Peralta and Cuesta1994), a semi-structured interview with 30 items rated on a seven-point scale.
Drug use was evaluated by a part of the European Adaptation of a Multidimensional Assessment Instrument for Drug and Alcohol Dependence (EuropAsi) (Kokkevi & Hartgers, Reference Kokkevi and Hartgers1995). In the inclusion visit, a systematic register of drug misuse habits was performed. For the present study, we focussed on cannabis consumption, and we registered its use as dichotomous exposure or no exposure. The number of traumatic experiences was collected from the list of events that appear in the Traumatic Experiences in Psychiatric Outpatients Questionary (TQ) (Davidson & Smith, Reference Davidson and Smith1990). This tool is an 18-item self-reported questionnaire that assesses the presence of stressful events across the lifespan. As Mas et al. (Reference Mas, Boloc, Rodríguez, Mezquida, Amoretti, Cuesta, González-Peñas, García-Alcón, Lobo, González-Pinto, Corripio, Vieta, Castro-Fornieles, Mané, Saiz-Ruiz, Gassó, Bioque and Bernardo2020) highlighted, due to the high heterogeneity of traumatic experiences on the item list, we only recorded the total number of experiences. These data were encoded and registered as ‘No exposure’ (non-traumatic experiences during childhood) and ‘Any exposure’ (one or more traumatic experiences during childhood) (Vassos et al., Reference Vassos, Sham, Kempton, Trotta, Stilo, Gayer-Anderson, Di Forti, Lewis, Murray and Morgan2019; Mas et al., Reference Mas, Boloc, Rodríguez, Mezquida, Amoretti, Cuesta, González-Peñas, García-Alcón, Lobo, González-Pinto, Corripio, Vieta, Castro-Fornieles, Mané, Saiz-Ruiz, Gassó, Bioque and Bernardo2020).
Obstetric complications
OCs were assessed using the Lewis–Murray scale through familiar interviews (Lewis et al., Reference Lewis, Owen, Murray, Schulz and Tamminga1989). This approach has proved accurate in previous samples (Borrajo et al., Reference Borrajo, Zandio, Zarzuela, Serrano, Rosa, Fañanás, Peralta and Cuesta2011). The Lewis–Murray scale allows describing adverse events as absent, equivocal or definite. We only included definite scores as present ones. The scale also groups OCs into three categories, A, B and C (Cannon et al., Reference Cannon, Jones and Murray2002; Mezquida et al., Reference Mezquida, Fernandez-Egea, Treen, Mane, Berge, Savulich, Garcia-Alvarez, Garcia-Portilla, Bobes, Bernardo, Garcia-Rizo, Mané, Bergé, Savulich, Garcia-Alvarez, García-Portilla, Bobes, Bernardo and Garcia-Rizo2018) according to the type of complication defined as follows:
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A. Complications of pregnancy (syphilis or rubella, rhesus isoimmunisation/Rh incompatibility, severe preeclampsia, requiring hospitalisation or induction of labour and bleeding before delivery of threatened abortion);
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B. Abnormal foetal growth and development (twin delivery, preterm birth week less than 37 weeks or long-term birth week of more than 42 weeks, weight at birth less than 2500 g and any important physical abnormality);
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C. Difficulties in delivery (including premature rupture of membranes, duration of delivery more than 36 h or less than 3 h, umbilical cord prolapse, complicated caesarean delivery, abnormal foetal presentation, use of forceps and being in an incubator for more than 4 weeks).
Statistical analysis
Socio-demographic and other descriptive variables were assessed through univariate analyses. As for OCs, both the total numbers as well as their subtypes (A, B and C) were considered as dichotomic variables (yes/no). The Total-T group comprehended all the OCs. Particularly, as we were interested in evaluating the effect of OCs according to their timing of appearance, we created another group for analysis purposes, viz., any OC during gestation AB (from the combination of groups A and B).
To assess differences among patients with or without OCs in terms of psychopathology, independent t-test analyses of the PANSS and its subscales between the groups studied (OCs and their subtypes) were performed. Then, analyses of covariance (one-way ANCOVA) were performed to remove possible confounding factors in the association between OCs and psychopathology. In the model, PANSS subscales (positive, negative or general psychopathology) or total PANSS score were included as the dependent variable, OCs and their subtypes, age, sex, cannabis use (yes/no), childhood adversity (yes/no) and CPZ dosage were included as the independent variables.
The Statistical Package for Social Science (SPSS) version 23.0 (IBM Corp., Armonk, NY, USA) was used for statistical analyses. All statistical tests were two-tailed, and significance was determined at the 0.05 level.
Results
Clinical and socio-demographic characteristics of the sample are described in Table 1.
Table 1. Clinical and socio-demographic characteristics of the sample
PANSS, positive and negative syndrome scale SD, standard deviation.
As outlined in the Methods section, the Lewis–Murray scale items are described as present only if the definite value was confirmed. The description represents the proportion of patients with abnormalities in each group out of the total evaluated. The reduction in the number of subjects is due to the consideration of missing data when at least one of the abnormalities accounting in a group was missing, and at the same time, none of them was present.
In Table 2, there is a description of the clinical differences measured by the PANSS subscales/total scale scores between groups in relation to the presence (yes) or absence (no) of the described events. Overall, patients who were exposed to stressful events during the perinatal period displayed a more severe psychopathological profile than patients who did not experience them (except for negative symptomatology in A-complications in pregnancy). Besides the significant outcomes in Table 2, subjects with difficulties during the whole pregnancy period (AB) presented with differences which showed a trend towards significance in positive subscale (p = 0.064) and total score (p = 0.053). For difficulties in delivery, the positive subscale also showed differences with a trend towards significance (p = 0.083). However, neither of them displayed a significant association when included in the regression analyses.
Table 2. Comparisons between groups depending on the presence (yes) or absence (no) of obstetric complications
Lewis A, complications of pregnancy; Lewis AB, any obstetric complication during pregnancy; Lewis B, abnormal fetal growth and development; Lewis C, difficulties in delivery; Lewis T, total; PANSS, positive and negative syndrome scale; SD, standard deviation.
*p < 0.05, ^p < 0.10.
We then performed a regression analyses (one-way ANCOVA). Only models in which PANSS and its subscales were significantly different among OCs groups are reported.
For difficulties during the whole pregnancy period, when we considered the PANSS general subscale as the dependent variable, the following independent variables, that is, LewisAB (F = 4.054; p = 0.045) and daily equivalent doses of CPZ (F = 7.362; p = 0.007) were significantly associated, while age (F = 0.702; p = 0.403), sex (F = 0.211; p = 0.646), cannabis use (F = 0.839; p = 0.361) and childhood adversity (F = 0.588; p = 0.444) were not associated.
For difficulties during delivery, when we considered the PANSS general subscale as the dependent variable, the following independent variables, Lewis C (F = 6.826; p = 0.010) and daily equivalent doses of CPZ (F = 7.885; p = 0.005) were significantly associated, while age (F = 0.791; p = 0.375), sex (F = 0.565; p = 0.453), cannabis use (F = 1.306; p = 0.255) and childhood adversity (F = 0.415; p = 0.520) were not associated. When considering the PANSS total scale as the dependent variable, Lewis C (F = 4.795; p = 0.030) and daily equivalent doses of CPZ (F = 10.119; p = 0.002), were significantly associated, while age (F = 0.968; p = 0.326), sex (F = 0.080; p = 0.778) cannabis use (F = 0.997; p = 0.319) and childhood adversity (F = 0.878; p = 0.350) were not.
For OCs taken all together, when considering the PANSS positive subscale as the dependent variable, LewisT (F = 6.950; p = 0.009) was significantly associated, while daily equivalent doses of CPZ (F = 3.384; p = 0.067), age (F = 0.466; p = 0.496), sex (F = 2.027; p = 0.156), cannabis use (F = 3.113; p = 0.079) and childhood adversity (F = 0.050; p = 0.824) were not associated. When considering the PANSS general subscale as the dependent variable, the following independent variables, Lewis T (F = 7.755; p = 0.006) and daily equivalent doses of CPZ (F = 6.818; p = 0.010) were significantly associated, while age (F = 1.185; p = 0.278), sex (F = 0.947; p = 0.332), cannabis use (F = 0.1.065; p = 0.303) and childhood adversity (F = 0.754; p = 0.386) were not associated. Finally, when considering the PANSS total scale as the dependent variable, the independent variables Lewis T (F = 6.608 p = 0.011) and daily equivalent doses of CPZ (F = 9.053; p = 0.003) were significantly associated, while age (F = 1.434; p = 0.232), sex (F = 0.193; p = 0.661), cannabis Use (F = 0.682; p = 0.410) and childhood adversity (F = 1.375; p = 0.242) were not associated.
Discussion
The findings from our study show a worse psychopathological profile among people with FEP that experienced difficulties during the perinatal period compared with patients who were not exposed to them. These results confirm the association between OCs and the presentation of clinical symptomatology in a cohort of FEP. Notably, our results were not confounded by other known risk factors such as age, sex, cannabis use or stressful childhood events.
Compared with patients who were not exposed to perinatal stress, patients that experienced difficulties during delivery displayed a more severe psychopathological profile in relation to total PANSS score but also for the three subscales, positive, negative and general psychopathology. All were statistically significant except for the positive symptom subscale, which only showed a trend towards significance. However, when co-varied by all the potential confounders, only PANSS general psychopathology and total score maintained significant associations. Similar findings were observed when all the OC variables were considered. In this case, patients who presented OCs displayed a statistically significant difference in clinical profile. However, when the covariates were included in the analysis, the PANSS negative subscale did not retain its significant association, while the rest did (positive, general subscale, and total scale score). Patients with difficulties during the whole pregnancy period also displayed a worse clinical profile, which proved significant in the general psychopathology subscale and maintained its association when covariates were included in the statistical model. Thus, in our sample, perinatal risk factors are associated with the general psychopathology subscale and the total PANSS score.
Our results are in line with previous findings; in chronic schizophrenia patients, difficulties in delivery have been associated with more severe symptomatology from the general psychopathological subscale from the PANSS (Mezquida et al., Reference Mezquida, Fernández-Egea, Treen, Mané, Bergé, Savulich, García-Álvarez, García-Portilla, Bobes, Bernardo and García-Rizo2021), while the lower Apgar score, which is a simple and objective method evaluating the degree of birth asphyxia, was associated with negative symptoms in early-onset schizophrenia (Kotlicka-Antczak et al., Reference Kotlicka-Antczak, Gmitrowicz, Sobów, Rabe-Jabłonska and Rabe-Jabłońska2001). Although other similar results were described, they considered OCs as a unique construct and did not differentiate between pregnancy and delivery periods (Kotlicka-Antczak et al., Reference Kotlicka-Antczak, Gmitrowicz, Sobów, Rabe-Jabłonska and Rabe-Jabłońska2001; Borkowska & Rybakowski, Reference Borkowska and Rybakowski2002; Jones et al., Reference Jones, Gallagher, Moss and McFalls2011). Although Mechri and associates (Mechri et al., Reference Mechri, Mrad, Mokni, Gaddour, Letaif and Gaha2008) reported that higher sub-scores were observed during the period of childbirth, no further specification was obtained in relation with psychopathology besides more severe negative symptomatology. In contrast to other studies, we did not find any difference in relation to sex (Gallagher et al., Reference Gallagher, Jones and Eaton2014). As expected, the antipsychotic dose evaluated in CPZ equivalents was also associated with the clinical psychopathology. Indeed, one study suggested that the use of risperidone resulted in better compensation of psychopathological deficits (negative symptoms) in patients who had OCs (Borkowska & Rybakowski, Reference Borkowska and Rybakowski2002).
Our results rely mostly on an increased effect of OCs in the general psychopathology score and not in relation to negative symptomatology, as emphasised in previous studies. An important issue that needs to be taken into account, particularly in this study, is the ‘type of psychotic patient’ included, because only one previous study described symptomatology in non-affective FEP (Bernardini et al., Reference Bernardini, Wan, Crisafio, Massey and Compton2015). Notably, around 17% of individuals with first-episode non-affective psychosis ‘shift’ to affective psychosis over time (Kim et al., Reference Kim, Baek, Choi, Lee, Kwon and Hong2011) and OCs have been related to clinical presentation in affective disorders (Mackay et al., Reference Mackay, Anderson, Pell, Zammit and Smith2017). The general psychopathology score captures a wide array of symptoms of psychopathology, which could be referred to as transdiagnostic and OCs have been associated with a wide psychopathological presentation in childhood and adolescence (Roffman et al., Reference Roffman, Sipahi, Dowling, Hughes, Hopkinson, Lee, Eryilmaz, Cohen, Gilman, Doyle and Dunn2021). As previously described in metabolism (Garcia-Rizo et al., Reference Garcia-Rizo, Kirkpatrick, Fernandez-Egea, Oliveira and Bernardo2016), our results do not suggest a specific association between perinatal events and psychosis but with serious mental disorders.
Difficulties during delivery are often related to birth asphyxia, a condition with potentially fatal consequences (Graham et al., Reference Graham, Ruis, Hartman, Northington and Fox2008). In psychosis, birth asphyxia has been described as a risk factor for developing psychosis (Radua et al., Reference Radua, Ramella-Cravaro, Ioannidis, Reichenberg, Phiphopthatsanee, Amir, Yenn Thoo, Oliver, Davies, Morgan, McGuire, Murray and Fusar-Poli2018; Pugliese et al., Reference Pugliese, Bruni, Carbone, Calabrò, Cerminara, Sampogna, Luciano, Steardo, Fiorillo, Garcia and De Fazio2019; Davies et al., Reference Davies, Segre, Estradé, Radua, De Micheli, Provenzani, Oliver, Salazar de Pablo, Ramella-Cravaro, Besozzi, Dazzan, Miele, Caputo, Spallarossa, Crossland, Ilyas, Spada, Politi, Murray, McGuire and Fusar-Poli2020) with long-term implications. Recent studies have shown its effect in neuroanatomy in schizophrenia (Wortinger et al., Reference Wortinger, Engen, Barth, Andreassen, Nordbø Jørgensen and Agartz2020) and also in bipolar disorder (Haukvik et al., Reference Haukvik, McNeil, Lange, Melle, Dale, Andreassen and Agartz2014). Indeed research in animal models has studied the interaction between perinatal asphyxia and schizophrenia risk genes (Wakuda et al., Reference Wakuda, Iwata, Iwata, Anitha, Takahashi, Yamada, Vasu, Matsuzaki, Suzuki and Mori2015; Paparelli et al., Reference Paparelli, Iwata, Wakuda, Iyegbe, Murray and Takei2017). In the general population, birth asphyxia has been associated with unspecific psychopathology such as hyperexcitability, irritability, timidity, aggressiveness, reduced activity, concentration and motivation (Nabieva, Reference Nabieva2009). Furthermore, birth asphyxia is a risk factor widely described not only for schizophrenia (Dalman et al., Reference Dalman, Thomas, David, Gentz, Lewis and Allebeck2001; Pugliese et al., Reference Pugliese, Bruni, Carbone, Calabrò, Cerminara, Sampogna, Luciano, Steardo, Fiorillo, Garcia and De Fazio2019) but also for other pathologies such as personality disorder (Fazel et al., Reference Fazel, Bakiyeva, Cnattingius, Grann, Hultman, Lichtenstein and Geddes2012) and pervasive developmental disorders (Van Handel et al., Reference Van Handel, Swaab, De Vries and Jongmans2007).
Several limitations need to be highlighted when considering our findings. OCs were not recorded at birth but retrospectively in a familiar interview, which has been accepted as valid in a psychosis sample (Borrajo et al., Reference Borrajo, Zandio, Zarzuela, Serrano, Rosa, Fañanás, Peralta and Cuesta2011). OCs were categorised from a clinical scale and further information regarding the timing and duration of the insult is required (Ellman et al., Reference Ellman, Murphy, Maxwell, Calvo, Cooper, Schaefer, Bresnahan, Susser and Brown2019). The heterogeneity of methods evaluating OCs should be considered. While our approach is based on the Lewis–Murray scale, other authors evaluated OCs with the McNeil–Sjostrom questionnaire (Mechri et al., Reference Mechri, Mrad, Mokni, Gaddour, Letaif and Gaha2008) while others directly obtained OCs from the “social history” section of the hospital records (Jones et al., Reference Jones, Gallagher, Moss and McFalls2011).
When considering all the results, we note that difficulties during delivery are more related to psychopathology than difficulties during the pregnancy period, suggesting an important effect of labour complications on patient outcomes later in life. Our results have interesting implications in terms of early intervention services/strategies in psychosis, as patients at initial stages with a background of OCs and unspecified symptomatology shall be closely monitored due to the heterogeneity of the clinical presentation of psychosis.
Conclusions
Our results confirm that the presence of difficulties during the perinatal period is associated with a more severe clinical presentation at onset and in the first stages of the illness. Our approach to differentiating the events according to the timing of the event distinguished the effect of difficulties during pregnancy and during delivery into different clinical areas. Our results highlight the need of describing the timing of the event during the perinatal period to better understand its impact on the clinical presentation at onset. This might help to have a greater understanding of its impact on the clinical and functional outcome, giving way to the design and the implementation of early and personalised interventions with the potential to modulate the outcome of schizophrenia following a first episode of the disease.
Acknowledgements
The authors would like to thank the participants for their willingness to be part of this study.
Authors contributions
MB wrote the protocol. NV, GM, CGR and IV designed the study and wrote the first draft of the manuscript. BB and MC critically revised the first draft of the manuscript. MC, EV, MB, AL, AG-P, L P-C, IC, MG, IB and L M-S drafted the second draft of the manuscript. All authors contributed to and have approved the final manuscript.
Financial support
This study is part of a coordinated-multicentre Project, funded by the Ministerio de Economía y Competitividad (PI08/0208; PI11/00325; PI14/00612), Instituto de Salud Carlos III – Fondo Europeo de Desarrollo Regional. Unión Europea. Una manera de hacer Europa, Centro de Investigación Biomédica en Red de salud Mental, CIBERSAM, Instituto de Salud Carlos III, by the CERCA Programme/Generalitat de Catalunya and Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (2017SGR1355). Departament de Salut de la Generalitat de Catalunya, en la convocatoria corresponent a l’any 2017 de concessió de subvencions del Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016–2020, modalitat Projectes de recerca orientats a l’atenció primària, amb el codi d’expedient SLT006/17/00345. This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project “PI20/00661” and co-funded by the European Union. NV has received financial support for CME activities and travel funds from the following entities (unrelated to the present work): Angelini, Janssen-Cilag, Lundbeck and Otsuka. Dr. Verdolini thanks the BITRECS project, which has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 754550 and from “La Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN18/50310006.IV is supported by a BITRECS fellowship that received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 754 550 and from “La Caixa” Foundation, under the agreement LCF/PR/GN18/5031000. CGR has received grants from/or served as consultant, advisor or speaker for the following entities Adamed, Angelini, Casen-Recordati, Janssen-Cilag and Lunbeck.EV has received research support from or served as consultant, adviser or speaker for AB-Biotics, Actavis, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Ferrer, Forest Research In- stitute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lund- beck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefónica, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), and the Stanley Medical Research Institute, unrelated to the present work. MB has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of, has received honoraria from talks and/or consultancy of Adamed, Angelini, Ferrer, Janssen-Cilag, Lundbeck, Otsuka, Pfizer and Sanofi. AG-P has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Alter, An- gelini, Exeltis, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. MG served as a consultant or advisor for Ferrer, Lundbeck and Janssen. IB has received honoraria or travel support from Otsuka-Lundbeck, Angelini and Janssen, research support from Fun-dación Alicia Koplowitz and grants from Spanish Ministry of Health, Instituto de Salud Carlos III. MB has been a consultant for received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, AMGEN, Eli Lilly, Ferrer, Forum Pharmaceuticals, Gedeon, Janssen-Cilag, Lundbeck, Otsuka, Pfizer and Roche.
Statements and declarations
The datasets generated during and/or analysed during the current study are available from the corresponding author on request.
Appendix
*PEPs group: Silvia Amoretti 1,21, Florencia Forte 1,2, Jessica Merchán-Naranjo7, Elena Urbiola7, Anna Alonso-Solís8, Eva Grasa8, Iñaki Zorrilla6, Edurne García Corres6, Concepcion De la Camara5, Pedro M Ruiz-Lazaro5, Maria Jose Escarti12, Olga Rivero12, Amira Trabsa9, Teresa Legido9, Maria Serra3, Maria Sague-Vilella3, Elena de la Serna3, J Castro-Fornielles3, Fernando Contreras13, Mª Paz García-Portilla14, Pilar Saiz14 , Rafael Segarra 15, Arantzazu Zabala15, Luis Sanchez-Pastor16, Roberto Rodriguez-Jimenez16, Judith Usall17, Anna Butjosa17, Salvador Sarró18, Edith Pomarol-Clotet18, Angela Ibañez19, AM Sanchez-Torres4, Vicent Balanzá-Martínez20
1Bipolar and Depressives Disorder Unit, Hospital Clinic de Barcelona, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
2 Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, Clinical Institute of Neuroscience, University of Barcelona, CIBERSAM, IDIBAPS, Barcelona, Spain.
3Child and Adolescent Psychiatry and Psychology Department, Hospital Clinic of Barcelona, Institute of Neurosciences, CIBERSAM, IDIBAPS, University of Barcelona, Barcelona, Spain.
4 Department of Psychiatry, Navarre Hospital Complex, IdiSNA, Navarre Institute for Health Research, Pamplona, Spain.
5 Department of Medicine and Psychiatry, Universidad de Zaragoza; Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza; CIBERSAM, Madrid, Spain.
6 Hospital Universitario de Alava, Servicio de Psiquiatría, BIOARABA, CIBERSAM,University of the Basque Country, Spain.
7Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, CIBERSAM, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain.
8 Department of Psychiatry, CIBERSAM, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
9 Hospital del Mar Medical Research Institute (IMIM), Autonomous University of Barcelona, CIBERSAM, Barcelona, Spain.
10 The University of Manchester Humanitarian and Conflict Response Institute, UK.
11 Department of Psychiatry, RCSI University of Medicine and Health Science, Dublin, Ireland.
12 Servicio de Psiquiatría, Hospital Universitario Doctor Peset, Universitat de València, CIBERSAM, Valencia, Spain.
13 Psychiatry Department, Bellvitge University Hospital-IDIBELL; University of Barcelona, Barcelona, CIBERSAM, Barcelona, Spain.
14 Department of Psychiatry, School of Medicine, CIBERSAM, University of Oviedo, Spain.
15 Department of Neurosciences, University of the Basque Country, UPV/EHU; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM; Department of Psychiatry, Cruces University Hospital, BioCruces Health Research Institute, Spain.
16 Instituto de Investigación Hospital 12 de Octubre (i + 12), Madrid, Spain; CIBERSAM, Spain.
17 Parc Sanitari Sant Joan de Déu, Teaching, Research & Innovation Unit, Sant Boi de Llobregat, Barcelona; CIBERSAM, Sant Joan de Déu Research Foundation, Esplugues de Llobregat, Barcelona; Department of Personality, Evaluation and Psychological Treatment, Faculty of Psychology, University of Barcelona, Spain.
18 FIDMAG Hermanas Hospitalarias Research Foundation. Network Centre for Biomedical Research in Mental Health (CIBERSAM), Spain.
19 Servicio de Psiquiatría, Hospital Ramón y Cajal, Universidad de Alcalá, CIBERSAM, IRYCIS, Madrid, Spain.
20 Clinic Hospital (INCLIVA), Valencia, Spain.
21 Group of Psychiatry, Mental Health and Addictions, Psychiatric Genetics Unit, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain; Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
22 Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain.
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