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ScienceDirect Comprehensive Psychiatry 55 (2014) 861 – 865 www.elsevier.com/locate/comppsych
Neuroinf lammation in the fetus exposed to maternal obsessive– compulsive disorder during pregnancy: A comparative study on cord blood tumor necrosis factor-alpha levels Faruk Uguz a,⁎, Erdem Onder Sonmez a , Mine Sahingoz a , Zeynel Gokmen b , Mustafa Basaran c , Kazim Gezginc d , Gulsum Sonmez b , Nazmiye Kaya a , Emre Yilmaz a , Sami Sait Erdem e , Hasan Haluk Dulger f , Humeyra Cicekler f , Erkan Tasyurek f a
Department of Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey b Department of Neonatology, Konya Research and Training Hospital, Konya, Turkey c Department of Obstetrics and Gynecology, Konya Research and Training Hospital, Konya, Turkey d Department of Obstetrics and Gynecology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey e Department of Biochemistry, Konya Research and Training Hospital, Konya, Turkey f Department of Biochemistry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
Abstract Objective: The relationship between maternal psychiatric disorders and fetal neurodevelopment is unclear. Obsessive–compulsive disorder (OCD) is relatively frequent during pregnancy. The study aimed to investigate whether maternal OCD during pregnancy affects fetal circulating tumor necrosis factor-alpha (TNF-α) levels, an important pro-inflammatory cytokine, by comparing cord blood TNF-α levels in newborn infants of women with and without OCD. Methods: The study sample included 7 women with OCD and 30 healthy women. OCD and other psychiatric diagnoses were screened by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The blood sample for the determination of TNF-α level was obtained from the umbilical cord during delivery. Results: Cord blood TNF-α levels in newborn infants exposed to maternal OCD were significantly higher compared to non-exposed infants. Maternal anxiety symptom level was found to positively correlate with cord blood TNF-α levels in newborn infants of women with OCD. Conclusion: The study results imply that maternal OCD during pregnancy may lead to neuroinflammation in the developing fetal brain through higher levels of circulating TNF-α. © 2014 Elsevier Inc. All rights reserved.
1. Introduction
⁎ Corresponding author at: Necmettin Erbakan Üniversitesi Meram Tıp Fakültesi, Psikiyatri Anabilim Dalı, Akyokuş, 42080, Konya, Turkey. Tel.: +90 332 223 6306. E-mail addresses: [email protected] (F. Uguz), [email protected] (E. Onder Sonmez), [email protected] (M. Sahingoz), [email protected] (Z. Gokmen), [email protected] (M. Basaran), [email protected] (K. Gezginc), [email protected] (G. Sonmez), [email protected] (N. Kaya), [email protected] (E. Yilmaz), [email protected] (S.S. Erdem), [email protected] (H.H. Dulger), [email protected] (H. Cicekler), [email protected] (E. Tasyurek). 0010-440X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.comppsych.2013.12.018
Although there are growing scientific data on the relationship between psychiatric disorders and neonatal outcomes, compared to depression, anxiety disorders have been studied relatively less. Obsessive–compulsive disorder (OCD) is a frequently observed psychiatric disorder during pregnancy. Its prevalence rate has been reported to vary between 0.2% and 5.2% in the pregnancy period [1–8]. A number of studies have addressed the role of anxiety symptoms on fetal outcome. Recently, a case–control study suggested that maternal generalized anxiety disorder was associated with intrauterine growth restriction [9]. Moreover, some authors have reported that maternal anxiety influences
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fetal cerebral circulation [10]. Infants prenatally exposed to maternal stress are more likely to have behavioral, cognitive and emotional problems but the mechanisms accounting for the influence of maternal stress are not fully understood [11,12]. However, to our knowledge, there is no study examining the effects of OCD, a prevalent disorder anxiety disorder associated with considerable anxiety and psychological stress, on fetal development. Pro-inflammatory cytokines may influence neurogenesis and impair hippocampal plasticity [13]. Tumor necrosis factor alpha (TNF-α), is an important pro-inflammatory cytokine that has been shown to exert critical functions in survival, proliferation and neuronal differentiation of neural progenitor cells [14]. In vitro studies have suggested that TNF-α has a negative effect on embryonic and adult neurogenesis [15,16]. In addition, Seguin et al. [13] reported a marked reduction in hippocampal cellular proliferation following a systemic administration of TNF-α. Moreover, proinflammatory cytokines such as TNF-α are reported to be associated with the development cerebral palsy and neonatal brain white matter lesions [17–19]. The relationship between psychiatric disorders and TNF-α has been widely examined. However, most of the studies include mood disorders. A meta-analysis demonstrated that depressed subjects have higher concentrations of TNF-α compared to control subjects [20]. Several studies have examined levels of TNF-α in anxiety disorders, but data on OCD are controversial [21–25]. Arranz et al. [26] reported that in anxious women, TNF-α was released more. On the other hand, the stress responses involve the release of TNF-α, which in turn results in an enhanced release of corticotropin-releasing hormone (CRH) [20]. For those patients suffering from OCD during pregnancy, it may be possible for the fetus to be affected by maternal OCD. Therefore we have hypothesized that maternal OCD may affect fetal neurogenesis via alterations in circulating TNF-α levels. In this study, we aimed to investigate TNF-α levels in the cord blood of newborn infants of mothers with and without OCD during pregnancy. 2. Methods 2.1. Subjects The study was carried out among women who delivered by elective caesarean section at the Obstetric Clinic of Konya Research and Training Hospital in Konya, Turkey, and the Obstetric Clinic of Meram Faculty of Medicine of Necmettin Erbakan University in Konya, Turkey. The study sample comprised 7 women with a diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [27] uncomplicated with any other psychiatric disorder and 30 control women without any psychiatric diagnosis who met the study criteria and who delivered at the same clinic. The inclusion criteria for the study were the following: voluntary participation to the study and current age between 18 and 40 years, a history of medical
illnesses (e.g., endocrine abnormalities, cardiovascular and pulmonary system diseases, neurological disease and metabolic disease), a history of pregnancy related complications (e.g., gestational hypertension, imminent abortion, placenta previa and other placental abnormalities, vaginal bleeding, and gestational diabetes), any malformation in newborn infants, a history of maternal infection which can negatively affect fetal growth (e.g., toxoplasma, rubella, cytomegalovirus, herpes simplex, mycoplasma and chlamydia), the existence of any active maternal infection, having mental retardation, the existence of multiple pregnancies, the existence of intrauterine growth restriction, low birth weight, preterm delivery or emergency caesarean section, a history of bipolar affective disorder, schizophrenia or related psychotic disorders, the existence of comorbidity with depressive and other anxiety disorders reported smoking or alcohol consumption during pregnancy, use of systemic corticosteroids during pregnancy such as betamethasone dipropionate, use of any psychotropic medication during pregnancy, and the existence of hypoxia in the baby during childbirth were exclusion criteria. The study procedure was approved by the ethics committee of Meram Faculty of Medicine of Necmettin Erbakan University. 2.2. Assessments The sociodemographic and obstetric characteristics were recorded with a semistructured interview form developed by the authors. To determine OCD and other psychiatric disorders the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)(SCID-I) [28] was used. The gestational age at delivery was calculated on the basis of the date of last menstruation. The indication or plan of elective caesarean section was independent from the study procedure. Anxiety symptom levels were assessed with the Beck Anxiety Inventory (BAI) [29]. 2.3. Procedures Initially, the objectives and procedures of the study were explained to all participants, and written informed consent forms were obtained. After the sociodemographic and obstetric features of the participants hospitalized for elective caesarean section were recorded, a psychiatric interview by means of SCID-I was carried out by psychiatrists with at least 4 years of experience on psychiatric disorders and the diagnostic instruments. The severity of anxiety symptoms in the women with OCD but not the control subjects were assessed with BAI. During the caesarean section, a blood sample for TNF analysis was obtained from the umbilical cord by a pediatry specialist. The blood was immediately centrifuged for 10 min at 3000 × g and 4 °C. The serum was stored at − 80 °C until measured. Serum TNF-α concentrations were determined by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions (Boster, Inc.).
F. Uguz et al. / Comprehensive Psychiatry 55 (2014) 861–865
2.4. Statistical analysis The data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 16.0, for Windows. All variables were tested with the Kolmogorov–Smirnov test to determine whether the test distributions were normal or not. Categorical variables among the study groups were compared using the chi-square test or Fisher’s exact test when necessary. Comparisons for continuous variables were performed using t test or Mann–Whitney U test for abnormally distributed variables. Correlations related to TNF-α cord blood levels were assessed with Spearman’s correlation analysis. All significant levels were 2-tailed and set at the level of 0.05.
3. Results The mean age of the participants (n = 37) was 26.70 ± 5.06 years. All women were married, mostly primary school graduates (n = 30, 81.1%) and unemployed (n = 30, 81.1%). The mean number of children was 1.91 ± 0.86, and the mean gestation length at delivery was 39.35 ± 1.41 weeks. Nine women (23.3%) were primiparous. The type of anesthesia performed at caesarean section was general in 17 (45.9%) and epidural in 20 (54.1%) subjects. The proportion of male gender of babies was 59.5%. All of the women with OCD reported an onset of the disorder prior
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to the pregnancy. The mean total duration of OCD was 76.02 ± 59.38 weeks. Table 1 presents the sociodemographic features and cord blood TNF-α levels in the study groups. There were no a significant differences between the study groups with regard to age, employment status, family income level, gender of the baby, number of children, type of anesthesia performed at caesarean section, gestational age and the proportion of primiparity. Birth weight was significantly lower in newborn infants of mothers with OCD compared to those of healthy mothers. The mean TNF-α levels in the cord blood of newborn infants of women with and without OCD were 96.43 ± 88.86 pg/ml and 14.19 ± 19.94 pg/ml, respectively. The difference between the groups was statistically significant (z = −2.09, P = 0.036). According to the correlation analyses, the cord serum TNF-α levels in newborn infants of women with OCD were unrelated to maternal age (r = 0.210, P = 0.212), number of children (r = 0.187, P = 0.267), duration of pregnancy (r = 0.030, P = 0.861), and birth weight of newborn infants (r = −0.082, P = 0.630). The correlation test indicated that cord serum TNF-α levels were positively associated with maternal BAI scores (r = 0.824, P = 0.006).
4. Discussion The main finding of the current study is the presence of higher levels of circulating TNF-α in fetuses that are exposed
Table 1 Sociodemographic and obstetrical characteristics of the study groups.
Age, mean ± SD, years Education, n (%) Primary school Secondary school University Employment status, n (%) Employed Family income level, n (%) Low (b$10,000/year) Moderate ($10,000–30,000/year) High (N$30,000/year) Primiparity, n (%) Type of anesthesia Epidural General Gender of baby Female Numbers of children, mean ± SD Gestational age at birth, mean ± SD Birth weight, g, mean ± SD Cord blood TNF-α levels, ng/ml
Women with OCD n=7
Healthy controls n = 30
P value
27.42 ± 3.51
27.93 ± 5.37
0.815 a 0.294 b
6 (85.7) 0 (0) 1 (14.3)
24 (80.0) 5 (16.7) 1 (3.3)
2 (28.6)
6 (20.0)
3 (42.9) 3 (42.9) 1 (14.3) 2 (28.6)
15 (50.0) 11 (36.7) 4 (13.3) 7 (23.3)
3 (42.9) 4 (57.1)
17 (56.7) 13 (43.3)
2 (28.6) 1.71 ± 0.76 38.71 ± 1.49 3147 ± 391 96.43 ± 88.86
13 (43.3) 1.86 ± 0.81 39.51 ± 1.38 3466 ± 335 14.19 ± 19.94
0.631 c 0.941 b
1.000 c 0.680 c
0.677 c
OCD: Obsessive–compulsive disorder TNF-α: Tumor necrosis factor-alpha. a t test. b χ 2 test. c Fisher’s exact test. d Mann–Whitney U test.
0.656 d 0.191 a 0.034 a 0.036 d
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to maternal OCD compared to the fetuses that are not exposed. To our knowledge, this is the first study on this topic. The circulating TNF-α levels in the fetus may be important with regard to brain development of the fetus. Subject to future confirmatory large scale studies, we propose that OCD in mothers during pregnancy may lead to chronic inflammation in the developing fetal brain. Chronic brain inflammation is related to detrimental and unfavorable conditions for neurogenesis [14]. Excessive inflammatory response triggered by pro-inflammatory cytokines may affect glial cell functions and neurotrophic systems and decrease neurogenesis [30]. Similarly, elevated levels of cytokines have been shown to interfere with glial cell development and proliferation in the late second trimester of pregnancy [18]. Exposure to inflammation during pregnancy or early in life may be associated with neurodegeneration, and increased risk of cerebral palsy, autism spectrum disorders, multiple sclerosis, cognitive disorders and schizophrenia [17]. Indeed, it has been reported that there is a role of developmental neuroinflammation in progressive brain changes to schizophrenia [31]. Moreover, a cohort study of Danish births suggested that severe stress to a mother during the first trimester of pregnancy may increase the risk of schizophrenia in the offspring [32]. For these reasons, we think that clinically significant OCD during pregnancy may not only affect mental status or quality of life of the mother but also brain development of in the fetus. The underlying mechanism for higher cord-blood TNF-α levels in newborn infants of mothers with OCD is currently unclear. The transplacental transport of TNF-α may be an explanation for the results. However, previous studies have shown mixed results regarding serum TNF-α levels in patients with OCD [22–24,33]. Recently, a meta-analysis has suggested no significant difference in plasma TNF-α levels in patients with and without OCD [24]. In addition, it has been reported that TNF-α exhibits no or minimal transfer from term placenta [34,35]. Consequently, to explain the elevated cord serum TNF-α solely on the basis of transplacental transport may not be adequate. Psychosocial stress may elevate plasma levels of several cytokines [36]. Some authors have reported that TNF-α levels were increased in women with anxiety [26], while others found that depression and anxiety symptoms during pregnancy were unrelated to the levels of proinflammatory cytokines [37]. Therefore, the connection between anxiety and TNF-α levels in pregnant women is unclear. In the current study, the cord serum TNF-α levels were positively correlated with the levels of anxiety symptoms. In other words, elevated maternal anxiety due to OCD may affect circulating TNF-α in fetus. Although underlying biological cause is unknown, we think that the higher levels of TNF-α in cord blood of infants exposed to prenatally maternal OCD may result from higher distressing status during their fetal period compared to nonexposed infants.
The present study has several limitations, which may affect the interpretation of the results. First, the sample size, particularly the number of women with OCD was small and included women who were admitted to the obstetric clinics for delivery. Therefore, it may not be representative of all pregnant women with OCD. Second, the study had a crosssectional design but not a prospective observation. For this reason, we did not determine the course of anxiety symptoms during the pregnancy. Third, we did not use any instruments to determine the severity of obsessive– compulsive symptoms. Anxiety symptom levels in women with OCD were assessed solely on the basis of BAI. Fourth, the sample composed of women with elective caesarean only because to determine the cord blood samples in newborn of women delivered with vaginal way was difficult in the clinics. However, this condition may consider as a limitation. Finally, we did not examine body mass index and its association with TNF-α levels in the pregnant women. In conclusion, the results of this study suggest that the circulating TNF-α level is significantly higher in those fetuses whose mothers have OCD compared to the fetuses of healthy mothers. In addition, the results imply that maternal OCD, particularly in those patients with higher anxiety levels, may lead to neuroinflammation in the fetal brain. However, the limitations of the current study preclude us from generalizing the effects of the higher circulating TNFα levels. Therefore, our results should be replicated by further prospective studies with larger sample size.
Role of funding source None.
Declaration of interest The authors have no conflict of interest with any commercial or other associations in connection with submitted paper. References [1] Adewuya AO, Ola BA, Aloba OO, Mapayi BM. Anxiety disorders among Nigerian women in late pregnancy: a controlled study. Arch Womens Ment Health 2006;9:325-8. [2] Andersson L, Sundström-Poromaa i, Bixo M, Wulff M, Bondestam K, Åström M. Point prevalence of psychiatric disorders during the second trimester of pregnancy: a population-based study. Am J Obstet Gynecol 2003;189:148-54. [3] Andersson L, Sundström-Poromaa i, Wulff M, Åström M, Bixo M. Depression and anxiety disorder during pregnancy and six months postpartum: a follow-up study. Acta Obstet Gynecol Scand 2006;85:937-44. [4] Borri C, Mauri M, Oppo A, Banti S, Rambelli C, Ramacciotti D, et al. Axis i psychopathology and functional impairment at the third month of pregnancy: results from the Perinatal Depression-Research and
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ScienceDirect Comprehensive Psychiatry 55 (2014) 861 – 865 www.elsevier.com/locate/comppsych
Neuroinf lammation in the fetus exposed to maternal obsessive– compulsive disorder during pregnancy: A comparative study on cord blood tumor necrosis factor-alpha levels Faruk Uguz a,⁎, Erdem Onder Sonmez a , Mine Sahingoz a , Zeynel Gokmen b , Mustafa Basaran c , Kazim Gezginc d , Gulsum Sonmez b , Nazmiye Kaya a , Emre Yilmaz a , Sami Sait Erdem e , Hasan Haluk Dulger f , Humeyra Cicekler f , Erkan Tasyurek f a
Department of Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey b Department of Neonatology, Konya Research and Training Hospital, Konya, Turkey c Department of Obstetrics and Gynecology, Konya Research and Training Hospital, Konya, Turkey d Department of Obstetrics and Gynecology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey e Department of Biochemistry, Konya Research and Training Hospital, Konya, Turkey f Department of Biochemistry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
Abstract Objective: The relationship between maternal psychiatric disorders and fetal neurodevelopment is unclear. Obsessive–compulsive disorder (OCD) is relatively frequent during pregnancy. The study aimed to investigate whether maternal OCD during pregnancy affects fetal circulating tumor necrosis factor-alpha (TNF-α) levels, an important pro-inflammatory cytokine, by comparing cord blood TNF-α levels in newborn infants of women with and without OCD. Methods: The study sample included 7 women with OCD and 30 healthy women. OCD and other psychiatric diagnoses were screened by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The blood sample for the determination of TNF-α level was obtained from the umbilical cord during delivery. Results: Cord blood TNF-α levels in newborn infants exposed to maternal OCD were significantly higher compared to non-exposed infants. Maternal anxiety symptom level was found to positively correlate with cord blood TNF-α levels in newborn infants of women with OCD. Conclusion: The study results imply that maternal OCD during pregnancy may lead to neuroinflammation in the developing fetal brain through higher levels of circulating TNF-α. © 2014 Elsevier Inc. All rights reserved.
1. Introduction
⁎ Corresponding author at: Necmettin Erbakan Üniversitesi Meram Tıp Fakültesi, Psikiyatri Anabilim Dalı, Akyokuş, 42080, Konya, Turkey. Tel.: +90 332 223 6306. E-mail addresses: [email protected] (F. Uguz), [email protected] (E. Onder Sonmez), [email protected] (M. Sahingoz), [email protected] (Z. Gokmen), [email protected] (M. Basaran), [email protected] (K. Gezginc), [email protected] (G. Sonmez), [email protected] (N. Kaya), [email protected] (E. Yilmaz), [email protected] (S.S. Erdem), [email protected] (H.H. Dulger), [email protected] (H. Cicekler), [email protected] (E. Tasyurek). 0010-440X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.comppsych.2013.12.018
Although there are growing scientific data on the relationship between psychiatric disorders and neonatal outcomes, compared to depression, anxiety disorders have been studied relatively less. Obsessive–compulsive disorder (OCD) is a frequently observed psychiatric disorder during pregnancy. Its prevalence rate has been reported to vary between 0.2% and 5.2% in the pregnancy period [1–8]. A number of studies have addressed the role of anxiety symptoms on fetal outcome. Recently, a case–control study suggested that maternal generalized anxiety disorder was associated with intrauterine growth restriction [9]. Moreover, some authors have reported that maternal anxiety influences
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F. Uguz et al. / Comprehensive Psychiatry 55 (2014) 861–865
fetal cerebral circulation [10]. Infants prenatally exposed to maternal stress are more likely to have behavioral, cognitive and emotional problems but the mechanisms accounting for the influence of maternal stress are not fully understood [11,12]. However, to our knowledge, there is no study examining the effects of OCD, a prevalent disorder anxiety disorder associated with considerable anxiety and psychological stress, on fetal development. Pro-inflammatory cytokines may influence neurogenesis and impair hippocampal plasticity [13]. Tumor necrosis factor alpha (TNF-α), is an important pro-inflammatory cytokine that has been shown to exert critical functions in survival, proliferation and neuronal differentiation of neural progenitor cells [14]. In vitro studies have suggested that TNF-α has a negative effect on embryonic and adult neurogenesis [15,16]. In addition, Seguin et al. [13] reported a marked reduction in hippocampal cellular proliferation following a systemic administration of TNF-α. Moreover, proinflammatory cytokines such as TNF-α are reported to be associated with the development cerebral palsy and neonatal brain white matter lesions [17–19]. The relationship between psychiatric disorders and TNF-α has been widely examined. However, most of the studies include mood disorders. A meta-analysis demonstrated that depressed subjects have higher concentrations of TNF-α compared to control subjects [20]. Several studies have examined levels of TNF-α in anxiety disorders, but data on OCD are controversial [21–25]. Arranz et al. [26] reported that in anxious women, TNF-α was released more. On the other hand, the stress responses involve the release of TNF-α, which in turn results in an enhanced release of corticotropin-releasing hormone (CRH) [20]. For those patients suffering from OCD during pregnancy, it may be possible for the fetus to be affected by maternal OCD. Therefore we have hypothesized that maternal OCD may affect fetal neurogenesis via alterations in circulating TNF-α levels. In this study, we aimed to investigate TNF-α levels in the cord blood of newborn infants of mothers with and without OCD during pregnancy. 2. Methods 2.1. Subjects The study was carried out among women who delivered by elective caesarean section at the Obstetric Clinic of Konya Research and Training Hospital in Konya, Turkey, and the Obstetric Clinic of Meram Faculty of Medicine of Necmettin Erbakan University in Konya, Turkey. The study sample comprised 7 women with a diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [27] uncomplicated with any other psychiatric disorder and 30 control women without any psychiatric diagnosis who met the study criteria and who delivered at the same clinic. The inclusion criteria for the study were the following: voluntary participation to the study and current age between 18 and 40 years, a history of medical
illnesses (e.g., endocrine abnormalities, cardiovascular and pulmonary system diseases, neurological disease and metabolic disease), a history of pregnancy related complications (e.g., gestational hypertension, imminent abortion, placenta previa and other placental abnormalities, vaginal bleeding, and gestational diabetes), any malformation in newborn infants, a history of maternal infection which can negatively affect fetal growth (e.g., toxoplasma, rubella, cytomegalovirus, herpes simplex, mycoplasma and chlamydia), the existence of any active maternal infection, having mental retardation, the existence of multiple pregnancies, the existence of intrauterine growth restriction, low birth weight, preterm delivery or emergency caesarean section, a history of bipolar affective disorder, schizophrenia or related psychotic disorders, the existence of comorbidity with depressive and other anxiety disorders reported smoking or alcohol consumption during pregnancy, use of systemic corticosteroids during pregnancy such as betamethasone dipropionate, use of any psychotropic medication during pregnancy, and the existence of hypoxia in the baby during childbirth were exclusion criteria. The study procedure was approved by the ethics committee of Meram Faculty of Medicine of Necmettin Erbakan University. 2.2. Assessments The sociodemographic and obstetric characteristics were recorded with a semistructured interview form developed by the authors. To determine OCD and other psychiatric disorders the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)(SCID-I) [28] was used. The gestational age at delivery was calculated on the basis of the date of last menstruation. The indication or plan of elective caesarean section was independent from the study procedure. Anxiety symptom levels were assessed with the Beck Anxiety Inventory (BAI) [29]. 2.3. Procedures Initially, the objectives and procedures of the study were explained to all participants, and written informed consent forms were obtained. After the sociodemographic and obstetric features of the participants hospitalized for elective caesarean section were recorded, a psychiatric interview by means of SCID-I was carried out by psychiatrists with at least 4 years of experience on psychiatric disorders and the diagnostic instruments. The severity of anxiety symptoms in the women with OCD but not the control subjects were assessed with BAI. During the caesarean section, a blood sample for TNF analysis was obtained from the umbilical cord by a pediatry specialist. The blood was immediately centrifuged for 10 min at 3000 × g and 4 °C. The serum was stored at − 80 °C until measured. Serum TNF-α concentrations were determined by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions (Boster, Inc.).
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2.4. Statistical analysis The data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 16.0, for Windows. All variables were tested with the Kolmogorov–Smirnov test to determine whether the test distributions were normal or not. Categorical variables among the study groups were compared using the chi-square test or Fisher’s exact test when necessary. Comparisons for continuous variables were performed using t test or Mann–Whitney U test for abnormally distributed variables. Correlations related to TNF-α cord blood levels were assessed with Spearman’s correlation analysis. All significant levels were 2-tailed and set at the level of 0.05.
3. Results The mean age of the participants (n = 37) was 26.70 ± 5.06 years. All women were married, mostly primary school graduates (n = 30, 81.1%) and unemployed (n = 30, 81.1%). The mean number of children was 1.91 ± 0.86, and the mean gestation length at delivery was 39.35 ± 1.41 weeks. Nine women (23.3%) were primiparous. The type of anesthesia performed at caesarean section was general in 17 (45.9%) and epidural in 20 (54.1%) subjects. The proportion of male gender of babies was 59.5%. All of the women with OCD reported an onset of the disorder prior
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to the pregnancy. The mean total duration of OCD was 76.02 ± 59.38 weeks. Table 1 presents the sociodemographic features and cord blood TNF-α levels in the study groups. There were no a significant differences between the study groups with regard to age, employment status, family income level, gender of the baby, number of children, type of anesthesia performed at caesarean section, gestational age and the proportion of primiparity. Birth weight was significantly lower in newborn infants of mothers with OCD compared to those of healthy mothers. The mean TNF-α levels in the cord blood of newborn infants of women with and without OCD were 96.43 ± 88.86 pg/ml and 14.19 ± 19.94 pg/ml, respectively. The difference between the groups was statistically significant (z = −2.09, P = 0.036). According to the correlation analyses, the cord serum TNF-α levels in newborn infants of women with OCD were unrelated to maternal age (r = 0.210, P = 0.212), number of children (r = 0.187, P = 0.267), duration of pregnancy (r = 0.030, P = 0.861), and birth weight of newborn infants (r = −0.082, P = 0.630). The correlation test indicated that cord serum TNF-α levels were positively associated with maternal BAI scores (r = 0.824, P = 0.006).
4. Discussion The main finding of the current study is the presence of higher levels of circulating TNF-α in fetuses that are exposed
Table 1 Sociodemographic and obstetrical characteristics of the study groups.
Age, mean ± SD, years Education, n (%) Primary school Secondary school University Employment status, n (%) Employed Family income level, n (%) Low (b$10,000/year) Moderate ($10,000–30,000/year) High (N$30,000/year) Primiparity, n (%) Type of anesthesia Epidural General Gender of baby Female Numbers of children, mean ± SD Gestational age at birth, mean ± SD Birth weight, g, mean ± SD Cord blood TNF-α levels, ng/ml
Women with OCD n=7
Healthy controls n = 30
P value
27.42 ± 3.51
27.93 ± 5.37
0.815 a 0.294 b
6 (85.7) 0 (0) 1 (14.3)
24 (80.0) 5 (16.7) 1 (3.3)
2 (28.6)
6 (20.0)
3 (42.9) 3 (42.9) 1 (14.3) 2 (28.6)
15 (50.0) 11 (36.7) 4 (13.3) 7 (23.3)
3 (42.9) 4 (57.1)
17 (56.7) 13 (43.3)
2 (28.6) 1.71 ± 0.76 38.71 ± 1.49 3147 ± 391 96.43 ± 88.86
13 (43.3) 1.86 ± 0.81 39.51 ± 1.38 3466 ± 335 14.19 ± 19.94
0.631 c 0.941 b
1.000 c 0.680 c
0.677 c
OCD: Obsessive–compulsive disorder TNF-α: Tumor necrosis factor-alpha. a t test. b χ 2 test. c Fisher’s exact test. d Mann–Whitney U test.
0.656 d 0.191 a 0.034 a 0.036 d
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to maternal OCD compared to the fetuses that are not exposed. To our knowledge, this is the first study on this topic. The circulating TNF-α levels in the fetus may be important with regard to brain development of the fetus. Subject to future confirmatory large scale studies, we propose that OCD in mothers during pregnancy may lead to chronic inflammation in the developing fetal brain. Chronic brain inflammation is related to detrimental and unfavorable conditions for neurogenesis [14]. Excessive inflammatory response triggered by pro-inflammatory cytokines may affect glial cell functions and neurotrophic systems and decrease neurogenesis [30]. Similarly, elevated levels of cytokines have been shown to interfere with glial cell development and proliferation in the late second trimester of pregnancy [18]. Exposure to inflammation during pregnancy or early in life may be associated with neurodegeneration, and increased risk of cerebral palsy, autism spectrum disorders, multiple sclerosis, cognitive disorders and schizophrenia [17]. Indeed, it has been reported that there is a role of developmental neuroinflammation in progressive brain changes to schizophrenia [31]. Moreover, a cohort study of Danish births suggested that severe stress to a mother during the first trimester of pregnancy may increase the risk of schizophrenia in the offspring [32]. For these reasons, we think that clinically significant OCD during pregnancy may not only affect mental status or quality of life of the mother but also brain development of in the fetus. The underlying mechanism for higher cord-blood TNF-α levels in newborn infants of mothers with OCD is currently unclear. The transplacental transport of TNF-α may be an explanation for the results. However, previous studies have shown mixed results regarding serum TNF-α levels in patients with OCD [22–24,33]. Recently, a meta-analysis has suggested no significant difference in plasma TNF-α levels in patients with and without OCD [24]. In addition, it has been reported that TNF-α exhibits no or minimal transfer from term placenta [34,35]. Consequently, to explain the elevated cord serum TNF-α solely on the basis of transplacental transport may not be adequate. Psychosocial stress may elevate plasma levels of several cytokines [36]. Some authors have reported that TNF-α levels were increased in women with anxiety [26], while others found that depression and anxiety symptoms during pregnancy were unrelated to the levels of proinflammatory cytokines [37]. Therefore, the connection between anxiety and TNF-α levels in pregnant women is unclear. In the current study, the cord serum TNF-α levels were positively correlated with the levels of anxiety symptoms. In other words, elevated maternal anxiety due to OCD may affect circulating TNF-α in fetus. Although underlying biological cause is unknown, we think that the higher levels of TNF-α in cord blood of infants exposed to prenatally maternal OCD may result from higher distressing status during their fetal period compared to nonexposed infants.
The present study has several limitations, which may affect the interpretation of the results. First, the sample size, particularly the number of women with OCD was small and included women who were admitted to the obstetric clinics for delivery. Therefore, it may not be representative of all pregnant women with OCD. Second, the study had a crosssectional design but not a prospective observation. For this reason, we did not determine the course of anxiety symptoms during the pregnancy. Third, we did not use any instruments to determine the severity of obsessive– compulsive symptoms. Anxiety symptom levels in women with OCD were assessed solely on the basis of BAI. Fourth, the sample composed of women with elective caesarean only because to determine the cord blood samples in newborn of women delivered with vaginal way was difficult in the clinics. However, this condition may consider as a limitation. Finally, we did not examine body mass index and its association with TNF-α levels in the pregnant women. In conclusion, the results of this study suggest that the circulating TNF-α level is significantly higher in those fetuses whose mothers have OCD compared to the fetuses of healthy mothers. In addition, the results imply that maternal OCD, particularly in those patients with higher anxiety levels, may lead to neuroinflammation in the fetal brain. However, the limitations of the current study preclude us from generalizing the effects of the higher circulating TNFα levels. Therefore, our results should be replicated by further prospective studies with larger sample size.
Role of funding source None.
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