1 Department of Clinical Sciences, Division of Obstetrics and Gynecology, Umeå University, Umeå, Sweden.
2 Department of Obstetrics and Gynecology, Sunderby Hospital, Luleå, Sweden.
3 Department of Womens and Childrens Health, University Hospital, Uppsala, Sweden.
4 Department of Clinical Sciences, Division of Psychiatry, Umeå University, Umeå, Sweden.
Received for publication September 22, 2003; accepted for publication December 3, 2003.
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ABSTRACT |
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anxiety; depression; pregnancy
Abbreviations: Abbreviations: CI, confidence interval; CES-D [Scale], Center for Epidemiologic Studies Depression [Scale]; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; OR, odds ratio; PRIME-MD, Primary Care Evaluation of Mental Disorders.
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INTRODUCTION |
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Although a number of studies have indicated a relation between maternal antenatal depression and/or anxiety and neonatal outcome, few population-based studies have investigated the issue. Most previous studies have been performed with small samples, mainly in specific risk groups such as teenage mothers, women of low socioeconomic status, and women of certain ethnic groups (1, 11, 12). In addition, there has been a deficit of studies on antenatal depression and/or anxiety using diagnostic criteria adhering to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (13). The aim of this study was to investigate neonatal outcome in an unselected population-based sample of pregnant women diagnosed with antenatal depressive and/or anxiety disorders in comparison with healthy mothers. In the light of previous study results, the main hypothesis was that there would be associations between antenatal depression and/or anxiety and adverse neonatal outcome in terms of spontaneous preterm delivery and/or small-for-gestational-age birth.
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MATERIALS AND METHODS |
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Exclusion criteria for the original study were 1) detection of a malformation or missed spontaneous abortion at the ultrasound examination, 2) inability to read and understand the questionnaire because of language difficulties, and 3) not providing informed consent. Furthermore, in the present study, only singletons, livebirths, and subjects with complete medical records regarding the newborns were included. Use of psychoactive medication during pregnancy was not an exclusion criterion.
Psychiatric diagnosis
Psychiatric disorders were diagnosed using the Primary Care Evaluation of Mental Disorders (PRIME-MD) classification system (15). The PRIME-MD system conforms to DSM-IV criteria and has been validated for use in primary care settings. Agreement between PRIME-MD diagnoses and those of independent mental health professionals is excellent, with a sensitivity of 83 percent, a specificity of 88 percent, a positive predictive value of 80 percent, and an overall accuracy of 88 percent (15). Given its utility and ease of use, we considered PRIME-MD to be a suitable tool for assessing the prevalence of psychiatric disorders in an obstetric outpatient setting. The PRIME-MD system, which is fully described elsewhere (15), consists of two components: a one-page patient questionnaire and a 12-page clinician evaluation guide, which is a structured interview for the clinician to follow when evaluating responses on the patient questionnaire. The original clinician evaluation guide contained modules for mood, anxiety, and eating disorders, alcohol abuse, social phobia, and obsessive-compulsive disorder. Clinicians administer only those modules that are indicated by the patient on the patient questionnaire.
The PRIME-MD system evaluates the presence of 20 possible mental disorders; this study focused on 13 diagnoses of interest. Among these 13 diagnoses, eight correspond to the specific requirements of the DSM-IV (major depressive disorder, dysthymia, partial remission of major depressive disorder, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social phobia, and bulimia nervosa). An additional four diagnoses are considered to be "subthreshold" diagnoses, such as minor depressive disorder, anxiety not otherwise specified, eating disorder not otherwise specified, and binge eating disorder. Subthreshold diagnoses have fewer symptoms than are required for a specific DSM-IV diagnosis but were included because they are associated with considerable impairment in function (16). Finally, a rule-out diagnosis of bipolar disorder was included. A modified form of the PRIME-MD patient questionnaire was used for this study. It contained 25 questions evaluating somatoform disorder, mood disorders, anxiety disorders (including social phobia and obsessive-compulsive disorder), and eating disorders. Somatoform disorders, alcohol abuse, and rule-out diagnoses of mood disorder and/or anxiety due to physical disorder, medication use, or drug use were not assessed.
Study design
The women completed the PRIME-MD patient questionnaire before attending the ultrasound examination. Along with the patient questionnaire, they were asked to provide their name, date of birth, and telephone number and an informed consent statement allowing for a telephone interview. If any key question indicated a mental disorder, the woman was considered screen-positive, and a telephone interview was conducted within 12 weeks after the ultrasound examination, using a computerized version of the clinician evaluation guide. Women who received a PRIME-MD diagnosis and also were asking for help and/or had thoughts about committing suicide were immediately referred to a psychiatric specialist. One research nurse and four obstetricians performed the telephone interviews.
Three months after delivery, the medical records of the women and their offspring were thoroughly reviewed. Only cases with complete medical records, livebirths, and singleton pregnancies were included in the study. The reason for the inclusion of only singletons was that infants from multiple births are well known to be at greater risk of preterm birth and deteriorated fetal growth (17).
The main results are fully described elsewhere (18). A total of 2,263 women were examined by ultrasound screening during the inclusion period. After exclusions due to refusal to participate (10 women), language difficulties (82 women), excess numbers of patients (362 women), and other factors (14 women), 1,795 women received the PRIME-MD patient questionnaire. Sixty-four women did not answer the questionnaire, and 105 did not sign the informed consent form. A further 22 women were excluded because of missed spontaneous abortion or malformation, and 49 could not be reached within the stipulated 14 days. Complete medical records regarding the newborns were retrieved for 1,492 subjects. These 1,492 women delivered 1,513 children. Six children were excluded because of stillbirth, and 42 twins were removed from the analyses, leaving a total of 1,465 children.
From the medical records of the mothers, data on age, parity, body mass index in the first trimester, marital status, socioeconomic status, smoking and tobacco use, alcohol consumption, and the prevalence of chronic disease were extracted. Data on birth length, birth weight, pH of and base deficit in umbilical artery blood, Apgar score at 1 and 5 minutes, neonatal intensive care, and the most common pediatric diagnoses were recorded from the pediatric medical charts. The diagnoses recorded for the study were overall preterm birth, spontaneous preterm birth, small-for-gestational-age birth, respiratory distress, asphyxia, and malformation. Pediatricians examined and diagnosed the newborns during the hospital stay postpartum.
The study was approved by the Ethics Committee of Umeå University, Umeå, Sweden.
Statistical analyses
A comparison regarding overall preterm delivery was made between the study population of 1,465 women and the 755 women who were not included in the study group. The latter group consisted of nonresponders (n = 179) and the 576 women who did not meet the criteria for inclusion in the study after removal of twins (n = 12) and stillbirths (n = 4). Frequencies were compared between groups by means of the chi-squared test.
The study was designed to detect an increase in the rate of overall premature births from 6 percent to 12 percent in women with depressive and/or anxiety disorders compared with controls ( = 0.05, ß = 0.20). Bivariate logistic regression analysis was used to compute odds ratios for neonatal outcome in terms of birth weight, small-for-gestational-age birth, overall preterm birth, and spontaneous preterm birth. Adjusted odds ratios for all variables regarding neonatal outcome were computed using a multiple logistic regression model, which included possible maternal confounding factors and mediators, selected according to prior studies (1).
Maternal confounders and mediators were defined as follows: maternal age as completed years of age at the time of the psychiatric investigation; parity as primiparity or parity of one or more; marital status as being married to/cohabiting with the father of the child or single parenting; and socioeconomic status as professional employee or laborer, according to Swedish socioeconomic indices. Smoking status was recorded at the first antenatal care visit and was categorized into nonsmoking (not daily smoking), smoking of 19 cigarettes per day, and smoking of 10 or more cigarettes per day. Likewise, oral use of finely ground tobacco was categorized into nonuse and use. First-trimester body mass index (weight (kg)/height (m)2) was categorized according to the recommendation of the World Health Organization: underweight (body mass index <18.5), normal (body mass index 18.524.9), overweight (body mass index 25.029.9), and obese (body mass index 30). Chronic diseases were considered prevalent when a history of heart disease, diabetes mellitus, hypertension, or renal disease was recorded at the first antenatal visit.
Neonatal variables were categorized accordingly. Birth weight was categorized into <2,500 g, 2,5003,999 g, and 4,000 g. The values of umbilical artery blood pH below 7.2 and/or base deficit lower than 12 mmol/liter were used as biochemical markers for acidosis. Apgar scores below 4 points 1 and/or 5 minutes after birth were regarded as indicating established asphyxia in the analyses. Preterm births were divided into two groups because the overall rate of preterm delivery is partly medically determined, as in cases with severe complications that threaten the fetus and/or mother. In this study, the traditional cutoff point of less than 37 weeks of completed gestation was used as the definition of preterm delivery. Gestational age was estimated according to the result of the second-trimester ultrasound screening. No other methods were used in spontaneous pregnancies. Gestational age in pregnancies resulting from in vitro fertilization was estimated according to the day of embryo transfer. Spontaneous preterm birth was defined as rupture of membranes and/or premature labor before 37 completed weeks of gestation. The division into separate groups was supported by results from prior studies suggesting that preterm birth comprises etiologically distinct categories (19, 20).
Small-for-gestational-age birth was defined as birth weight below the 2.5th percentile for expected weight according to gestational age. In Sweden, in 2001, the mean birth weight was 3,629 g for boys and 3,505 g for girls.
All statistical analyses were performed using SPSS for Windows, version 10.0 (SPSS, Inc., Chicago, Illinois). A two-sided p value less than 0.05 was considered significant.
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RESULTS |
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Eleven (5.4 percent) of the 204 women with a PRIME-MD diagnosis received some sort of treatment for their psychiatric condition. Only one of them was using antidepressant medication at the time of the second-trimester ultrasound screening. One additional woman was prescribed antidepressant medication later in pregnancy. In both of these cases, the drug taken was a selective serotonin reuptake inhibitor. None of the women without a PRIME-MD diagnosis were noted to use psychoactive medication. Prepregnancy use of antidepressant medication was noted in 18 women (1.2 percent). However, all women taking antidepressant medication prior to pregnancy had withdrawn from it prior to the first midwife visit.
Neonatal outcome
Comparison between the women who were not included in the study (excluded subjects and nonresponders) and the study population revealed no significant differences regarding overall preterm births. The number of preterm births was 26 (4.3 percent) among women not included in the study group and 76 (5.2 percent) in the study population (p = 0.44). Among women not included, data were missing for 149 subjects.
The bivariate unadjusted analysis revealed no significant associations between any antenatal PRIME-MD diagnosis and deteriorated neonatal outcome (birth weight <2,500 g: odds ratio (OR) = 1.41 (95 percent confidence interval (CI): 0.58, 3.49); birth weight 4,000 g: OR = 1.32 (95 percent CI: 0.94, 1.88); small-for-gestational-age birth: OR = 0.68 (95 percent CI: 0.16, 2.97); overall preterm birth: OR = 1.05 (95 percent CI: 0.54, 2.02); spontaneous preterm birth: OR = 0.83 (95 percent CI: 0.32, 2.14)). A borderline-significant bivariate association between antenatal depressive disorder and increased birth weight was revealed (birth weight <2,500 g: OR = 1.20 (95 percent CI: 0.41, 3.48); birth weight
4,000 g: OR = 1.45 (95 percent CI: 1.00, 2.10); small-for-gestational-age birth: OR = 0.01 (95 percent CI not calculated); overall preterm birth: OR = 1.32 (95 percent CI: 0.68, 2.56); spontaneous preterm birth: OR = 1.04 (95 percent CI: 0.40, 2.69)). Finally, no significant bivariate associations were found between antenatal anxiety disorder and neonatal outcome (birth weight <2,500 g: OR = 1.45 (95 percent CI: 0.34, 6.26); birth weight
4,000 g: OR = 1.11 (95 percent CI: 0.60, 2.05); small-for-gestational-age birth: OR = 2.23 (95 percent CI: 0.51, 9.82); overall preterm birth: OR = 0.90 (95 percent CI: 0.28, 2.96); spontaneous preterm birth: OR = 0.52 (95 percent CI: 0.07, 3.89)).
The distribution of potential maternal confounding factors and mediators for psychiatric disorders is presented in table 1. Significant associations with a PRIME-MD diagnosis were observed for not being married or cohabiting, low socioeconomic status, smoking 10 or more cigarettes daily, or having a body mass index of 30 or more. The relations of neonatal outcome to any PRIME-MD diagnosis, any depressive disorder, and any anxiety disorder are shown in tables 2, 3, and 4, respectively. There were no significant differences in any of the studied variables between the newborns of women with a depressive and/or anxiety disorder and the newborns of women without a diagnosis (table 2). Newborns of women with exclusively depressive disorders (major depressive disorder, dysthymia, partial remission of major depressive disorder, minor depressive disorder, and bipolar disorder) did not differ significantly from newborns of women without a diagnosis (table 3). As table 4 shows, there were no significant differences between the newborns of healthy women and the newborns of women with anxiety disorders (anxiety not otherwise specified, generalized anxiety, panic disorder, obsessive-compulsive disorder, and social phobia).
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DISCUSSION |
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Orr et al. (1) found a significant relation between spontaneous preterm delivery and reported depressive symptoms. A major reason for the divergent results might be that both aims and diagnostic instruments differed between studies, since Orr et al. used the Center for Epidemiologic Studies Depression (CES-D) Scale for assessment of depressive symptoms, not depression as a clinical diagnosis. In their study, 117 (8.4 percent) of the women had a CES-D score in the upper 10th percentile. The prevalence of depressive disorders diagnosed according to PRIME-MD in our study was 11.6 percent, and major depression was present in 46 women (3.1 percent). Besides the use of different methods, another possible reason for the diverse results might be that the populations were different and that the risk of premature birth differs considerably between continents. Premature birth per se is about twice as common in the United States as in Sweden (21, 22), with point prevalences of 12.0 percent and 5.7 percent, respectively. Our data on premature birth correspond well with the reported number of premature births in Sweden, in its entirety. The population in the study by Orr et al. (1) consisted of African-American women, who are already known to be at greater risk of preterm delivery than White women (23, 24). One explanation offered is that US Black women are chronically exposed to specific stressors that adversely affect pregnancy outcome and that race is a marker for that stress but not in itself a risk factor for preterm delivery (23).
Kelly et al. (25) found independent associations between maternal psychiatric and substance abuse diagnoses and low birth weight and preterm delivery in an ethnically heterogeneous population in California. Psychiatric and substance use diagnoses were retrospectively determined by means of International Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic codes recorded on the maternal hospital discharge summary. In women with a psychiatric diagnosis, the adjusted odds ratio for low birth weight (<2,500 g) was 2.0 (95 percent CI: 1.7, 2.3). For preterm delivery, the adjusted odds ratio was 1.6 (95 percent CI: 1.4, 1.9). However, one of the study limitations noted by those authors was the possibility that unmeasured confounders, such as maternal smoking, could have biased the risk estimates.
Two studies on a large Danish population found no relation between elevated distress scores and fetal growth retardation (9) but revealed a moderate relation between elevated distress scores and preterm delivery (26). Women who experienced one or more highly stressful life events during pregnancy had an odds ratio of 1.76 for preterm delivery (95 percent CI: 1.15, 2.71). Again, however, these two studies assessed depression and anxiety not as clinical diagnoses but rather as scores for distress symptoms.
Hoffman and Hatch (3) pointed out a possible association between prenatal depressive symptoms at 28 weeks of gestation and deteriorated fetal growth in 222 women of lower social class, raising questions as to whether being of a lower social class is a vulnerability factor per se. In their study, CES-D scores were used for assessment of depressive symptoms in 666 women. They did not find any associations between depressive scores and adverse neonatal outcomes in other potentially high-risk subgroups, such as smokers, women with a history of adverse neonatal/obstetric outcomes, and women with social vulnerabilities.
In line with our study results, Perkin et al. (27) did not find maternal anxiety and depression to be associated with obstetric complications such as preterm delivery, labor induction, labor acceleration, analgesia during the first stage of labor, and nonspontaneous delivery (all types of delivery other than spontaneous vaginal delivery) in a population of White women.
In our study, we found no association between depressive and/or anxiety disorders and preterm delivery or small-for-gestational-age birth. Because prevalence rates for preterm delivery are comparatively low in Sweden, our study only had enough statistical power to detect at least a doubling of the rate. However, given the fact that the rate of spontaneous preterm delivery was actually lower among women with any PRIME-MD diagnosis than among healthy subjects, it is unlikely that a larger sample size would have yielded different results. Nevertheless, it must be emphasized that our results might not be generalizable to other populations, particularly those with higher rates of preterm birth. Furthermore, in the unadjusted analysis, a borderline-significant association between antenatal depression and a birth weight of 4,000 g or more was evident. This association was lost in the multivariate analysis, probably because of the adjustment for maternal body mass index. Adjustment was also made for smoking, which is known to deteriorate fetal growth. A reasonable explanation for the absent associations between depressive disorders and deteriorated birth weight in the adjusted analyses might be that obesity and smoking have opposite effects on fetal growth. Although this was not assessable within the study design, this suggestion implies that the diagnosis of intrauterine growth restriction, particularly among obese depressed subjects, might be beyond our screening interventions, since a number of growth-restricted fetuses would be found within the normal range for fetal growth.
Given these limitations to the interpretation of our results, our study indicates that in otherwise healthy populations with well-established antenatal care, depressive and/or anxiety disorders per se appear not to affect the risk of preterm birth, low birth weight, and/or small-for-gestational-age birth. Apart from the assessment of clinical diagnoses and the population-based sample, yet another strength of our study was that second-trimester ultrasound screening was used for estimation of gestational length, leaving no doubt as to whether or not gestational age was correct (14).
A striking finding in prior studies is that use of psychopharmacologic medication often remains unclear. In our study, only two women were noted to use antidepressant medications during pregnancy. Although these figures might be due to the unwillingness of women to inform their midwife or obstetrician of the use of such drugs, the low frequency of psychoactive medication use could also be explained by cultural traditions, implying that women in Sweden and their physicians try, as far as possible, to avoid using medication during pregnancy and lactation. The matter of medication use might be of interest, since prior research has found associations between antidepressant therapy, a shorter duration of gestation, and lower birth weight (28, 29). Unfortunately, these studies investigated gestational age as a continuous variable and not preterm delivery as an outcome. A limitation of the present investigation is that the assessment of psychiatric diagnoses was made at only one time point during pregnancy, raising questions about whether symptoms remained unchanged, were transitory, or might have developed after the point of screening. For example, Evans et al. (30) noted a significant increase in depression scores between 18 and 32 weeks of pregnancy. Accordingly, Hoffman and Hatch (3) found that, independent of social class, depression scores were higher in the third trimester of pregnancy than in the first and second trimesters.
In conclusion, this study indicates that maternal antenatal depressive disorders and/or anxiety disorders are not independent risk factors for deteriorated neonatal outcome, such as preterm delivery and small-for-gestational-age birth, in a country with well-developed welfare systems. Further research is needed to explore associations with health care utilization during pregnancy, complications of delivery, and psychiatric health postpartum. There is also a need for more research on possible long-term effects of such disorders on childrens development.
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ACKNOWLEDGMENTS |
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The authors thank all personnel involved in ultrasound screening at the two study sites. The authors are especially grateful to Marie Wallgren and Yvonne Hoff, who provided invaluable help with the telephone interviews.
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NOTES |
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REFERENCES |
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